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Medical Nutrition Therapy: A Case Based Approach

Kathryn M. Kolasa, PhD, RDN, LDN Kathryn M. Kolasa Affiliations Brody School of Medicine at East Carolina University, 3080 Dartmouth Dr, Greenville, NC 27858 Search for articles by this author

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DOI: https://doi.org/10.1016/j.jneb.2022.02.003

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Medical Nutrition Therapy | 6th Edition

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Building a bridge from classroom to clinical practice, this casebook is composed of 29 realistic case studies appropriate for introductory and advanced level courses in nutrition and medical nutrition therapy. Each case study uses the medical record as its structure and is designed to resemble the electronic medical record. The student "solves the case" by using the medical record information provided such as hospital admission data, laboratory test results, intake/output records, and the physician and other health care provider progress notes. The case is followed by a series of questions that focus on pathophysiology; assessment; clinical, nutritional, and behavioral outcomes; interventions; and appropriate follow-up for the patient. Questions are posed within the framework of the Nutrition Care Process. This real-world approach helps prepare the student for the professional setting. Objectives for student learning within each case are built around the nutrition care process and competencies for dietetic education. Faculty will find that they can incorporate these cases in multiple ways. Using the entire case allows for students to thoroughly research the MNT for a particular diagnosis. Instructors can also use components of cases within their classroom teaching to highlight particular topics such as malnutrition, nutrition support, or fluid and electrolyte balance. New one-page excerpts of cases guide the instructor and student to focus on an abbreviated version of the case allowing for small group work and problem based learning.

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Diagnosis and problem identification, planning and intervention, case presentation, case study: a patient with type 1 diabetes who transitions to insulin pump therapy by working with an advanced practice dietitian.

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Claudia Shwide-Slavin; Case Study: A Patient With Type 1 Diabetes Who Transitions to Insulin Pump Therapy by Working With an Advanced Practice Dietitian. Diabetes Spectr 1 January 2003; 16 (1): 37–40. https://doi.org/10.2337/diaspect.16.1.37

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Registered dietitians (RDs) who have earned the Board Certified–Advanced Diabetes Manager (BC-ADM) credential hold a master’s or doctorate degree in a clinically relevant area and have at least 500 hours of recent experience helping with the clinical management of people with diabetes. 1 They work in both inpatient and outpatient settings, including diabetes or endocrine-based specialty clinics, primary care offices, hospitals, and private practices. Advanced practice dietitians provide all components of diabetes care, including advanced assessment (medical history and physical examination), diagnosis, medical management, education, counseling, and overall case management.

The role of RDs in case and disease management was explored in a recent article 2 that included interviews with three dietitians who work as case managers or disease managers. All three reported experiencing challenges in practice and noted that the meaning of “case management” varies from one health care setting to another. This is also true for RD, BC-ADMs. Advanced practice dietitians specializing in diabetes require case management expertise that stresses communication skills, knowing the limits of your own discipline, knowing how to interact with other health care professionals, and knowing when to seek the expertise of other members of the diabetes care team.

Clinical practice includes assessment and data collection, diagnosis and problem identification, planning, and intervention. In many cases, diabetes educators who are dietitians and those who are nurses are cross-trained to perform the same roles. The first one to meet with a client handles that client’s assessment, and cases are discussed and interventions planned at weekly team meetings.

For advanced practice dietitians, the first session with a client often involves a complete physical assessment, not just a nutrition history. This includes a comprehensive medical history of all body systems. The diabetes-focused physical examination, just as performed by clinicians from other disciplines, includes height and weight measurement, body mass index (BMI) calculation, examination of injection sites, assessment of injection technique, and foot assessment.

Assessment also includes reviewing which medications the client is taking, evaluating their effectiveness and side effects, and determining the need for adjustment based on lifestyle, dietary intake, and blood glucose goals.

When carbohydrate counting is added to therapy, dietitians calculate carbohydrate-to-insulin ratios and teach clients how to use carbohydrate counting instead of a sliding-scale approach to insulin. Medications are adjusted based on clients’ lifestyles until blood glucose goals are achieved.

The therapeutic problem solving, regimen management, case management, and self-management training performed by advanced practice dietitians exceeds the traditional role of most dietetics professionals. 3

A role delineation study for clinical nurse specialists, nurse practitioners, RDs, and registered pharmacists, 4 conducted in 2000 by the American Nurses Credentialing Center, reported equal findings among all four groups for the skills used to identify pathophysiology, analyze diagnostic tests, and list problems. Assessment for medical nutrition therapy typically includes evaluation of food intake, metabolic status, lifestyle, and readiness to change. For people with diabetes, monitoring glucose and measuring hemoglobin A 1c (A1C), lipids, blood pressure, and renal status are essential to evaluating nutrition-related outcomes.

The U.S. Air Force health care system conducted a pilot test giving RDs clinical privileges and evaluating their clinical judgment in patient nutritional care. A protocol was approved, and dietitians were allowed to order and interpret selected outpatient laboratory tests independently. The higher-level clinical judgments and laboratory privileges were linked to additional certifications. 5

The Diabetes Prevention Program (DPP) also provided a unique opportunity for dietitians to demonstrate advance practice roles. 6 Dietitians served as lifestyle coaches, contacting participants at least once a month to address intervention goals. As case managers, they interviewed potential volunteers, assessed past experience with weight loss, and scheduled quarterly outcome assessments and weekly reviews of each participant’s progress at team meetings. Within the DPP’s central management, dietitians served as program coordinators and served on national study committees related to participant recruitment and retention, quality control, the use of protocols, and lifestyle advisory groups. 7

Dietitians now play key roles in translating DPP findings and serving as community advocates to reduce the incidence of obesity and the health care burden of type 2 diabetes. This includes serving in a consultative role to other health care team members on issues regarding weight loss and risk factor reduction.

Advanced practice RDs offer comprehensive diabetes patient care services, including identifying patient goals and expected outcomes, selecting nonpharmacological and pharmacological treatments, and developing integrated plans of care. Problems discussed with patients range from acute and chronic diabetes complications to comorbid conditions, other conditions, preventive interventions, and self-management education. Advanced practice RDs also review patients’ health care resources and order laboratory tests if information is not available from referral sources. They provide supportive counseling and referral to specialists, as needed. And, they provide a full report of their findings and any regimen changes and recommendations they make to referring clinicians after each visit.

These activities and responsibilities go beyond the scope and standards of practice for the RDs and for RD, CDEs. 8 They will be included in the scope of practice document for RD, BC-ADMs that is now being developed by the Diabetes Care and Education Practice Group of The American Dietetic Association.

The following case study illustrates the clinical role of advanced practice dietitians in the field of diabetes.

B.C. is a 51-year-old white man who was diagnosed with type 1 diabetes 21 years ago. He believes that his diabetes has been fairly well controlled during the past 20 years and that his insulin needs have increased. He was recently remarried, and his wife is now helping him care for his diabetes.

His endocrinologist referred him to the RD for an urgent visit because 4 days ago he had a hypoglycemic event requiring treatment in the emergency room (ER). He has come to see the dietitian because his doctor and his wife insisted that he do so.

B.C. has had chronic problems with asymptomatic hypoglycemia. His last doctor’s visit was 3–4 weeks ago, when areas of hypertrophy were found. His endocrinologist asked him to change his injection sites from his thigh to his abdomen after the ER incident.

He does not think he needs any diabetes education but would like help in losing 10 lb. His body mass index is 25 kg/m 2 .

His medications include pravastatin (Pravacol), 10 mg daily; NPH insulin, 34 units in the morning and 13 units at bedtime; and regular insulin at breakfast and dinner following a sliding-scale algorithm. He also takes lispro (Humalog) insulin as needed to correct high blood glucose.

Before his ER visit, B.C. monitored his blood glucose only minimally, testing fasting and sometimes before dinner but not keeping records. Since his severe hypoglycemia 4 days ago, he has begun checking his blood glucose four times a day, before meals and bedtime.

Lab Results

B.C.’s most recent laboratory testing results were as follows:

A1C: 8.3% (normal 4.2–5.9%)

Lipid panel

• Total cholesterol: 207 mg/dl (normal: 100–200 mg/dl)

• HDL cholesterol: 46 mg/dl (normal: 35–65 mg/dl)

• LDL cholesterol: 132 mg/dl (normal: <100 mg/dl)

• Triglycerides: 144 mg/dl (normal: <150 mg/dl)

Creatinine: 0.9 mg/dl (normal: 0.5–1.4 mg/dl)

Microalbumin: 4 μg (normal: 0–29 μg)

At his initial visit with the RD for crisis management of asymptomatic hypoglycemia, she examined his injection sites and asked if he had made the changes recommended by his clinician. She reviewed his injection technique, diet history, incidence of hypoglycemia, and hypoglycemia treatment methods. She discussed with B.C. ways to reduce his risks of hypoglycemia, including food choices, insulin timing, and absorption variations at different injection sites.

The RD reinforced his clinician’s instruction to avoid old injection sites and added a new recommendation to lower insulin doses because of improved absorption at the new sites.

B.C. was now checking his blood glucose and recording results in a handheld electronic device in a form that could be downloaded, e-mailed, or faxed, but he was not recording his food choices. The dietitian asked him to keep food records and started his carbohydrate-counting education. A follow-up visit was scheduled for 1 week later.

At the second visit, B.C.’s mid-afternoon blood glucose was <70 mg/dl. He did not respond to treatment with 15 g carbohydrate from 4 oz. of regular soda. His blood glucose continued to drop, measuring 47 mg/dl 15 minutes later. He drank another 8 oz. of soda, and his blood glucose increased to 63 mg/dl 1 hour later. He then drank another 8 oz. of soda and ate a sandwich before leaving the dietitian’s office. He called in 1 hour later to report that his blood glucose was finally up to 96 mg/dl.

B.C.’s records showed a pattern of mid-afternoon hypoglycemia. He was willing to add a shot of lispro at lunch to his regimen, so the RD recommended reducing his morning NPH to prevent lows later in the day.

The RD also calculated insulin and carbohydrate ratios for blood glucose correction and meal-related insulin coverage using the “1500 rule” and the “500 rule.”

The 1500 rule is a commonly accepted formula for estimating the drop in a person’s blood glucose per unit of fast-acting insulin. This value is referred to as an “insulin sensitivity factor” (ISF) or “correction factor.” To use the 1500 rule, first determine the total daily dose (TDD) of all rapid- and long-acting insulin. Then divide 1500 by the TDD to find the ISF (the number of mg/dl that 1 unit of rapid-acting insulin will lower the blood glucose level). B.C.’s average TDD was 41 units. Therefore, his estimated ISF was 37 mg/dl per 1 unit of insulin. The RD rounded this up to 40 mg/dl to be prudent, given his history of hypoglycemia.

The 500 rule is a formula for calculating the insulin-to-carbohydrate ratio. To use the 500 rule, divide 500 by the TDD. For B.C., the insulin-to-carbohydrate ratio was calculated at 1:12 (1 unit of insulin to cover every 12 g of carbohydrate), but again this was rounded up to 1:14 for safety. Later, his carbohydrate ratio was adjusted down to 1:10 based on blood glucose monitoring results before and 2 hours after meals.

The RD taught B.C. how to use the insulin-to-carbohydrate ratio instead of his sliding scale to adjust his insulin and asked him to try to follow the new recommendations. With his endocrinologist’s approval, she reduced his NPH doses to 34 units and added a shot of lispro at lunchtime, the dose to be based on the amount of carbohydrate in the meal and his before-meal blood glucose level.

The RD asked B.C. to return in 1 week for evaluation and review of his new regimen. However, 3 days later, he returned after having had another severe episode of hypoglycemia.

In the course of these early visits, a good rapport developed between B.C. and the dietitian. B.C. learned that his judgment on how hypo- and hyperglycemia felt was often inaccurate and led him to make insulin adjustments that contributed to his hypoglycemia problems. By improving B.C.’s understanding of insulin doses and blood glucose responses, the RD hoped to help him become more skilled at making insulin dose adjustments. For the time being, however, he was still at risk for asymptomatic hypoglycemia. He had recently filled a prescription for glucagon, but the RD needed to review and encourage its proper use. She also provided literature to support his wife in case she needed to administer glucagon for him.

At this third visit, the RD reduced B.C.’s morning NPH dose to 22 units because of his rapid drop in blood glucose between noon and 1:00 p.m. This reduction finally eliminated his mid-afternoon lows.

B.C. had started using carbohydrate counting to make his decisions about lunchtime insulin doses. He liked carbohydrate counting because it gave him a more viable reason for testing his blood glucose frequently. Over the years, B.C.’s glycemia had become increasingly difficult to control. He had stopped checking his blood glucose because he felt unable to improve the situation once he had the information. In the early 1990s, his endocrinologist had started him self-adjusting insulin doses using the exchange system, but he found that he was always “chasing his blood sugars.” Carbohydrate counting changed everything. He now knew what to do to improve his blood glucose levels, and that made him feel more in charge of his diabetes.

Still, although carbohydrate counting led to more frequent testing and better blood glucose control than his old sliding scale, it was not perfect. At home, he had mastered this technique, but he ate many of his meals in restaurants, where carbohydrate counting was more challenging.

B.C. found it difficult to carry different types of insulin. This and his lifestyle suggested the need to change his multiple daily injections from regular to lispro insulin. He continued checking his blood glucose before and 2 hours after meals. His insulin-to-carbohydrate ratio of 1:10 g and his ISF of 1:40 mg/dl allowed him to stay within his goal of no more than a 30-mg/dl increase in blood glucose 2 hours after meals. He continued to be asymptomatic of hypoglycemia, but lows occurred less frequently. The new goal of therapy was to recover his hypoglycemia symptoms at a more normal level of about 70 mg/dl. He was scheduled for another visit 2 weeks later.

Between visits to the RD, BC-ADM, his clinician identified problems with the timing of his long-acting insulin peak, resulting in early nocturnal lows. Based on the clinician’s clinical experience of lente demonstrating a slightly smoother peak, she changed B.C.’s long-acting insulin unit-for-unit from NPH to lente.

At B.C.’s next visit, he and the RD reviewed his insulin doses of 22 units of lente in the morning and 11 units of lente at night. His TDD including premeal lispro now averaged 49 units. His average blood glucose levels were 130 mg/dl fasting, 100 mg/dl mid-afternoon, 127 mg/dl before dinner, and 200 mg/dl at bedtime.

The bedtime levels were higher because of late meals, the fat content of restaurant meals, his meat food choices, and his inexperience at counting carbohydrates for prepared foods. The dietitian suggested mixing regular and lispro insulin to try and get the average bedtime blood glucose level to 140 mg/dl. Mixing his calculated dose to be one-third regular and two-third lispro would provide coverage lasting a little longer than that of just lispro to cover higher-fat foods that took longer to digest. At the same time, the dietitian encouraged B.C. to choose lower-fat foods to help reduce his LDL cholesterol and assist with weight loss. B.C. now had an incentive to keep accurate food records to help evaluate his accuracy at calculating insulin doses.

B.C. and the RD also reviewed his decisions for treating lows. At his first meeting, B.C. ate anything and everything when he experienced hypoglycemia, which often resulted in blood glucose levels >400 mg/dl. Now, he was appropriately using 15–30 g of quick-acting glucose—usually 4–8 oz. of orange juice. He based this amount on his blood glucose level, expecting about a 40-mg/dl rise over 30 minutes from 10 g of carbohydrate. He checked his glucose level before treating when possible and always checked 15–30 minutes after treating to evaluate the results. Once his glucose reached 80 mg/dl or above, he either ate a meal or ate 15 g of carbohydrate per hour to prevent a recurrence of hypoglycemia until his next meal.

In completing her assessment during the next few meetings with B.C., the RD identified a problem with erectile dysfunction. She notifed his clinician and referred him to a urologist. Eventually, the urologist diagnosed reduced blood flow and started B.C. on sildenafil (Viagra).

B.C. wanted to resume exercise to help his weight loss efforts. Because exercise improves insulin sensitivity and can acutely lower blood glucose, the dietitian taught B.C. how to reduce his insulin doses by 25–50% for planned physical activity to further reduce his risks of hypoglycemia. He learned to carry his blood glucose meter, fluids, and carbohydrate foods during and after exercise. His pre-exercise blood glucose goal was set at 150 mg/dl. The dietitian instructed B.C. to test his blood glucose again after exercise and to eat carbohydrate foods if it was <100 mg/dl.

She also gave instructions for unplanned exercise. He would require additional carbohydrate depending on his blood glucose level before exercise, his previous experience with similar exercise, and the timing of the exercise. Education follow-ups were scheduled with the dietitian for 1 month later and every 3 months thereafter.

At his next annual eye exam, B.C. discovered that he had background retinopathy. He also reported feeling that his daily injection regimen had become too complicated. Still feeling limited in his ability to control his diabetes and looking for an alternative to insulin injections, he wanted to discuss continuous subcutaneous insulin infusion therapy (insulin pump therapy).

He, his endocrinologist, and his dietitian discussed the pros and cons of pump therapy and how it might affect his current situation. They reviewed available insulin pumps and sets and agreed on which ones would best meet his needs. The equipment was ordered, and a training session was scheduled with the dietitian (a certified pump trainer) in 1 month.

B.C. started using an insulin pump 2 years after his first visit with the dietitian. His insulin-to-carbohydrate ratio was adjusted for his new therapy regimen, and a new ISF was calculated to help him reduce high blood glucose levels. His endocrinologist set basal insulin rates at 0.3 units/hour to start at midnight and 0.5 units/hour to start at 3:00 a.m. This more natural delivery of insulin based on B.C.’s body rhythms and lifestyle further improved his diabetes control.

One week after starting pump therapy, B.C. called the dietitian to report large urine ketones and a blood glucose level of 317 mg/dl. His endocrinologist had changed his basal rates, but he wanted to meet with the dietitian to review his sites, set insertion, troubleshooting skills, and related issues. Working together, they eventually discovered that problems with his pump sites required using a bent-needle set to resolve absorption issues.

B.C’s relationship with his endocrinologist and dietitian was seamless. He met with the dietitian when his clinician was unavailable or when he needed more time to work through problems.

B.C. has met with the RD 15 times over 3 years. Eventually, he recovered symptoms of hypoglycemia when his blood glucose levels were 70 mg/dl. After 6 months of education meetings, his lab values had reached target ranges. Most recently, his LDL cholesterol was <100 mg/dl, his A1C results were <7%, his hypoglycemia symptoms were maintained at a blood glucose level of 70 mg/dl, and his blood glucose had been stabilized using the square-wave and dual-wave features on his insulin pump.

B.C. learned how to achieve recommended goals and to self-manage his diabetes with the help of his care team: endocrinologist, cardiologist, ophthalmologist, podiatrist, urologist, and advanced practice dietitian.

Advanced practice dietitians in diabetes work in many settings and see clients referred from many different types of medical professionals. They may see clients either before or after their appointments with other members of the health care team, depending on appointment availability and their need for nutrition therapy and diabetes education. Referring clinicians rely on their evaluations and findings. When necessary, clinician approval can be obtained for immediate interventions, enhancing the timeliness of care.

Why would an RD want to obtain the skills and certification necessary to earn the BC-ADM credential? The answer, as illustrated in the case study above, lies in their routine use of two sets of skills and performance of two roles: patient education and clinical management.

Dietitians who specialize in diabetes often find that their role expands beyond provider of nutrition counseling. As part of a multidisciplinary team, they become increasingly involved with patient care. As they move patients toward self-management of their disease, they necessarily participate actively in assessment and diagnosis of patients; planning, implementation, and coordination of their diabetes care regimens; and monitoring and evaluation of their treatment options and strategies. They find that their daily professional activities go beyond diabetes education, crossing over into identifying problems, providing or coordinating clinical care, adjusting therapy, and referring to other medical professionals. They often work independently, providing consultation both to people with diabetes and to other diabetes care team members.

The BC-ADM credential acknowledges this professional autonomy while promoting team collaboration and thus improving the quality of care for people with diabetes. The new certification formally recognizes advanced practice dietitians as they move beyond their traditional roles and into clinical problem solving and case management.

Claudia Shwide-Slavin, MS, RD, BC-ADM, CDE, is a private practice dietitian in New York, N.Y.

Note of disclosure: Ms. Shwide-Slavin has received honoraria for speaking engagements from Medtronic Minimed, which manufactures insulin pumps, and Eli Lilly and Co., which manufactures insulin products for the treatment of diabetes.

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Climbing Nutrition

Case study #1: simon (20-year-old athletic male).

by Brian Rigby, MS, CISSN

March 31, 2016 10 Replies

Case Studies

Since I started this blog almost a year ago, I’ve written many articles on good practices in sports nutrition, eating for climbing performance, and also on popular myths that ought to be debunked. I hope that through these articles you have been able to make healthy changes to your diet, and as a result have seen your climbing improve.

This is all good, but there’s still something missing—sometimes it’s hard to bridge the gap between theory and practice. For this reason, I’m debuting a new type of feature I’ll be running every now and again on Climbing Nutrition: Case Studies . Basically, I’m going to show you some of the process I would go through were I to see a particular individual as a client.

Though each case study is by nature individual (and therefore not necessarily cut to fit your own physiology), the basic work remains similar—so you should be able to go through the process yourself to come up with your own results.

Alright, let’s begin:

Client Information

Name: Simon Age: 20 Sex: Male Height: 5′ 10″ (178 cm) Weight: 145 lbs (66 kg)

Client’s Reason for Inquiry

I climb 3-4 days each week and ski (teaching and touring) another 2. For a long time, I’ve tried to keep my weight low in order to have the best strength-to-weight ratio, but whenever I make gains on the strength side from my training it doesn’t seem to transfer to my climbing. I’ve been stuck at v5-v6 for about a year now.

Simon’s weight and height gives him a BMI (body mass index) of 20.8, well within the healthy range of 18.5 to 24.9. A flaw in the design of the BMI, however, is that it cannot accurately measure fat mass vs. lean mass. Athletes tend to have greater amounts of lean mass (and less fat) than the average individual whom the BMI was designed for, and so in reality Simon is likely even leaner than the BMI indicates (in extreme cases, large athletes can appear to be “overweight” according to their BMI due to muscle mass). Without a body fat reading we cannot know for certain, but it’s probable that Simon has no more than 10-12 lbs of (perfectly healthy) fat he could lose before dropping into an unhealthy range. Thus, as far as strength-to-weight ratio is concerned, losing weight is not likely to yield a major benefit, especially for the amount of work it would require to lose fat below this already low level.

In our correspondence, Simon says he eats around 2,400 calories each day. Since Simon exercises 5-6 days each week, it’s unlikely this is enough calories to support his strength goals. Instead, this amount of energy is likely to be on the lower end of weight maintenance—a sort of metabolic limbo where the body attempts to preserve muscle tissue but doesn’t have enough energy to support muscle growth. Chances are good that Simon could eat significantly more calories each day and still maintain weight, or gain only minimal weight through muscle gain. He will also have more energy to train harder (or longer at a higher intensity), which will have even more significant effects on his strength.

Client Caloric Goal

Using the Harris-Benedict Energy Equation , we can calculate that Simon has a basal metabolic rate (BMR) of roughly 1,675 kcal/day.

Harris-Benedict Energy Equation

Imperial: (4.55 * weight in lbs) + (15.88 * height in inches) – (5 * age in years) = BMR
Men: Add 5 calories to the calculated BMR
Women: Subtract 161 calories from the calculated BMR

A BMR only covers the essential functions necessary for sustaining life at its most basic level, though; unless Simon is literally lying in bed all day—eating nothing, drinking nothing, doing nothing—we need to multiply it by the appropriate modifier. There are two ways of doing this: the simple, averaged approach; or the more complex, individualized approach. Since Simon has given me a breakdown of his weekly activities, I will ultimately use the individualized approach. First, however, I’ll show you the generalized approach in case you choose to use this method instead.

Harris-Benedict Activity Modifiers

Sedentary: BMR * 1.2
Light (1-3 days/week): BMR * 1.375
Moderate (3-5 days/week): BMR * 1.55
Vigorous (6-7 days/week): BMR * 1.725
Extreme (6-7 days/week, multiple workouts per day): BMR * 1.9

Since Simon exercises an average of 5-6 days per week (3-4 days climbing, 2 days skiing), he falls into the “Moderate” to “Vigorous” category of physical activity level. “Moderate” has a modifier of 1.55, while “Vigorous” has a modifier of 1.725. Thus, for a more moderate week, Simon will need roughly 2,600 kcal per day (1,675 kcal/day * 1.55), while a more vigorous week calls for roughly 2,900 kcal per day (1,675 kcal/day * 1.725).

Based on this information, Simon’s daily intake appears to be 200-500 calories shy of the recommended amount for maintainance—and low enough to have a noticeable negative impact on his climbing and training. By increasing calories to the recommended amount, he would have more energy, gain strength easier (and transfer that strength to climbing), and still maintain weight.

Really, though, it’s better to individualize your plan whenever you can. The problem with modifiers is that they’re very broad, subject to interpretation, and error-prone. For example, it would appear based on the above list that exercising for one hour three days a week and exercising for two hours five days a week are equivalent, when it’s instantly apparent that they’re not—but two people might still calculate their metabolic rates as equivalent based on the above modifiers, despite having wildly different lifestyles! Furthermore, there’s no concern with intensity. An hour of walking is equivalent to an hour of race-pace running, even though there is a huge difference in the calories burned by each activity. An individual approach overcomes these limitations.

To individualize your plan, you just need to know approximately how many calories your chosen exercises burn, and approximately how long you engage in them each day. There is still room for error (overestimation of intensity or time, for example), but these errors will likely be much smaller in magnitude—only a 25-100 calorie difference across a day, rather than a 200+ calories difference.

The first step in an individualized plan is to calculate your sedentary metabolic rate —your BMR multiplied by the sedentary modifier of 1.2. This sedentary rate accounts for all the little things we do everyday that are not included in your BMR, such as eating, sitting upright, walking around, standing, etc. Simon’s sedentary rate is roughly 2,000 calories per day (1,675 * 1.2 = 2,010).

Next, we determine the average caloric cost of the activities Simon engages in. The easiest way to go about this is to just use an online calculator such as this on e and plug in your weight and the activity you’re interested in.

For Simon (weight 145 lbs), ski touring will burn between 400 (for an easy pace on gentle terrain) to 525 (for vigorous effort) per hour, with higher rates possible for certain conditions. Teaching skiing is a little harder to quantify because it’s variable, but light downhill skiing burns roughly 264 calories per hour (this would only include the time actually skiing , not chairlifts, etc.) and it’ll likely be at least that.

According to the exercise calculator, climbing burns about 660 calories per hour, but we can be more specific here based on intensity. Based on this research , climbing burns roughly 17 kcal/minute for easy routes, 19 kcal/minute for moderate routes, and 22 kcal/minute for difficult routes (for an experienced climber). For a new climber, a difficult route—“difficult” is relative to skill, by the way, not absolute based on grades—burns 23 kcal/minute. Bouldering is of higher intensity, so it’s possible that it burns even more calories, but given the lack of data we’ll just assume it burns 22 kcal/minute. This is “on the wall” time only, which varies from person to person, but is likely to average 10-20 minutes per hour for bouldering. That means that each hour of bouldering will burn an average of 220-440 kcal.

Now, all we have to do is multiply each activity’s caloric cost by the time spent doing it and add that to Simon’s daily total. If we assume he climbs two hours per day with an average amount of “on the wall” time, he would burn 660 calories doing so. That means he should consume about 2,660 calories on a day he climbs (2,000 from his sedentary metabolic rate and 660 from his activities) to maintain weight. Or, on a day of ski touring that lasts six hours, he should consume 4,400 calories to maintain weight.

Macronutrient Breakdown

The final step is to determine the macronutrient breakdown of any given day. This is perhaps a little more complicated just because protein needs remain static (roughly 100-160 grams per day) while carbohydrate and fat needs will vary based on total daily activity. Normally when I work with clients, I provide a “base goal” for each macronutrient (in addition to calories) and then a “per hour of exercise” goal as well (with variations according to intensity), but here I’m going to show a slightly easier variation.

First, based on Simon’s BMR of 2,000 calories per day, protein should account for roughly 24% of the calories in his diet (120 grams of protein at 4 calories per gram equals 480 calories, divided into 2,000 calories equals 24%—the 120 grams is the important part). Since this is a sedentary day, we’ll leave carbohydrates towards the lower end at 50%, which leaves fat at 26%. Even though 50% isn’t ideal for aerobic activities such as ski touring , the actual percentage will wind up being significantly higher on ski touring days because protein doesn’t increase. If this isn’t clear right now, don’t worry, you’ll see the math in just a bit.

Simon’s Macronutrients on a Sedentary Day

Protein: 120 g (480 kcal; 24%)
Carbs: 250 g (1,000 kcal; 50%)
Fat: 58 g (520 kcal; 26%)

To determine what his needs will be on non-sedentary days, we’ll figure out the ratio of carbohydrate-to-fat calories. In Simon’s case, it’s roughly 2-to-1 (50% carbs to 26% fat, or 50:26 –> 1.92:1), and he should try to keep this ratio approximately the same on active days as well. That means getting two calories of carbohydrate-based energy for every single calorie of fat-based energy.

For those interested in the gram-to-gram breakdown, carbohydrates weigh in at 4 calories per gram and fat weighs in at 9 calories per gram, which makes the gram of carbohydrate to gram of fat ratio about 4.5:1 (1/2 gram of carbohydrates for every 1/9 gram of fat). This isn’t necessary to figure out the rest of Simon’s macronutrient schedule, though, so don’t worry too much about it.

On days when Simon climbs, he should consume an estimated 2,660 calories (or more or less depending on the total amount of climbing). When the 480 calories from protein are subtracted, we are left with 2,180 calories—66.6% of which should come from carbohydrates, and 33.3% of which should come from fat (that 2-to-1 ratio). That comes out to roughly 1,440 carbohydrate calories (55% of his total caloric intake) and 720 fat calories (27% of his total caloric intake), which is about 360 grams of carbs and 80 grams of fat. So Simon’s climbing day macronutrients look more like this:

Simon’s Macronutrients on a Climbing Day

Protein: 120g (480 kcal; 18%)
Carbs: 360 g (1,440 kcal; 55%)
Fat: 80 g (720 kcal; 27%)

Already you can see that carbohydrates are playing a much more significant role!

Now let’s do the same operation for the ski touring day. Removing the 480 calories of protein from the assumed 4,400 he will burn throughout the day, we are left with 3,920 total calories. At a 2:1 carb/fat ratio, about 2,600 of those calories should come from carbs while 1,300 should come from fat—this is equivalent to 650 grams of carbs and 144 grams of fat. Now, carbohydrates make up about 59% of his diet, fat is about 30%, and protein is only 11%!

Simon’s Macronutrients on a Ski Touring Day

Protein: 120 g (480 kcal; 18%)
Carbs: 650 g (2,600 kcal; 59%)
Fat: 144 g (1,300 kcal; 30%)

The greater Simon’s caloric need, the greater role carbohydrates will play in his day, according to our specified ratio. Moving from a sedentary day to a moderately active climbing day to a significantly active ski touring day, Simon’s carbohydrate goal moves from 50% to 55% to almost 60% while fat only moves from 26% to 30% (and protein dwindles in relative “importance”).

For most people, starting with a similar caloric ratio (roughly 1:2:1 protein/carbs/fat) as the one demonstrated here is probably adequate, especially if you do a combination of anaerobic (bouldering, single-pitch sport climbing, campus training, fingerboarding, etc.) and aerobic (low-intensity multi-pitch climbing, hiking, cycling, etc.) activities. If you’re much more on the anaerobic side of spectrum, you can safely alter the carb-to-fat ratio to be 1.5:1 (45% carbohydrates, 30% fat on a sedentary day) without affecting performance. If you engage in a lot of aerobic activity, you may wish to increase it to 2.75:1 (55% carbohydrates, 20% fat on a sedentary day) or even 4:1 (60% carbohydrates, 15% fat on a sedentary day).

Test in the Real World

Determining theoritical ratios is only the first step for any nutrition plan. After we have a target to aim for, we need to gauge it against real world results, which means implementing the plan and monitoring Simon’s weight. If Simon continues to maintain weight with the increased caloric load, then we know we’ve hit about the right area, and we might even increase calories slightly until we find the point at which he starts to gain weight (so we can be certain he is doing the most for muscle recovery and strength gain). If Simon gains weight, then we’ll back calories off slowly until he starts to maintain again. He shouldn’t lose weight since we’re increasing calories.

Aside from monitoring progress in a concrete way such as through weight maintenance (or body fat readings, if he had a way to do it), Simon should also subjectively feel stronger and more able to translate his training strength gains to his climbing. He should have more energy, recover faster, and stay strong longer. If all of this is true, and his weight is stable, then we would consider Simon’s plan to be successful and he would follow it until his goals changed. If there are problems that persist longer than a week or two (the amount of time it can sometimes take to “break in” a diet), then we’ll make some changes depending on the specifics of the problems.

Wrapping Up

Simon is a great example of an average, active male climber. His focus on staying lean no matter the cost was inhibiting his strength gains on the wall and providing no discernible benefit since he was already quite lean. By increasing his daily calories to a more appropriate level, he should be able to continue to maintain weight while improving his ability to gain strength. If followed accurately for an extended period of time, he may even gain small amounts of muscle and lose equal amounts of fat (AKA “body recomposition”), thereby dramatically improving his strength-to-weight ratio.

If Simon does not resemble you or your goals, don’t fret! This is just our first case study, and I’ll more than likely cover someone with a similar goal or physique to your own in the future. In the meantime, you should hopefully be able to apply the lessons learned from this first case study to yourself (provided your goal is weight maintenance) and get positive results.

If you have questions about this case study, please ask them in the comments below so I can answer publicly on this page and clarify the confusion for everyone! If you think you’d be a great example for a case study, fill out the form on this page and please be patient. I will do my best to answer your needs via email (at the least), or possibly use you as another example in the months to come.

Until next time!

10 comments

Very interesting from a theoretical point of view. But it seems almost impossible to implement in the real world. How does numbers and ratios translate to real food. It must take a lot of planning just to figure out what to actually eat. Also, how can you time your food intake on a normal workday that leaves little or no room for frequent food breaks and prepping.

Also, I have been a hardgainer my whole life and I can testify to eating enough calories is no way as easy as stated in post. Seems like you need to eat tons of food in very frequent intervals. Again the macro breakdown leads to a more practical issue: How does numbers translate to real food?

There are logistical issues, to be sure—issues that are probably better tackled in a separate post—but let me try to provide a little hope here. Let’s assume Simon will have the chance to eat 5 meals/snacks on a given climbing day. With his base carb requirement of 250 grams, that means he should eat approximately 50 grams of carbohydrate per meal, or just over a single cup of most cooked starchy carbs. A cup is not a lot, so this shouldn’t be infeasible. The remaining 110 grams of carbs that he needs from climbing can come from preloading before exercise (slow-digesting carbs to buoy blood glucose during his climb), intraexercise replenishment (such as a sports drink, or fruit), or afterwards in the form of extra food (over the next few hours, about an extra 2.5 cups of starchy carbs). In this case, I’m only focusing on carbohydrates because they are the most challenging to get enough of for most people, at least without resorting to highly concentrated forms like refined sugars.

A ski touring day would be more challenging, but since he will presumably be exercising with little break we can rely more on the above-mentioned concentrated sources, which will also be easier to digest during exercise. Dried fruit, sports drink mixed into his water, and granola bars all make it easier to get the necessary number of calories.

In all cases, it does take planning, but the end result is worth it, I think. Energy will be higher, recovery faster, and training gains will be increased. This isn’t to say everyone must plan like this, but rather than there’s value in doing it if you care to, just as there’s value in putting together a training schedule and sticking with it despite the logistical and motivational problems associated with putting together a weeks-long exercise schedule in advance. But, as I said, I think another post will ultimately do your question/comment more justice, so I’ll try to get one out soon!

you have a great blog here! would you like to make some invite posts on my blog?

Thanks! Send me an email here if you’re interested in guest posts .

Thank you for this post. It is very helpful. Because I don’t want to pay the $39.95 to read the article at https://link.springer.com/article/10.1007%2Fs00421-007-0501-0 , could you help me in determining the number of calories burned per minute for a 115# female for easy, moderate, and difficult bouldering ? I assume the numbers in the case study, 17 kcal/minute for easy routes, 19 kcal/minute for moderate routes, and 22 kcal/minute for difficult routes, are specific to Simon’s weight.

The numbers provided were based on the averages in the article itself, which were themselves based on an average weight of 64 kg (141 lb). It’s an imperfect approximation, but we just really don’t have any good data on the caloric cost of climbing so it’s the best I could offer! Based on weight, we could estimate up or down by the same factor as the weight change and get in the same ballpark, so a heavier 160 lb climber might burn 19 kcal/min while a lighter 120 lb climber might burn 15 kcal/min. But, these are only estimates because it’s tough to know precisely how the caloric costs associated with climbing relate to weight compared to how they do for running or other more well-studied sports. Sorry I couldn’t give a more precise answer!

I have a question with regard to carbohydrates. Do they include fibre or not? I used the formula kcal from all carbohydrates equals 4*gramms of carbohydrates + 2*gramms of fibre. And then I took the ratio 2:1 for all carbohydrates to fat. Is that correct in your opinion? The fibre should somehow be included since it contributes to the calorie intake.

Thank you very much and best regards, Chris

Fiber doesn’t have a significant effect on our caloric intake since it’s indigestible. Some fibers are fermentable by our gut bacteria and those bacteria will release short-chain fatty acids as a by product that will be absorbed and used by the cells lining our intestine and thereby technically add to our caloric intake, but overall the net calories from fiber will be negligible.

Since Simon is active on most days of the week, there are days when he is not. Compute for his TER on his sedentary days.??

Since Simon is active on most days of the week, there are days when he is not. Compute for his TER on his sedentary days.

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Case 6–2020: A 34-Year-Old Woman with Hyperglycemia

Presentation of case.

Dr. Max C. Petersen (Medicine): A 34-year-old woman was evaluated in the diabetes clinic of this hospital for hyperglycemia.

Eleven years before this presentation, the blood glucose level was 126 mg per deciliter (7.0 mmol per liter) on routine laboratory evaluation, which was performed as part of an annual well visit. The patient could not recall whether she had been fasting at the time the test had been performed. One year later, the fasting blood glucose level was 112 mg per deciliter (6.2 mmol per liter; reference range, <100 mg per deciliter [<5.6 mmol per liter]).

Nine years before this presentation, a randomly obtained blood glucose level was 217 mg per deciliter (12.0 mmol per liter), and the patient reported polyuria. At that time, the glycated hemoglobin level was 5.8% (reference range, 4.3 to 5.6); the hemoglobin level was normal. One year later, the glycated hemoglobin level was 5.9%. The height was 165.1 cm, the weight 72.6 kg, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) 26.6. The patient received a diagnosis of prediabetes and was referred to a nutritionist. She made changes to her diet and lost 4.5 kg of body weight over a 6-month period; the glycated hemoglobin level was 5.5%.

Six years before this presentation, the patient became pregnant with her first child. Her prepregnancy BMI was 24.5. At 26 weeks of gestation, the result of a 1-hour oral glucose challenge test (i.e., the blood glucose level obtained 1 hour after the oral administration of a 50-g glucose load in the nonfasting state) was 186 mg per deciliter (10.3 mmol per liter; reference range, <140 mg per deciliter [<7.8 mmol per liter]). She declined a 3-hour oral glucose tolerance test; a presumptive diagnosis of gestational diabetes was made. She was asked to follow a meal plan for gestational diabetes and was treated with insulin during the pregnancy. Serial ultrasound examinations for fetal growth and monitoring were performed. At 34 weeks of gestation, the fetal abdominal circumference was in the 76th percentile for gestational age. Polyhydramnios developed at 37 weeks of gestation. The child was born at 39 weeks 3 days of gestation, weighed 3.9 kg at birth, and had hypoglycemia after birth, which subsequently resolved. Six weeks post partum, the patient’s fasting blood glucose level was 120 mg per deciliter (6.7 mmol per liter), and the result of a 2-hour oral glucose tolerance test (i.e., the blood glucose level obtained 2 hours after the oral administration of a 75-g glucose load in the fasting state) was 131 mg per deciliter (7.3 mmol per liter; reference range, <140 mg per deciliter). Three months post partum, the glycated hemoglobin level was 6.1%. Lifestyle modification for diabetes prevention was recommended.

Four and a half years before this presentation, the patient became pregnant with her second child. Her prepregnancy BMI was 25.1. At 5 weeks of gestation, she had an elevated blood glucose level. Insulin therapy was started at 6 weeks of gestation, and episodes of hypoglycemia occurred during the pregnancy. Serial ultrasound examinations for fetal growth and monitoring were performed. At 28 weeks of gestation, the fetal abdominal circumference was in the 35th percentile for gestational age, and the amniotic fluid level was normal. Labor was induced at 38 weeks of gestation; the child weighed 2.6 kg at birth. Neonatal blood glucose levels were reported as stable after birth. Six weeks post partum, the patient’s fasting blood glucose level was 133 mg per deciliter (7.4 mmol per liter), and the result of a 2-hour oral glucose tolerance test was 236 mg per deciliter (13.1 mmol per liter). The patient received a diagnosis of type 2 diabetes mellitus; lifestyle modification was recommended. Three months post partum, the glycated hemoglobin level was 5.9% and the BMI was 30.0. Over the next 2 years, she followed a low-carbohydrate diet and regular exercise plan and self-monitored the blood glucose level.

Two years before this presentation, the patient became pregnant with her third child. Blood glucose levels were again elevated, and insulin therapy was started early in gestation. She had episodes of hypoglycemia that led to adjustment of her insulin regimen. The child was born at 38 weeks 5 days of gestation, weighed 3.0 kg at birth, and had hypoglycemia that resolved 48 hours after birth. After the birth of her third child, the patient started to receive metformin, which had no effect on the glycated hemoglobin level, despite adjustment of the therapy to the maximal dose.

One year before this presentation, the patient became pregnant with her fourth child. Insulin therapy was again started early in gestation. The patient reported that episodes of hypoglycemia occurred. Polyhydramnios developed. The child was born at 38 weeks 6 days of gestation and weighed 3.5 kg. The patient sought care at the diabetes clinic of this hospital for clarification of her diagnosis.

The patient reported following a low-carbohydrate diet and exercising 5 days per week. There was no fatigue, change in appetite, change in vision, chest pain, shortness of breath, polydipsia, or polyuria. There was no history of anemia, pancreatitis, hirsutism, proximal muscle weakness, easy bruising, headache, sweating, tachycardia, gallstones, or diarrhea. Her menstrual periods were normal. She had not noticed any changes in her facial features or the size of her hands or feet.

The patient had a history of acne and low-back pain. Her only medication was metformin. She had no known medication allergies. She lived with her husband and four children in a suburban community in New England and worked as an administrator. She did not smoke tobacco or use illicit drugs, and she rarely drank alcohol. She identified as non-Hispanic white. Both of her grandmothers had type 2 diabetes mellitus. Her father had hypertension, was overweight, and had received a diagnosis of type 2 diabetes at 50 years of age. Her mother was not overweight and had received a diagnosis of type 2 diabetes at 48 years of age. The patient had two sisters, neither of whom had a history of diabetes or gestational diabetes. There was no family history of hemochromatosis.

On examination, the patient appeared well. The blood pressure was 126/76 mm Hg, and the heart rate 76 beats per minute. The BMI was 25.4. The physical examination was normal. The glycated hemoglobin level was 6.2%.

A diagnostic test was performed.

DIFFERENTIAL DIAGNOSIS

Dr. Miriam S. Udler: I am aware of the diagnosis in this case and participated in the care of this patient. This healthy 34-year-old woman, who had a BMI just above the upper limit of the normal range, presented with a history of hyperglycemia of varying degrees since 24 years of age. When she was not pregnant, she was treated with lifestyle measures as well as metformin therapy for a short period, and she maintained a well-controlled blood glucose level. In thinking about this case, it is helpful to characterize the extent of the hyperglycemia and then to consider its possible causes.

CHARACTERIZING HYPERGLYCEMIA

This patient’s hyperglycemia reached a threshold that was diagnostic of diabetes 1 on two occasions: when she was 25 years of age, she had a randomly obtained blood glucose level of 217 mg per deciliter with polyuria (with diabetes defined as a level of ≥200 mg per deciliter [≥11.1 mmol per liter] with symptoms), and when she was 30 years of age, she had on the same encounter a fasting blood glucose level of 133 mg per deciliter (with diabetes defined as a level of ≥126 mg per deciliter) and a result on a 2-hour oral glucose tolerance test of 236 mg per deciliter (with diabetes defined as a level of ≥200 mg per deciliter). On both of these occasions, her glycated hemoglobin level was in the prediabetes range (defined as 5.7 to 6.4%). In establishing the diagnosis of diabetes, the various blood glucose studies and glycated hemoglobin testing may provide discordant information because the tests have different sensitivities for this diagnosis, with glycated hemoglobin testing being the least sensitive. 2 Also, there are situations in which the glycated hemoglobin level can be inaccurate; for example, the patient may have recently received a blood transfusion or may have a condition that alters the life span of red cells, such as anemia, hemoglobinopathy, or pregnancy. 3 These conditions were not present in this patient at the time that the glycated hemoglobin measurements were obtained. In addition, since the glycated hemoglobin level reflects the average glucose level typically over a 3-month period, discordance with timed blood glucose measurements can occur if there has been a recent change in glycemic control. This patient had long-standing mild hyperglycemia but met criteria for diabetes on the basis of the blood glucose levels noted.

Type 1 and Type 2 Diabetes

Now that we have characterized the patient’s hyperglycemia as meeting criteria for diabetes, it is important to consider the possible types. More than 90% of adults with diabetes have type 2 diabetes, which is due to progressive loss of insulin secretion by beta cells that frequently occurs in the context of insulin resistance. This patient had received a diagnosis of type 2 diabetes; however, some patients with diabetes may be given a diagnosis of type 2 diabetes on the basis of not having features of type 1 diabetes, which is characterized by autoimmune destruction of the pancreatic beta cells that leads to rapid development of insulin dependence, with ketoacidosis often present at diagnosis.

Type 1 diabetes accounts for approximately 6% of all cases of diabetes in adults (≥18 years of age) in the United States, 4 and 80% of these cases are diagnosed before the patient is 20 years of age. 5 Since this patient’s diabetes was essentially nonprogressive over a period of at least 9 years, she most likely does not have type 1 diabetes. It is therefore not surprising that she had received a diagnosis of type 2 diabetes, but there are several other types of diabetes to consider, particularly since some features of her case do not fit with a typical case of type 2 diabetes, such as her age at diagnosis, the presence of hyperglycemia despite a nearly normal BMI, and the mild and nonprogressive nature of her disease over the course of many years.

Less Common Types of Diabetes

Latent autoimmune diabetes in adults (LADA) is a mild form of autoimmune diabetes that should be considered in this patient. However, there is controversy as to whether LADA truly represents an entity that is distinct from type 1 diabetes. 6 Both patients with type 1 diabetes and patients with LADA commonly have elevated levels of diabetes-associated autoantibodies; however, LADA has been defined by an older age at onset (typically >25 years) and slower progression to insulin dependence (over a period of >6 months). 7 This patient had not been tested for diabetes-associated autoantibodies. I ordered these tests to help evaluate for LADA, but this was not my leading diagnosis because of her young age at diagnosis and nonprogressive clinical course over a period of at least 9 years.

If the patient’s diabetes had been confined to pregnancy, we might consider gestational diabetes, but she had hyperglycemia outside of pregnancy. Several medications can cause hyperglycemia, including glucocorticoids, atypical antipsychotic agents, cancer immunotherapies, and some antiretroviral therapies and immunosuppressive agents used in transplantation. 8 However, this patient was not receiving any of these medications. Another cause of diabetes to consider is destruction of the pancreas due to, for example, cystic fibrosis, a tumor, or pancreatitis, but none of these were present. Secondary endocrine disorders — including excess cortisol production, excess growth hormone production, and pheochromocytoma — were considered to be unlikely in this patient on the basis of the history, review of symptoms, and physical examination.

Monogenic Diabetes

A final category to consider is monogenic diabetes, which is caused by alteration of a single gene. Types of monogenic diabetes include maturity-onset diabetes of the young (MODY), neonatal diabetes, and syndromic forms of diabetes. Monogenic diabetes accounts for 1 to 6% of cases of diabetes in children 9 and approximately 0.4% of cases in adults. 10 Neonatal diabetes is diagnosed typically within the first 6 months of life; syndromic forms of monogenic diabetes have other abnormal features, including particular organ dysfunction. Neither condition is applicable to this patient.

MODY is an autosomal dominant condition characterized by primary pancreatic beta-cell dysfunction that causes mild diabetes that is diagnosed during adolescence or early adulthood. As early as 1964, the nomenclature “maturity-onset diabetes of the young” was used to describe cases that resembled adult-onset type 2 diabetes in terms of the slow progression to insulin use (as compared with the rapid progression in type 1 diabetes) but occurred in relatively young patients. 11 Several genes cause distinct forms of MODY that have specific disease features that inform treatment, and thus MODY is a clinically important diagnosis. Most forms of MODY cause isolated abnormal glucose levels (in contrast to syndromic monogenic diabetes), a manifestation that has contributed to its frequent misdiagnosis as type 1 or type 2 diabetes. 12

Genetic Basis of MODY

Although at least 13 genes have been associated with MODY, 3 genes — GCK , which encodes glucokinase, and HNF1A and HNF4A , which encode hepatocyte nuclear factors 1A and 4A, respectively — account for most cases. MODY associated with GCK (known as GCK-MODY) is characterized by mild, nonprogressive hyperglycemia that is present since birth, whereas the forms of MODY associated with HNF1A and HNF4A (known as HNF1A-MODY and HNF4A-MODY, respectively) are characterized by the development of diabetes, typically in the early teen years or young adulthood, that is initially mild and then progresses such that affected patients may receive insulin before diagnosis.

In patients with GCK-MODY, genetic variants reduce the function of glucokinase, the enzyme in pancreatic beta cells that functions as a glucose sensor and controls the rate of entry of glucose into the glycolytic pathway. As a result, reduced sensitivity to glucose-induced insulin secretion causes asymptomatic mild fasting hyperglycemia, with an upward shift in the normal range of the fasting blood glucose level to 100 to 145 mg per deciliter (5.6 to 8.0 mmol per liter), and also causes an upward shift in postprandial blood glucose levels, but with tight regulation maintained ( Fig. 1 ). 13 This mild hyperglycemia is not thought to confer a predisposition to complications of diabetes, 14 is largely unaltered by treatment, 15 and does not necessitate treatment outside of pregnancy.

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Key features suggesting maturity-onset diabetes of the young (MODY) in this patient were an age of less than 35 years at the diagnosis of diabetes, a strong family history of diabetes with an autosomal dominant pattern of inheritance, and hyperglycemia despite a close-to-normal body-mass index. None of these features is an absolute criterion. MODY is caused by single gene–mediated disruption of pancreatic beta-cell function. In MODY associated with the GCK gene (known as GCK-MODY), disrupted glucokinase function causes a mild upward shift in glucose levels through-out the day and does not necessitate treatment. 13 In the pedigree, circles represent female family members, squares male family members, blue family members affected by diabetes, and green unaffected family members. The arrow indicates the patient.

In contrast to GCK-MODY, the disorders HNF1A-MODY and HNF4A-MODY result in progressive hyperglycemia that eventually leads to treatment. 16 Initially, there may be a normal fasting glucose level and large spikes in postprandial glucose levels (to >80 mg per deciliter [>4.4 mmol per liter]). 17 Patients can often be treated with oral agents and discontinue insulin therapy started before the diagnosis of MODY. 18 Of note, patients with HNF1A-MODY or HNF4A-MODY are typically sensitive to treatment with sulfonylureas 19 but may also respond to glucagon-like peptide-1 receptor agonists. 20

This patient had received a diagnosis of diabetes before 35 years of age, had a family history of diabetes involving multiple generations, and was not obese. These features are suggestive of MODY but do not represent absolute criteria for the condition ( Fig. 1 ). 1 Negative testing for diabetes-associated autoantibodies would further increase the likelihood of MODY. There are methods to calculate a patient’s risk of having MODY associated with GCK , HNF1A , or HNF4A . 21 , 22 Using an online calculator ( www.diabetesgenes.org/mody-probability-calculator ), we estimate that the probability of this patient having MODY is at least 75.5%. Genetic testing would be needed to confirm this diagnosis, and in patients at an increased risk for MODY, multigene panel testing has been shown to be cost-effective. 23 , 24

DR. MIRIAM S. UDLER’S DIAGNOSIS

Maturity-onset diabetes of the young, most likely due to a GCK variant.

DIAGNOSTIC TESTING

Dr. Christina A. Austin-Tse: A diagnostic sequencing test of five genes associated with MODY was performed. One clinically significant variant was identified in the GCK gene (NM_000162.3): a c.787T→C transition resulting in the p.Ser263Pro missense change. Review of the literature and variant databases revealed that this variant had been previously identified in at least three patients with early-onset diabetes and had segregated with disease in at least three affected members of two families (GeneDx: personal communication). 25 , 26 Furthermore, the variant was rare in large population databases (occurring in 1 out of 128,844 European chromosomes in gnomAD 27 ), a feature consistent with a disease-causing role. Although the serine residue at position 263 was not highly conserved, multiple in vitro functional studies have shown that the p.Ser263Pro variant negatively affects the stability of the glucokinase enzyme. 26 , 28 – 30 As a result, this variant met criteria to be classified as “likely pathogenic.” 31 As mentioned previously, a diagnosis of GCK-MODY is consistent with this patient’s clinical features. On subsequent testing of additional family members, the same “likely pathogenic” variant was identified in the patient’s father and second child, both of whom had documented hyperglycemia.

DISCUSSION OF MANAGEMENT

Dr. Udler: In this patient, the diagnosis of GCK-MODY means that it is normal for her blood glucose level to be mildly elevated. She can stop taking metformin because discontinuation is not expected to substantially alter her glycated hemoglobin level 15 , 32 and because she is not at risk for complications of diabetes. 14 However, she should continue to maintain a healthy lifestyle. Although patients with GCK-MODY are not typically treated for hyperglycemia outside of pregnancy, they may need to be treated during pregnancy.

It is possible for a patient to have type 1 or type 2 diabetes in addition to MODY, so this patient should be screened for diabetes according to recommendations for the general population (e.g., in the event that she has a risk factor for diabetes, such as obesity). 1 Since the mild hyperglycemia associated with GCK-MODY is asymptomatic (and probably unrelated to the polyuria that this patient had described in the past), the development of symptoms of hyperglycemia, such as polyuria, polydipsia, or blurry vision, should prompt additional evaluation. In patients with GCK-MODY, the glycated hemoglobin level is typically below 7.5%, 33 so a value rising above that threshold or a sudden large increase in the glycated hemoglobin level could indicate concomitant diabetes from another cause, which would need to be evaluated and treated.

This patient’s family members are at risk for having the same GCK variant, with a 50% chance of offspring inheriting a variant from an affected parent. Since the hyperglycemia associated with GCK-MODY is present from birth, it is necessary to perform genetic testing only in family members with demonstrated hyperglycemia. I offered site-specific genetic testing to the patient’s parents and second child.

Dr. Meridale V. Baggett (Medicine): Dr. Powe, would you tell us how you would treat this patient during pregnancy?

Dr. Camille E. Powe: During the patient’s first pregnancy, routine screening led to a presumptive diagnosis of gestational diabetes, the most common cause of hyperglycemia in pregnancy. Hyperglycemia in pregnancy is associated with adverse pregnancy outcomes, 34 and treatment lowers the risk of such outcomes. 35 , 36 Two of the most common complications — fetal overgrowth (which can lead to birth injuries, shoulder dystocia, and an increased risk of cesarean delivery) and neonatal hypoglycemia — are thought to be the result of fetal hyperinsulinemia. 37 Maternal glucose is freely transported across the placenta, and excess glucose augments insulin secretion from the fetal pancreas. In fetal life, insulin is a potent growth factor, and neonates who have hyperinsulinemia in utero often continue to secrete excess insulin in the first few days of life. In the treatment of pregnant women with diabetes, we strive for strict blood sugar control (fasting blood glucose level, <95 mg per deciliter [<5.3 mmol per liter]; 2-hour postprandial blood glucose level, <120 mg per deciliter) to decrease the risk of these and other hyperglycemia-associated adverse pregnancy outcomes. 38 – 40

In the third trimester of the patient’s first pregnancy, obstetrical ultrasound examination revealed a fetal abdominal circumference in the 76th percentile for gestational age and polyhydramnios, signs of fetal exposure to maternal hyperglycemia. 40 – 42 Case series involving families with GCK-MODY have shown that the effect of maternal hyperglycemia on the fetus depends on whether the fetus inherits the pathogenic GCK variant. 43 – 48 Fetuses that do not inherit the maternal variant have overgrowth, presumably due to fetal hyperinsulinemia ( Fig. 2A ). In contrast, fetuses that inherit the variant do not have overgrowth and are born at a weight that is near the average for gestational age, despite maternal hyperglycemia, presumably because the variant results in decreased insulin secretion ( Fig. 2B ). Fetuses that inherit GCK-MODY from their fathers and have euglycemic mothers appear to be undergrown, most likely because their insulin secretion is lower than normal when they and their mothers are euglycemic ( Fig. 2D ). Because fetal overgrowth and polyhydramnios occurred during this patient’s first pregnancy and neonatal hypoglycemia developed after the birth, the patient’s first child is probably not affected by GCK-MODY.

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Pathogenic variants that lead to GCK-MODY, when carried by a fetus, change the usual relationship of maternal hyperglycemia to fetal hyperinsulinemia and fetal overgrowth. GCK-MODY–affected fetuses have lower insulin secretion than unaffected fetuses in response to the same maternal blood glucose level. In a hyperglycemic mother carrying a fetus who is unaffected by GCK-MODY, excessive fetal growth is usually apparent (Panel A). Studies involving GCK-MODY–affected hyperglycemic mothers have shown that fetal growth is normal despite maternal hyperglycemia when a fetus has the maternal GCK variant (Panel B). The goal of treatment of maternal hyperglycemia when a fetus is unaffected by GCK-MODY is to establish euglycemia to normalize fetal insulin levels and growth (Panel C); whether this can be accomplished in the case of maternal GCK-MODY is controversial, given the genetically determined elevated maternal glycemic set point. In the context of maternal euglycemia, GCK-MODY–affected fetuses may be at risk for fetal growth restriction (Panel D).

In accordance with standard care for pregnant women with diabetes who do not meet glycemic targets after dietary modification, 38 , 39 the patient was treated with insulin during her pregnancies. In her second pregnancy, treatment was begun early, after hyperglycemia was detected in the first trimester. Because she had not yet received the diagnosis of GCK-MODY during any of her pregnancies, no consideration of this condition was given during her obstetrical treatment. Whether treatment affects the risk of hyperglycemia-associated adverse pregnancy outcomes in pregnant women with known GCK-MODY is controversial, with several case series showing that the birth weight percentile in unaffected neonates remains consistent regardless of whether the mother is treated with insulin. 44 , 45 Evidence suggests that it may be difficult to overcome a genetically determined glycemic set point in patients with GCK-MODY with the use of pharmacotherapy, 15 , 32 and affected patients may have symptoms of hypoglycemia when the blood glucose level is normal because of an enhanced counterregulatory response. 49 , 50 Still, to the extent that it is possible, it would be desirable to safely lower the blood glucose level in a woman with GCK-MODY who is pregnant with an unaffected fetus in order to decrease the risk of fetal overgrowth and other consequences of mildly elevated glucose levels ( Fig. 2C ). 46 , 47 , 51 In contrast, there is evidence that lowering the blood glucose level in a pregnant woman with GCK-MODY could lead to fetal growth restriction if the fetus is affected ( Fig. 2D ). 45 , 52 During this patient’s second pregnancy, she was treated with insulin beginning in the first trimester, and her daughter’s birth weight was near the 16th percentile for gestational age; this outcome is consistent with the daughter’s ultimate diagnosis of GCK-MODY.

Expert opinion suggests that, in pregnant women with GCK-MODY, insulin therapy should be deferred until fetal growth is assessed by means of ultrasound examination beginning in the late second trimester. If there is evidence of fetal overgrowth, the fetus is presumed to be unaffected by GCK-MODY and insulin therapy is initiated. 53 After I have counseled women with GCK-MODY on the potential risks and benefits of insulin treatment during pregnancy, I have sometimes used a strategy of treating hyperglycemia from early in pregnancy using modified glycemic targets that are less stringent than the targets typically used during pregnancy. This strategy attempts to balance the risk of growth restriction in an affected fetus (as well as maternal hypoglycemia) with the potential benefit of glucose-lowering therapy for an unaffected fetus.

Dr. Udler: The patient stopped taking metformin, and subsequent glycated hemoglobin levels remained unchanged, at 6.2%. Her father and 5-year-old daughter (second child) both tested positive for the same GCK variant. Her father had a BMI of 36 and a glycated hemoglobin level of 7.8%, so I counseled him that he most likely had type 2 diabetes in addition to GCK-MODY. He is currently being treated with metformin and lifestyle measures. The patient’s daughter now has a clear diagnosis to explain her hyperglycemia, which will help in preventing misdiagnosis of type 1 diabetes, given her young age, and will be important for the management of any future pregnancies. She will not need any medical follow-up for GCK-MODY until she is considering pregnancy.

FINAL DIAGNOSIS

Maturity-onset diabetes of the young due to a GCK variant.

Acknowledgments

We thank Dr. Andrew Hattersley and Dr. Sarah Bernstein for helpful comments on an earlier draft of the manuscript.

This case was presented at the Medical Case Conference.

No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org .

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Case report
Open access
Published: 23 April 2024

Genetic exploration of Dravet syndrome: two case report

Agung Triono 1 ,
Elisabeth Siti Herini ORCID: orcid.org/0000-0003-2571-8310 1 &

Journal of Medical Case Reports volume 18 , Article number: 215 ( 2024 ) Cite this article

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Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental comorbidities. This article focuses on manifestations in two Indonesian children with Javanese ethnicity who experienced Dravet syndrome with an SCN1A gene mutation, presenting genetic analysis findings using next-generation sequencing.

Case presentation

We present a case series involving two Indonesian children with Javanese ethnicity whom had their first febrile seizure at the age of 3 months, triggered after immunization. Both patients had global developmental delay and intractable seizures. We observed distinct genetic findings in both our cases. The first patient revealed heterozygous deletion mutation in three genes ( TTC21B , SCN1A , and SCN9A ). In our second patient, previously unreported mutation was discovered at canonical splice site upstream of exon 24 of the SCN1A gene. Our patient’s outcomes improved after therapeutic evaluation based on mutation findings When comparing clinical manifestations in our first and second patients, we found that the more severe the genetic mutation discovered, the more severe the patient’s clinical manifestations.

These findings emphasize the importance of comprehensive genetic testing beyond SCN1A , providing valuable insights for personalized management and tailored therapeutic interventions in patients with Dravet syndrome. Our study underscores the potential of next-generation sequencing in advancing genotype–phenotype correlations and enhancing diagnostic precision for effective disease management.

Peer Review reports

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and comorbidities including intellectual disability, behavioral problems, sleep disturbances, gait disturbances, and an increased risk of sudden unexpected death in epilepsy [ 1 , 2 ]. The incidence of DS is approximately 1 in every 15,700 births [ 3 ]. The first symptom of DS is seizures in the first year of life, followed by developmental delay [ 1 ]. This first seizure is either generalized tonic–clonic or focal (occasionally hemiclonic) clonic, and in more than half of the cases, it is a febrile seizure, making it difficult to distinguish from a self-limiting febrile seizure. Infection, hot environment, exhaust, sunlight, or exercise can initiate an attack of DS [ 4 , 5 ]. Approximately 80% of patients with DS carry a pathogenic variant of the sodium channel alpha 1 subunit ( SCN1A ) gene resulting in haploinsufficiency Nav1.1, the alpha-1 subunit of the sodium channel. PCDH19, SCN2A, SCN8A, SCN1B, GABRA1, GABRB3, GABRG2, KCNA2, CHD2, CPLX1, HCN1A, and STXBP1 variants may also be involved in DS or DS-like phenotypes. Accordingly, genetic testing is required to identify other genes that play a role in the DS phenotype and to expand genotype-DS phenotype correlations to enhance the future management of this disease [ 6 ]. In the last decade, next-generation sequencing (NGS) technology has been able to analyze a set of genes (targeted panel sequencing), exome [(whole exome sequencing (WES)], or genome [whole genome sequencing (WGS)] in a single sequencing process, making it possible to diagnose rare diseases such as early childhood epilepsy [ 7 ]. Identification of the genetic basis of DS can provide additional information regarding pathophysiology, prognosis, and individual drug therapy options according to the patient’s condition.

We present a case series involving two children, one aged 11 years and 2 months, and the other aged 1 year and 4 months. Both children were diagnosed with DS, exhibiting symptoms of intractable seizures, global developmental delay, and seizures triggered by postimmunization fever. Despite displaying similar symptoms, the two individuals possess different genetic variants of the SCN1A gene and also possible novel mutation in DS. We also discuss the main clinical characteristics, treatment course, and management of DS at tertiary referral hospitals in Indonesia.

A boy with Javanese ethnicity aged 11 years and 2 months with uncontrollable seizures regularly visits our hospital. The patient had his first seizure at the age of 3 months with a duration of 15 min, and it was triggered after receiving diphtheria–pertussis–tetanus (DPT) immunization, which was accompanied by fever. The patient has about six to seven seizures per day for 1 min in the form of generalized tonic–clonic and absence seizures. He was the first child of nonconsanguineous healthy parents with normal prenatal and birth history. He has a younger sister with normal development. There is no history of family members with febrile seizure. The patient was born at 40 weeks of gestation, with a birth weight of 4000 g, length of 52 cm, and head circumference of 33 cm. The patient is currently experiencing global developmental delay and is still in kindergarten. He had learning difficulties and was unable to speak words at an age-appropriate level. He had delayed motor development and was unable to perform age-appropriate motor activities. Head circumference was 46.5 cm (microcephaly). There were no signs of meningeal irritation nor Babinski response. The motor examination revealed no increased tone in the upper and lower limb. Other systemic examinations revealed no abnormalities. Interictal electroencephalography (EEG) showed diffuse epileptiform irritative abnormality on a normal background (Fig. 1 ). Magnetic resonance imaging (MRI) of the brain showed cerebral atrophy, bilateral frontal subarachnoid enlargement, bilateral occipital lobe and polymicrogyria, and a neuroglial cyst in the right temporal lobe (Fig. 2 ). He was recommended to get genetic testing done since he was suspected of having DS.

Electroencephalography (EEG) shows diffuse epileptiform irritative abnormality on a normal background

Axial brain magnetic resonance imagery shows cerebral atrophy, bilateral frontal subarachnoid enlargement, bilateral occipital lobe polymicrogyria, and a neuroglial cyst in the right temporal lobe

Whole genome sequencing (WGS), whole exome sequencing (WES), and Sanger sequencing were performed at 3Billion (Seoul, Korea). The WGS and WES procedures were conducted according to the protocols of Richards et al . [ 8 ] and Seo et al . [ 9 ], respectively. Both WES and WGS are comprised of four main parts: (1) high-quality sequencing; (2) sequencing data analysis including alignment to the genome reference consortium human 37 (GRCh37)/hg19 for WES, also alignment to the genome reference consortium human 38 (GRCh38) and revised Cambridge reference sequence (rCRS) of the mitochondrial genome for WGS; (3) variant annotation and prioritization by EVIDENCE [a software that was developed in house to prioritize variants based on the American College of Medical Genetics and Genomics (ACMG) guidelines [ 10 ]]; and (4) variant interpretation in the context of the patient’s symptoms and reporting of disease-causing variants. Once EVIDENCE prioritizes the top candidate variants/genes, 3Billion’s highly-trained clinical/medical geneticists manually curate each variant to identify the disease-causing variant for reporting.

In our initial examination, we performed WES on patient 1 and subsequently identified a copy number variant (CNV), prompting us to proceed with WGS. The WGS analysis revealed a heterozygous pathogenic 552.9 Kb deletion variant in 2q24.3. The heterozygous deletion NC_000002.12:g.165811316_166364199delinsTGTACACTA at 2q24.3 spans across three genes ( TTC21B , SCN1A , and SCN9A ). The variant is not observed in the gnomAD SVs v2.1.1 dataset. SCN1A is subject to haploinsufficiency. Other pathogenic variants have been reported in this region. There are multiple similarly affected individuals reported with similar likely pathogenic copy–number–loss overlapping this region [ 11 , 12 ]. Therefore, this variant was classified as pathogenic. Due to region-spanning mutation in SCN1A, which suitable with clinical manifestation, the patient was diagnosed with DS (OMIM 607208: since we were unable to perform a Sanger sequencing study on both of the parents, the pattern of inheritance is still uncertain.

The arents were counseled about their child’s condition and agreed to undergo multipronged therapy. Before the patient was diagnosed with DS, he had received valproic acid (30 mg/kg per day), phenobarbital (2.5 mg/kg per day), and oxcarbazepine (5 mg/kg per day), also physio, occupation, and speech therapy but had not shown significant improvement. He was seizure-free for 3 months after oxcarbazepine was changed to levetiracetam (27 mg/kg per day). However, the patient then had another episodes of less than 5 minutes general tonic–clonic seizure (GTCS)-induced by fever. Interictal EEG was performed to evaluate his condition, and we found that the diffuse epileptiform irritative abnormality persisted.

A 1 year and 4 month-old-girl with Javanese ethnicity was referred to our hospital due experiencing myoclonic seizure followed by 20 minute GTCS at 3 months, after fever following DPT immunization. She then continued to experience generalized tonic–clonic seizures one to two times per day for 10–15 seconds. At 9 months of age, the patient received a second DPT immunization, and on the same day, she had another generalized tonic–clonic seizure that lasted > 30 minutes, resulting in her admission to the pediatric intensive care unit. Before the first seizure, the patient could lift her head, grasp a toy and make eye contact, but after that, she could neither lift her head nor grasp an object. The patient has no previous history of trauma.

She had a normal head circumference increased physiological reflexes in all extremities. Other systemic examinations revealed no abnormalities. Computed tomography (CT) scan examination of the head showed a subdural hygroma in the right and left frontoparietal region, without any other abnormalities (Fig. 3 ). Electroencephalography (EEG) at the beginning of the seizure did not show any abnormalities, but the EEG follow-up 7 months after the onset of the seizure showed an abnormal epileptiform (spike wave) with a normal background (Fig. 4 ). Thus, she was suspected of having DS and was recommended to undergo genetic examination.

Axial brain computed tomography scan shows a subdural hygroma in the right and left frontoparietal region, without any other abnormalities

Electroencephalography shows abnormal irritative epileptiform with a normal background

Whole exome sequencing (WES) showed a likely pathogenic variant identified as a heterozygous mutation of the SCN1A gene with genomic position 2-166859265-T-C (GRCh37), [NM_001165963.4:C.4003-2A > G [NP_001159435.1:p.?]. The variant is located in the canonical splice site upstream of exon 24 of SCN1A gene (NM_001165963.4 transcript). Since this variant is an essential splicing variant, the protein consequence is uncertain and therefore represented as (p.?). In this patient’s genetic mutation, the canonical junction site occurs which is expected to alter the junction and result in loss or disruption of normal protein function. However, using an in silico predictor, spliceAI ( https://spliceailookup.broadinstitute.org/ ), the variant is predicted to result in a loss of 22 base pairs at end of exon 24. This loss is expected to create a frameshift at the Gly1342 position. Sanger sequencing confirmed the patient’s genotype (Fig. 5 A), but the mother’s Sanger analysis was negative (Fig. 5 B). Due to familial issues, Sanger sequencing was not performed on the father, leaving the inheritance pattern unresolved.

A Sanger sequencing result of patient 2 showed a heterozygous mutation of the SCN1A gene with the genomic position 2-166859265-T-C (GRCh37), [NM_001165963.4:C.4003-2A >G [NP_001159435.1:p.?] (red arrow); and B Sanger sequencing result of patient 2’s mother showed normal sequence

The parents were counseled about their child’s condition and agreed to undergo multipronged therapy. Before patient was diagnosed with DS, she received clonazepam (0.01 mg/kg per day), valproic acid (29 mg/kg per day), and phenytoin (5 mg/kg per day), but seizure persisted. When phenytoin was stopped, with valproic acid (30 mg/kg per day) and clonazepam (0.04 mg/kg per day) adjusted, seizures were greatly decreased. Later, patient only experienced one seizure per year. The patient routinely received physio, speech, and occupational therapy.

When comparing the clinical features and outcomes of the two patients (Table 1 ), we found that our first patient, who had three medications, was still having a generalized seizure induced by fever with duration less than 5 minutes after they had been seizure-free for 3 months (at the age 11 years and 8 months. Our second patient, however, only experienced one seizure annually after receiving two medications (at the age 1 year and 10 months). This difference implies that the clinical state of the first patient was worse than that of the second.

Research on the identification of DS genetic mutations using NGS has never been done in Indonesia. In 2010, we conducted a study to identify pathogenic variants of the SCN1A gene using the Sanger sequencing method and successfully reported cases of novel SCN1A mutations in Indonesia in patients with severe myoclonic epilepsy in infancy (SMEI) and borderline SMEI (SMEB). The first boy identified with SMEI experienced a variety of seizures, including his first febrile seizure and general tonic–clonic seizure at 7 months of age, and later suffered from myoclonic seizures, left-sided hemiconvulsions, also focal convulsions without fever, along with delayed speech development. The second patient with SMEB had his first febrile seizures with GTCS after immunization at 3 months old, then later on experienced status epilepticus, GTCS, and atonic convulsions without fever [ 13 ]. We also conducted another research on the spectrum of generalized epilepsy with febrile seizure plus (GEFS+) focusing on clinical manifestations and SCN1A gene mutations. That study analyzed a total of 34 patients who suffered from SMEI (7 patients), SMEB (7 patients), febrile seizure plus (FS+) and absence/myoclonic/atonic/partial seizures (11 patients), and FS+ (9 patients) [ 14 ].

However, the research that we have done uses the Sanger sequencing genetic examination, which is expensive and takes considerable time. Additionally, it is unable to find any other gene besides SCN1A in patients with DS. A study by Djémié et al . in Belgium reported the discovery of 28 pathogenic variants of the SCN1A gene using the NGS method which were previously missed or undiagnosed using Sanger sequencing [ 7 ]. To link DS cases more effectively, we are attempting to conduct NGS genetic tests, specifically WES and WGS.

Dravet syndrome (DS) was infrequently reported in Indonesia due to its difficulty in diagnosis, misdiagnosis as febrile seizures or other epilepsy syndromes, or lack of follow-up and genetic testing in our country. According to the to the International League Against Epilepsy (ILAE) [ 15 ], the diagnostic criteria for this condition should consist of a number of the following symptoms: (1) a family history of epilepsy or febrile seizures; (2) normal development before seizures onset; (3) seizure before 1 year of age; (4) EEG with generalized spike and polyspike waves; (5) pleomorphic epilepsy (myoclonic, focal, clonic, absence, and generalized seizures); (6) focal abnormalities or early photosensitivity; (7) psychomotor retardation after 24 months; (8) exacerbation of seizures with increased body temperature; and (9) the appearance of subsequent ataxia, pyramidal signs or interictal myoclonus after the beginning of psychomotor slowing. Both of our patients had seizures beginning with increased body temperature and regression of development after seizure onset, which were resistant to the majority of anticonvulsant medications. The seizures began as generalized tonic–clonic seizures, followed by absence seizures. Both of our patients also experienced subsequent ataxia and pyramidal signs. Thus, they were suspected of having DS and were advised to undergo genetic testing.

Infants with DS have normal physical and psychomotor development at the time of their first seizure, which typically occurs between the ages of 5 and 8 months. In our case series, both of our patients experienced their first seizure at the age of 3 months [ 16 , 17 ]. In the first year of life, the most common form of seizure is febrile tonic–clonic. Some patients may experience myoclonic and dyscognitive seizures infrequently. Frequently, protracted seizures result in status epilepticus. In the first year of life, seizures are precipitated by fever/illness, immunization, and cleansing [ 16 ]. As the infant develops, he or she will experience a variety of seizure types, as well as fever and emotional stress, flashes of light, and overexertion being seizure triggers. The child with DS will develop hypotonia, ataxia, incoordination, and pyramidal signs, dysautonomia events, cognitive impairment, and behavioral disturbances such as attention deficit, hyperactivity, or autistic characteristics [ 15 ]. Some of the conditions above are very consistent with what happened to our patients.

The EEG performed during the early phases of the disease is normal. However, as the child grows, generalized spike waves with isolated or brief discharges of fast polyspike waves may be present [ 15 , 18 ]. In the first case, we found diffuse epileptiform irritative abnormality with a normal background, whereas in the second case, initially it was found normal, then a few months later it became abnormal irritative epileptiform with a normal background.

Genetic testing is developing rapidly and playing a significant role in the specific diagnosis and management of epilepsy [ 19 , 20 ]. Several genes with pathogenic mutations produce DS or DS-like phenotypes, which inevitably require different drug therapy approaches. Genes that cause DS can be grouped based on how they work: specifically, three sodium channel-related genes ( SCN2A, SCN8A , and SCN1B ), one potassium channel-related gene ( KCNA2 ), three gamma-aminobutyric acid receptors ( GABAR ) genes ( GABRA2, GABRB3 , and GABRG2 ), a cyclic nucleotide gated cation channel gene ( HCN1 ), and other functional genes including CHD2, CPLX1 , and STXBP1 . Approximately 80% of patients with DS have a pathogenic variant of the SCN1A gene, from which the majority of SCN1A variants are de novo, but 10% of people inherit the SCNA1 mutation from one or both parents [ 6 ]. Both of our patients had a mutation in the SCN1A gene, which is the most common mutation seen in DS.

Furthermore, TTC21B and SCN9A mutations were also found in our first patient. A study conducted by Suls et al . also reported a four generation Bulgarian family with epilepsy, revealing a heterozygous 400 kb deletion on chromosome 2q24 that included the SCN1A and TTC21B genes [ 21 ]. The patients exhibited variable phenotypes, but all experienced generalized tonic–clonic seizures around the first year of life, with some presenting myoclonic or absence seizures. Febrile seizures occurred in three of the four patients during infancy. Notably, one patient had mild mental retardation, another had psychomotor slowing, and a third had mental retardation from early infancy; all showed reduced seizures on medication. The findings in that study parallel the situation observed in our initial patient case. Meanwhile, a study by Singh et al . identified a heterozygous mutation in the SCN9A gene in two patients diagnosed with DS [ 22 ]. One of these patients also exhibited a mutation in the SCN1A gene. The study provided evidence suggesting that the SCN9A gene on chromosome 2q24 could potentially serve as a modifier for DS. Among 109 patients with DS, 8% were found to have an SCN9A mutation. This included six patients with double heterozygosity for SCN9A and SCN1A mutations and three patients with only heterozygous SCN9A mutations, supporting the notion of a multifactorial inheritance pattern [ 22 ]. The previous research confirmed the severity of clinical symptoms in our first patient, whom we identified mutations in the SCN1A, SCN9A , and TTC21B genes.

In the last decade, there has been a very rapid development of neurogenetic science and diagnostic technology. NGS is the latest method of genetic examination that allows for the discovery of causal mutations, including de novo, novel, and familial mutations related to epilepsy syndromes that have variable phenotypic features [ 23 ]. The first generation of DNA sequencing using the Sanger method could only examine one gene at a time and had limitations especially when examining large genomic regions, so the NGS method is more widely used today [ 7 , 23 ]. A study conducted by Kim et al . in Seoul reported an increase in diagnostic yield using WES after targeted panel sequencing with negative results in infantile onset epilepsy by 8%. This result suggests that WES assays increase the opportunity to search for new epilepsy genes and uncover less well-known epileptic phenotypes from known neurological diseases [ 24 ]. The WES examination also allows for the discovery of de novo or inherited mutations if the patient and both parents are examined [ 25 ].

According to the recommendations of the North American consensus panel, clobazam and valproic acid are the first-line therapies for antiepileptic drugs, followed by stiripentol, topiramate and levetiracetam. Patients with a suboptimal response to clobazam and valproic acid have been advised to consider the ketogenic diet as a second-line treatment [ 17 ]. SCN1A is a gene that codes for sodium channel channels, so drugs that work as sodium channel blockers, such as lamotrigine, phenytoin, carbamazepine, oxcarbazepine, lacosamide, and rufinamide, are contraindicated in patients with DS because they can increase the frequency of seizures [ 4 ]. After the failure of first- and second-line therapy, surgical therapies, such as vagus nerve stimulation (VNS), were moderately agreed upon and should be considered [ 17 ]. Besides medication, controlling infections and body temperature variations also showed to decrease the frequency of seizures and severity of the disease [ 18 ]. Initially, the first patient received oxcarbazepine and the second patient got phenytoin, which had been contraindicated to patients with DS. Futhermore, after eliminating medications that were contraindicated, both patients’ outcome improved.

In this study, we discovered unique mutations that have never been documented before, particularly in Indonesia, where NGS analysis of DS genetic variants has never been done. However, the limitation of this study, is that the information comes from two cases only. Further research is needed to explore more cases from Indonesia population.

In summary, our case series utilizing next-generation sequencing (NGS) unveils the intricate genetic landscape of Dravet syndrome (DS) in two Indonesian pediatric cases. By using WGS and WES, we identified distinct mutations in the SCN1A gene, as well as contributions from genes, such as TTC21B and SCN9A . The power of WGS lies in its ability to uncover rare pathogenic variants, including a 552.9 Kb deletion in the 2q24.3 region. These findings emphasize the importance of comprehensive genetic testing beyond SCN1A , providing valuable insights for personalized management and tailored therapeutic interventions in patients with DS. Our study underscores the potential of NGS in advancing genotype–phenotype correlations and enhancing diagnostic precision for effective disease management. Furthermore, we found that the clinical condition of the first patient was worse than that experienced by the second patient. This difference suggests that the more severe the genetic mutation detected, the more severe the clinical manifestations of the patient.

Availability of data and materials

The dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

American College Of Medical Genetics

Copy number variant

Computed tomography

Dravet syndrome

Developmental and epileptic encephalopathy

Electroencephalography

Febrile seizure plus

Generalized epilepsy with febrile seizure plus

Genome reference consortium human 37

Genome reference consortium human 38

General tonic clonic seizure

International league against epilepsy

Magnetic resonance imaging

Next-generation sequencing

Revised Cambridge reference sequence

Sodium channel alpha 1 subunit

Severe myoclonic epilepsy of infancy-borderline

Severe myoclonic epilepsy in infancy

Vagus nerve stimulation

Whole-exome sequencing

Whole-genome sequencing

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Acknowledgements

The authors express their gratitude to the patient and their families for their cooperation, as well as to all the staff and nurses who provided care for the patient. We are also thankful for the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada for funding this research and providing English editing services for assistance in the editing and proofreading process. Additionally, we appreciate the assistance of Kristy Iskandar, Marissa Leviani Hadiyanto and Khansadhia Hasmaradana Mooiindie during the data collection and editing phases.

This study was supported by the Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, (Dana Masyarakat to ESH). The funding body did not influence the study design, data analysis, data interpretation, nor manuscript writing.

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Agung Triono & Elisabeth Siti Herini

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ESH, AG, and G made substantial contributions to the conception and design of the work. AG contributed to data acquisition. ESH, AG, and G performed the data analyses and the interpretation of the data. ESH and AG drafted the text and prepared the figures. ESH, AG, and G revised, read, and approved the final manuscript. All authors approve the present version for publication, and are accountable for all aspects related to the study.

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Triono, A., Herini, E.S. & Gunadi Genetic exploration of Dravet syndrome: two case report. J Med Case Reports 18 , 215 (2024). https://doi.org/10.1186/s13256-024-04514-2

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Sudden unexpected postnatal collapse and BUB1B mutation: first forensic case report

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Massimiliano Esposito ORCID: orcid.org/0000-0001-7880-3450 1 ,
Francesco Sessa 2 ,
Chiara Nannola 3 ,
Maria Serenella Pignotti 4 ,
Pantaleo Greco 5 &
Monica Salerno 2

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Sudden unexpected postnatal collapse (SUPC) is a sudden collapse of the clinical conditions of a full-term or near-term newborn, within the first 7 days of life, that requires resuscitation with positive ventilation and who either dies, has hypoxic-ischemic encephalopathy, or requires intensive care. The incidence of SUPC is very low, and most often presents a negative prognosis. The BUB1B gene is a mitotic checkpoint of serine/threonine kinase B that encodes a protein crucial for maintaining the correct number of chromosomes during cell division. Mutations in the BUB1B gene are linked to mosaic variegated aneuploidy syndrome 1 (MVA1), a rare autosomal recessive disorder characterized by diffuse mosaic aneuploidies involving several chromosomes and tissues. This paper discusses a case of a newborn who had a spontaneous delivery. After 2 h and 10 min, the infant showed generalized hypotonia and cyanosis, and his doctors performed orotracheal intubation, cardiac massage, pharmacological hemodynamic therapy, mechanical ventilation, antibiotic therapy, and hypothermic treatment. The newborn was discharged after 5 months with the diagnosis of hypoxic-ischemic encephalopathy. Suspecting an SUPC, a complete genetic analysis was performed demonstrating a compound heterozygous mutations in the BUB1B gene. The newborn died at 6 months of life, 1 month after discharge. A complete autopsy was performed, determining that the cause of death was due to sepsis starting from a brocopneumonic process, with outcomes of hypoxic-ischemic encephalopathy (HIE). In this scenario, it is not possible to demonstrate the causal effect of this mutation, considering that it could play a causal or concausal role in the onset of SUPC. Further research based on multicenter studies, as well as on animal models, could be very useful to clarify the pathological effect of this mutation.

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Introduction

Sudden unexpected postnatal collapse (SUPC) is a sudden collapse of the clinical conditions of the full-term or almost full-term newborn, within the first 7 days of life, who requires resuscitation with positive ventilation and who either dies, presents hypoxic-ischemic encephalopathy, or requires therapy intensive [ 1 ]. The incidence of SUPC is very low and very often has a negative prognosis [ 2 , 3 , 4 ].

According to a study conducted in Karolinska University Hospital, Stockholm, Sweden, the incidence of SUPC is greatly underestimated, ranging from 2.6 cases to 133 cases/100,000. About half of the children die and of the remaining survivors half die of neurological sequelae. In more than half of cases, SUPC cannot be traced back to an etiological event [ 1 ]. The first 2 h of life are the period of greatest risk for SUPC, coinciding with breastfeeding and uninterrupted skin-to-skin contact between a mother and her newborn. SUPC is associated with prone position/skin-to-skin/co-bedding in 74% [ 5 ].

The present case report describes for the first time a case of SUPC in which an autopsy and comprehensive genetic investigation was performed and demonstrated a mutation of the BUB1B gene.

The gene family known as Budding Uninhibited By Benzimidazoles (BUB1, BUB1B, and BUB3) plays a crucial role in the spindle checkpoint during mitosis. BUB1 is essential for tasks such as chromosome congression, kinetochore localization, and establishing/maintaining efficient bipolar attachment to spindle microtubules. Acting as a paralogous gene to BUB1, BUB1B associates with unattached or incorrectly attached kinetochores, stabilizes kinetochore-microtubule attachment, and contributes to proper chromosome alignment. BUB1B is a gene involved in chromosome segregation, particularly during anaphase, through the regulation of the spindle assembly checkpoint (SAC) [ 6 , 7 ]. BUB1B, therefore, is also directly implicated in chromosome alignment. In humans, a reduced expression of BUB1B is correlated with spontaneous abortions or the onset of hereditary colorectal cancer, microcephaly, intellectual disability, developmental delay and some patient-specific phenotypic abnormalities, through mosaic variegated aneuploidy (MVA) [ 8 , 9 ]. The BUB1B gene mutation is extremely rare and very few studies have been published on humans. To date, there is no gender more predisposed to the BUB1 and subsequent MVA1 mutation, also because the mutation is rare and there are no studies that establish with certainty a difference in the expression of the mutation in males and females [ 10 ].

The present clinical case is the first case of SUPC related to the BUB1B mutation. Given the rarity not only of SUPC but above all of the BUB1B mutation, the aim of this case report is to inform the scientific community of the possibility of a correlation between the BUB1B mutation and the onset of a SUPC with consequences of hypoxic-ischemic encephalopathy. The genetic investigation conducted on the child was performed since it is an integral part of the clinical and forensic path in affected children who died after a SUPC [ 1 , 11 ]. Furthermore, genetic investigation is crucial in cases of infant deaths, being increasingly used in forensic practices, and making an important contribution in establishing the cause of death [ 12 , 13 , 14 , 15 ].

Case description

A 29-year-old woman was at her 38th week of gestation in her first pregnancy and went to the emergency department because of a ruptured membrane. The pregnancy had progressed normally, she had undergone screening procedures at the I, II, and III trimester of pregnancy as per guidelines [ 16 ], and antibiotic prophylaxis for Streptococcus agalactiae. The fetus was in a cephalic position, with normal fetal heartbeats. The cardiotocogram examination was performed and was normal. Then, the physiological birth took place with subsequent follow-ups.

The infant was born with a weight of 3860 g, length 50 cm, and head circumference 35 cm. The APGAR score was 6 in the first minute and 10 in the fifth and tenth minutes. The newborn was transferred to the ward with the mother in normal clinical conditions. After 2 h and 10 min, the infant showed generalized hypotonia, cyanosis, and his doctors performed orotracheal intubation, cardiac massage, pharmacological hemodynamic therapy, mechanical ventilation, antibiotic therapy, and hypothermic treatment. The newborn was hospitalized for 5 months and was discharged home with the diagnosis of hypoxic-ischemic encephalopathy. He died 6 months later.

Genetic investigation

The genetic analysis was conducted at the Bambino Gesù pediatric hospital (Rome, Italy). The DNA was extracted from the peripheral blood of the proband and the parents. The analysis focused on the coding regions and exon-intron junctions (± 5 bp) of genes associated with known clinical conditions (see supplementary file). Next Generation Sequencing (NGS) was performed in trio using the Twist Custom Panel (clinical exome - Twist Bioscience) kit on the NovaSeq6000 platform (Illumina). The analytical sensitivity and specificity were > 99%. The average coverage of the sequenced regions was 257.70X. For the interpretation of the results, only regions with a minimum read depth of 30X were considered.

Sanger sequencing was then used to validate WES results. NGS data analysis was carried out using BWA (Aligner) 0.6.1-r104-tpx or DRAGEN Germline. The clinical interpretation of genomic variants was done by Geneyx Analysis (Knowledge-Driven NGS Analysis tool powered by the Gene Cards Suite). Variants were classified as pathogenic/likely pathogenic/VUS/likely benign/benign, according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines [ 17 ]. Prediction of pathogenicity of non-synonymous variants was determined by in silico tools such as Sift, Provean, MutationTaster, and Regulation Spotter.

The sequence analysis revealed the heterozygous compound variants c.580 C > T and c.2309G > A in the BUB1B gene, which at the protein level result in the introduction of the premature stop codon p.Arg194Ter (rs28989186), and the amino acid change p.Arg770Gln (rs1422532977), respectively. The premature stop codon p.Arg194Ter (rs28989186) was found in heterozygosity in the father’s DNA, while the amino acid change p.Arg770Gln (rs1422532977) was found in heterozygous in the maternal’s DNA. The nonsense variant p.Argl94Tcr, segregating paternally, has an allelic frequency of 0.00001064 in the general population (gnomAD), is reported in scientific literature [ 18 ], and annotated in the ClinVar database (ID: 6760) and can be classified according to ACMG guidelines as pathogenic variant (class 5). The missense variant p.Arg770Gln (rs1422532977), obtained from maternal chromosome segregation, has an allelic frequency of 0.000003991 in the general population (gnomAD), is not reported in scientific literature, is annotated in the ClinVar database (ID: 1,436,353) and can be classified according to ACMG guidelines as a variant of uncertain significance (VUS) (class 3), i.e., with undefined functional and clinical effects.

Autopsy findings

A complete autopsy was performed, and the cadaver weighed 4443 g. Neonatal growth indices were measured (Table 1 ). The newborn had a percutaneous endoscopic gastrostomy on the abdomen. The evisceration of the organs was performed using the Letulle technique [ 19 ]. Organs were preserved and fixed in 10% buffered formalin. On macroscopic examination the brain had a reduced consistency.

While the left lung measured 9.5 × 8 × 4 cm, it weighed 87 g. The right lung measured 10.5 × 7 × 3.8 cm, weighed 87 g and showed: in the middle lobe a subpleural bullae measuring 1 × 0.8 cm, in the inferior lobe subpleural bullae measuring 2 × 1.9 cm, and in the lower lobe, two subpleural bullaes 2 × 0.9 cm and 2 × 1.5 cm (Fig. 1 ).

Subpleural bullae of the right lung

Histological investigation

Tissue samples were first dehydrated in graded ethanol, and then clarified in xylene and embedded in paraffin. Paraffin blocks were obtained and cut to a thickness of 4 μm, by a microtome and, finally, and sections were mounted on silane-coated slides (Dako, Glostrup, Denmark) were prepared and stored at the standard temperature room. The sections were then stained with hematoxylin and eosin (H&E). The Zeiss Axioplan (Carl Zeiss, Oberkochen, Germany) was used as an optical microscope, and then images were extracted through the Zeiss AxioCam MRc5 digital camera (Carl Zeiss, Oberkochen, Germany). The heart samples displayed foci of contraction band necrosis, and waviness. Lung sampling showed outbreaks of bronchopneumonia with septic emboli, acute emphysema, and edema (Fig. 2 ). Brain samples showed signs of stasis and edema. Histological samples of the liver, kidney, pancreas, intestine, spleen and adrenal glands were also performed and did not show any pathological elements.

The cause of death was due to sepsis starting from a brocopneumonic process, in a 6-month-old patient suffering from hypoxic-ischemic encephalopathy (HIE) due to SUPC.

H&E 50x. Lung, septic emboli

SUPC is defined as the collapse of the clinical conditions of a term or near-term newborn, in good clinical condition, who has an Apgar score > 8 at the tenth minute and who, suddenly and unexpectedly, manifests apnea, acute cyanosis or paleness, requiring resuscitation support characterized by cardio-pulmonary resuscitation with, more or less, oro-tracheal intubation [ 20 ]. The British Association of Perinatal Medicine has defined SUPC as a sudden collapse of the clinical condition of the full-term or near-term newborn, who, within the first 7 days of life, assigned to routine postnatal care, requires resuscitation with positive ventilation and who either dies, or has hypoxic-ischemic encephalopathy, or requires intensive care in an NICU [ 21 ].

Most cases of SUPC occur within the first 24 h of life: 36% within the first 2 h after birth, 29% between 2 and 24 h after birth, while 24% occur between 24 and 72 h after birth and 9% between the 4th and 7th day of life. There are only approximately 2,000 cases described in the literature reporting a widely varying incidence of SUPC, with estimates ranging from 1.92 per 100,000 live births to 38 per 100,000. The prognosis is, most of the time, negative, with a mortality rate of 50% of cases and, with the same frequency, they are inexplicable [ 1 , 22 ].

The timing of SUPC onset is very varied, some authors maintain that it develops in the first 24 h of life, others, however, maintain from 0 to 7 days of life, others, such as Becher et al. [ 23 ] stated that the manifestation appears within the first two hours of life in 73% of cases. A recent article reported five cases of SUPC in which all the newborns were full-term (36 to 38 weeks of gestation), born by vaginal delivery (4 cases) or by cesarean Sect. (1 case), with a collapse that occurred within 2.5 h of birth [ 24 ].

In the present clinical case, the newborn was born from a full-term pregnancy (38 + 2 weeks of gestation), with an Apgar score of 10/5 and a sudden collapse of clinical conditions 2 h after birth. Therefore, according to the criteria established by the guidelines [ 21 ], a diagnosis of SUPC was established.

One of the most common risk factors is uncontrolled skin-to-skin contact between the mother and newborn. In fact, during the first breastfeeding there is skin-to-skin contact between mother and newborn in the prone position [ 5 ]. According to some studies, however, it has not yet been clarified that this could lead to a risk factor for SUPC due to the asphyxial mechanism, in fact, some authors recommend carrying out nursing monitoring in this phase [ 24 ]. Even unmonitored skin-to-skin contact can constitute a risk factor, very little is known about the etiology of SUPC, which most of the time remains unknown, as newborns do not have problems related to prematurity and low Apgar scores at birth [ 20 ]. Becher et al. [ 23 ] state, in fact, that SUPC is rare in any center and there is no standard approach to investigations. In cases where collapse is not due to an underlying abnormality, breastfeeding and prone positioning are important associations.

In the present study, a diagnosis of SUPC was made through retrospective analysis of the medical records. Then a complete autopsy was performed showing the findings of an HIE with bronchopulmonary septic emboli. Finally, a complete genetic analysis was made that showed a mutation in the BUB1B gene.

Regarding the autopsy and histopathological-forensic findings of the outcomes of a HIE, it is consistent with other studies, since many of the newborns with SUPC die from hypoxic-ischemic encephalopathy. Indeed, Pejovic NJ et al. [ 7 ], showed that out of 26 cases of SUPC, 5 had HIE treated by hypothermia. However, to date, there are no published case reports in which a complete autopsy of a newborn with SUPC was performed, this, in fact, would be the first.

However, the finding of the BUB1B mutation has been identified for the first time. There are no studies that correlate the mutation of the BUB1B gene with SUPC, so it is not possible to establish a causal relationship between the two events, but it is important to report this to the scientific community.

Mutations in the BUB1B gene are associated with MVA1 and involve different chromosomes and tissues. MVA1 is typically related to problems during pregnancy (IUGR), neonatal (postnatal growth retardation and severe neurological damage including microcephaly) and development (developmental delay/cognitive disability, epileptic seizures and generalized hypotonia, different types of neoplasms) [ 25 ]. In mice, mutations in the BUB1B gene cause the onset of oncogenesis. A surveillance mechanism linking loss of BUB1B to the activation of the p53 pathway, promoting oncogenesis, has recently been reported [ 26 ]. Specifically, the most frequently encountered neoplasms are colorectal cancer, lung cancer, pancreatic cancer, but also thyroid follicular adenoma, leukemia, and glioblastoma [ 27 , 28 , 29 , 30 ]. A recent study also correlated the mutation of the BUB1B gene with the onset of pediatric neuroblastoma, bladder cancer, breast cancer, and endometrial carcinoma [ 31 , 32 , 33 , 34 ]. A published case report giving the clinical history of an Italian girl with a karyotype showing 12% mosaics with a new variant of the BUB1B gene (c.2679 A > T, p.Arg893Ser). The girl was two years old and presented with severe neurological disorders, microcephaly and epileptic seizures [ 35 ]. Another case report involved a child who, at 6 months of age, showed severe developmental delay, microcephaly, hypotonia, intractable seizures including infantile spasms with hypsarrhythmia, and Dandy-Walker malformation on MRI. Notably, the seizures were resistant to antiepileptic therapy and adrenocorticotropic hormone treatment. The authors concluded that knowledge of this genetic disease is important not only for a correct diagnosis but also for family genetic counseling [ 36 ]. In the present case, in fact, the child’s parents were informed during the hospital stay of the possible reappearance of the same mutation in future pregnancies, clarifying the possibility to perform a prenatal diagnosis.

In this manuscript, SUPC was followed by a 5-month hospitalization in which the infant experienced numerous healthcare-related infections from various microorganisms, including Staphylococcus epidermidis, Staphylococcus Homini, Candida Albicans, and Klebsiella Pneumoniae. Blood cultures were negative for Pneumocystis carinii. The infectious picture was also demonstrated through CT and chest x-ray. However, these infections were treated with appropriate antibiotics after susceptibility testing. After 5 months, laboratory tests were normal and the child did not have any infection but only bacterial contamination. The pulmonary findings examined showed pulmonary bulae. However, it would appear that bulae are attributable more to the long duration of hospitalization and the outcomes of nosocomial pulmonary infections, rather than to the genetic BUB1 mutation. Also Fig. 2 shows “hyphae” attributable to Candida Albicans infection.

The present case report showed the heterozygous compound variants in the BUB1B gene, which, at the protein level, result in the introduction of the premature stop codon and the amino acid change. Although the first mutation can be classified according to ACMG guidelines as a pathogenic variant, the other mutation can be classified as a VUS. In this scenario, it is not possible to demonstrate the causal effect of this mutation, considering that it could play a causal or concausal role in the onset of SUPC.

However, due to the rarity of the two pathologies (BUB1B mutation and SUPC), their relationship can be hypothesized but is not certain. Therefore, the aim of this case report is to inform the scientific community of a possible correlation between the two conditions, indicating that further studies are needed to confirm this. Moreover, in newborns who die from or following a SUPC it is necessary to perform an autopsy or a hospital autopsy complete with genetic investigation, as important elements could emerge capable of contributing to the knowledge of both the SUPC and the BUB1B mutation as well as the possible correlation between these two.

SUPC is a condition characterized by sudden post-natal collapse in newborns born to full-term mothers in good clinical condition. The etiology is almost completely unknown and very few autopsies have been performed on these newborns. Unfortunately, the lack of autopsy findings in these newborns and the absence of complete genetic investigations contribute to making this pathology poorly known. The present study reports, for the first time, the autopsy and genetic findings of an infant born with SUPC who showed both HIE outcomes and a BUB1B mutation. The genetic mutation of BUB1B is an extremely rare disease associated with MVA1 that leads to the onset of serious pathologies during pregnancy, as well as during the neonatal and growth period. The only experimental studies concern mouse models, while only very few clinical cases are published on human models. This means that it is an almost completely unknown genetic mutation, especially from a clinical point of view. It is not possible to establish with certainty whether the genetic alterations detected had a causal or concausal role in the onset of SUPC as there are only reports of individual case series or studies on mouse models. However, one aspect of the case report is to describe the forensic findings of an SUPC death in a patient with a BUB1B mutation, highlighting the importance of a multidisciplinary (genetic and forensic) approach. Furthermore, the aim of the presentation is also to study the genetic mutation and its implications, also with the aim of evaluating, through follow-up, the implications in the couple’s future pregnancies.

Data availability

All data are included in the main text.

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The authors thank the Scientific Bureau of the University of Catania for language support.

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Massimiliano Esposito

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Research Article

Scoping review of hearing loss attributed to congenital syphilis

Roles Data curation, Writing – original draft, Writing – review & editing

Affiliation Department of Pediatrics, Queen’s University, Kingston, Ontario, Canada

Roles Data curation, Formal analysis, Writing – review & editing

Affiliation Research Investigator, University of Alberta, Edmonton, Alberta, Canada

Roles Data curation, Writing – review & editing

Affiliation Department of Nursing, University of Alberta, Edmonton, Alberta, Canada

Affiliation Department of Anesthesiology, University of Alberta, Edmonton, Alberta, Canada

Roles Conceptualization, Formal analysis, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

Roles Conceptualization, Data curation, Project administration, Supervision, Writing – original draft, Writing – review & editing

Affiliation Division of Otolaryngology-Head & Neck Surgery, University of Alberta, Edmonton, Alberta, Canada

Aleena Amjad Hafeeez,
Karina Cavalcanti Bezerra,
Zaharadeen Jimoh,
Francesca B. Seal,
Joan L. Robinson,
Nahla A. Gomaa

Published: April 26, 2024
https://doi.org/10.1371/journal.pone.0302452
Peer Review
Reader Comments

There are no narrative or systematic reviews of hearing loss in patients with congenital syphilis.

The aim of this study was to perform a scoping review to determine what is known about the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis.

Eligibility criteria

PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), Proquest Dissertations and Theses Global, and SCOPUS were searched from inception to March 31, 2023. Articles were included if patients with hearing loss were screened for CS, ii) patients with CS were screened for hearing loss, iii) they were case reports or case series that describe the characteristics of hearing loss, or iv) an intervention for hearing loss attributed to CS was studied.

Sources of evidence

Thirty-six articles met the inclusion criteria.

Five studies reported an incidence of CS in 0.3% to 8% of children with hearing loss, but all had a high risk of bias. Seven reported that 0 to 19% of children with CS had hearing loss, but the only one with a control group showed comparable rates in cases and controls. There were 18 case reports/ case series (one of which also reported screening children with hearing loss for CS), reporting that the onset of hearing loss was usually first recognized during adolescence or adulthood. The 7 intervention studies were all uncontrolled and published in 1983 or earlier and reported variable results following treatment with penicillin, prednisone, and/or ACTH.

Conclusions

The current literature is not informative with regard to the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis.

Citation: Amjad Hafeeez A, Cavalcanti Bezerra K, Jimoh Z, Seal FB, Robinson JL, Gomaa NA (2024) Scoping review of hearing loss attributed to congenital syphilis. PLoS ONE 19(4): e0302452. https://doi.org/10.1371/journal.pone.0302452

Editor: Bolajoko O. Olusanya, Center for Healthy Start Initiative, NIGERIA

Received: October 6, 2023; Accepted: April 2, 2024; Published: April 26, 2024

Copyright: © 2024 Hafeeez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data are in the manuscript and/or supporting information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum . If not recognized and treated early in pregnancy, fetal transmission commonly occurs [ 1 ]. According to the international Joint Committee on Infant Hearing, congenital syphilis (CS) is a risk indicator for hearing loss [ 2 , 3 ]. The Centers for Disease Control and Prevention state: “Otosyphilis is caused by an infection of the cochleovestibular system with T . pallidum and typically presents with sensorineural hearing loss, tinnitus, or vertigo. Hearing loss can be unilateral or bilateral, have a sudden onset, and progress rapidly.” ( Neurosyphilis, Ocular Syphilis, and Otosyphilis ( cdc.gov ) ). Almost all cases of CS are treated with penicillin which is not known to be ototoxic.

For decades, congenital syphilis had almost disappeared in Canada and the United States due to low rates of syphilis in the community and universal prenatal screening.. The number of cases of confirmed early congenital syphilis born to women aged 15–39 years in Canada rose from 17 cases in 2018 to 117 in 2022 [ 4 ]. Trends in the United States (US) mirror this with an increase from 1325 congenital syphilis cases in 2018 to 3755 in 2022 [ 5 ].

The recent resurgence has increased interest in the clinical manifestations and complications of congenital syphilis. There are no published data summarizing the incidence or characteristics of hearing loss due to congenital syphilis. Despite the larger number of cases now occurring in Canada and the US, there are no evidence-based guidelines on screening or management of hearing loss in children with congenital syphilis. We therefore performed a scoping review. Our specific questions were:

How often is hearing loss due to congenital syphilis?
What is the incidence of hearing loss in children with congenital syphilis?
When hearing loss occurs from congenital syphilis, what is the usual age of onset? Is it unilateral or bilateral? How severe is it? How rapidly does it progress?
Is there evidence for any interventions for treatment of hearing loss attributed to congenital syphilis?

This will inform the studies that need to be done to determine the incidence and age of onset of hearing loss from CS, the severity of hearing loss, and interventions that warrant further study.

The methodology was based on the Preferred Reporting Items for a Systematic Review and Meta-analysis Extension for Scoping Reviews: The PRISMA-ScR statement [ 6 ] (See attached S1 Checklist ). A search was executed by a health librarian on the following databases: PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), Proquest Dissertations and Theses Global, and SCOPUS using controlled vocabulary (e.g.: MeSH, Emtree, etc.) and selecting key words representing the concepts “congenital syphilis" or "hearing loss” ( S1 Appendix ). Databases were searched from inception to October 17, 2021, with an updated search to March 31, 2023.

Articles were included if they described persons of any age with hearing loss that the authors of the article attributed to congenital syphilis. To delineate the burden and incidence of hearing loss from congenital syphilis, we included any studies that i) screened children with hearing loss for evidence of congenital syphilis or ii) screened children with congenital syphilis for hearing loss. We also included randomized controlled trials (RCTs), cross-sectional studies, case series, and case reports that described the characteristics of hearing loss, the long-term outcomes of hearing loss, or the results of any interventions for hearing loss. We excluded autopsy reports, animal studies, studies focusing solely on acquired syphilis and those published in a language other than English, French, or Portuguese.

Articles published in English were screened by two reviewers independently [AH, KC], and conflicts were resolved by a senior author [JR, NG]. Articles published in French had a single reviewer [FS]. There were no articles published in Portuguese. Because of the small number of recent articles, preprints were included. The protocol has not been published.

Studies were divided into four types: i) those that screened patients with hearing loss for congenital syphilis, ii) those that screened patients with congenital syphilis for hearing loss, iii) case reports or case series that describe the characteristics of hearing loss in patients with congenital syphilis, and iv) studies that describe an intervention for hearing loss attributed to congenital syphilis. Data were collected and managed using Research Electronic Data Capture (REDCap) tools [ 7 ] hosted at the University of Alberta with the extracted data determined by the study type. Data were entered by a single investigator. The JBI critical appraisal tool was used as appropriate to assess all included studies [ 8 – 11 ] ( S2 Appendix ). The critical appraisal and bias risk assessment was completed by a single reviewer [NG], and all studies were rated as high, unclear or low risk of bias.

The search yielded 1983 records of which 832 were duplicates. Screening led to 159 records for full-text review of which 36 met inclusion criteria ( Fig 1 ). The figure outlines the reasons for exclusion of other records.

PPT PowerPoint slide
PNG larger image
TIFF original image

https://doi.org/10.1371/journal.pone.0302452.g001

Screening of patients with hearing loss for congenital syphilis

There were 5 studies where patients with hearing loss were screened for CS. They were published from 1900 to 1990 and all had a high risk of bias (Tables 1 and 2 ). The incidence of CS ranged from 0.3% to 8% in children attending schools for the hearing impaired and was 2% in children seen at a clinic for the hearing impaired.

https://doi.org/10.1371/journal.pone.0302452.t001

https://doi.org/10.1371/journal.pone.0302452.t002

Screening of patients with CS for hearing loss

There were 7 studies of which 4 were published from 2016 to 2022 ( Table 3 ). The risk of bias was high for 1, unclear for 3, and low for 3. Hearing loss was reported in 0 to 19% of children with probable or proven CS. One study from the modern era showed an incidence of 6% (22/342) (12). However, a small recent study reported no hearing loss for 7 infants treated in utero, a 5% incidence for 37 treated at birth, and a 6% incidence in 49 controls [ 23 ].

https://doi.org/10.1371/journal.pone.0302452.t003

Case series and case reports of hearing loss attributed to CS

There were 10 case series (one of which was also included in Table 2 ) ( Table 4A ) and 8 case reports ( Table 4B ) of which all but 6 were published prior to 1980. The risk of bias was high for 5 articles, unclear for 3 and low for 10. In these reports, hearing loss was often first noted in adolescence or adulthood with the youngest being 5 years old at diagnosis. Many cases also had interstitial keratitis. Follow-up was too variable to allow determination of the expected rate of progression of hearing loss. A wide variety of therapies are reported with small numbers of patients and inconsistent results that were often subjective.

A ‐ Case series of hearing loss attributed to congenital syphilis. B ‐ Case reports of hearing loss attributed to congenital syphilis.

https://doi.org/10.1371/journal.pone.0302452.t004

Studies with interventions for hearing loss

The 7 studies included a range of 6 to 39 patients with the most recent one being from 1983 ( Table 5 ). All were observational. Most commonly patients were prescribed penicillin with addition of prednisone followed by ACTH if response was poor or transient. Outcomes were often subjective and inconsistent. Risk of bias was unclear for 5 studies and low for 2 studies.

https://doi.org/10.1371/journal.pone.0302452.t005

The scoping review shows that studies of hearing loss due to congenital syphilis are limited and low quality. All but one study reported as a pre-print [ 23 ] are observational studies and only 15 of 36 studies (42%) were at low risk of bias. One cannot determine the incidence or characteristics of hearing loss from congenital syphilis or the efficacy of interventions from this review. It seems unlikely that a systematic review would find further studies that could answer these questions.

As expected, there were major variations in the study methodologies employed to diagnose hearing loss. In the early 1900s, investigators used basic tuning fork tests and subjective behavioral responses [ 24 ]. Studies performed after the year 2000, used full diagnostic tests or Auditory Brainstem Responses (ABR) for neonates [ 21 ].

A small percentage of children attending schools for the hearing impaired had evidence of congenital syphilis. However, these data are of limited value without a control group from the same jurisdiction. The percentage of hearing loss that is due to congenital syphilis no doubt varies considerably by country and over time.

It is perhaps unexpected that almost all case reports and case series describe recognition of hearing loss only in adolescence or adulthood. It is possible that hearing loss started years prior but was not recognized, particularly, if the hearing loss was slowly progressive. The major problem with all these reports is that they do not exclude the possibility that the patient had acquired syphilis or had another etiology for their hearing loss.

Clearly, there is paucity of up-to-date literature regarding this important health problem. The majority of articles were published before 1980. The recent surge in congenital syphilis cases in Canada and the United States may lead to further studies. Recent results from neonatal hearing screening programs in low- or middle-income countries where the incidence of congenital syphilis never waned are informative. Besen reported screening 21,434 newborns in Brazil 2017 through 2019 and reported a prevalence of test failure in the Universal Neonatal Hearing Screening Program (UNHS) of 1.6% (95% CI: 1.4; 1.8). This study used Otoacoustic Emission and ABR to identify both cochlear and retrocochlear damage. They report that 1.7% (95% CI: 1.5; 1.8) had congenital syphilis but do not report how many with congenital syphilis had hearing loss [ 22 ]. In a follow-up report of 34,801 infants screened 2017 through 2021, they report that neonates with congenital syphilis were 2.38 times as likely to fail in the UNHS as those without congenital syphilis [ 48 ]. However, another small study from Brazil reported as a pre-print examined failed hearing screens at 2 months of life did not find an association between congenital syphilis and failed hearing screens [ 23 ].

It is not clear whether there is a treatment for hearing loss due to congenital syphilis. Antibiotics were presumably always given at the time of diagnosis of hearing loss if the patient had not previously been adequately treated. There are no convincing reports that this alone resulted in sustained improved hearing. Uncontrolled studies that included corticosteroids with or without ACTH reported variable response and improvement in hearing was often subjective.

The main limitation of this scoping review is the lack of high-quality studies.

Our scoping review outlines a general map of the trend of publications across the decades and shows that the incidence of hearing loss due to congenital syphilis is completely unknown. It is not clear whether the stage of maternal syphilis or the age at which infants are treated changes outcomes. The literature does not inform us as to whether treatment in-utero prevents development of hearing loss. Until there are high quality long-term observational studies, it is difficult to know what hearing screening to recommend for children with congenital syphilis. Hearing loss attributed to congenital syphilis is often first recognized in adolescence or adulthood. Therefore, there is a need to increase awareness that people of all ages with unexplained hearing loss of sudden or gradual onset should be screened for syphilis. Other than treatment of the congenital syphilis, no other treatments can be recommended until there are RCTs or cohort studies with valid control groups.

Supporting information

S1 checklist. preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (prisma-scr) checklist..

https://doi.org/10.1371/journal.pone.0302452.s001

S1 Appendix. Systematic review search strategy.

https://doi.org/10.1371/journal.pone.0302452.s002

S2 Appendix. Joanna Briggs Institute (JBI) critical appraisal checklist.

https://doi.org/10.1371/journal.pone.0302452.s003

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Medical nutrition therapy : a case study approach by Nahikian-Nelms, Marcia, author. Publication date 2014 Topics Diet therapy -- Case studies, Diet Therapy -- Case Reports, Nutritional Physiological Phenomena -- Case Reports, Diet therapy Publisher Stamford, Connecticut : Cengage Learning Collection
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d. Partial pressure of arterial carbon dioxide (PaCO2): <32 mm Hg (hyperventilation) e. WBC count: >12,000/mm3 or <4000/mm3. Study with Quizlet and memorize flashcards containing terms like Mr. Green is in the ED awaiting a CAT scan to rule out hemorrhagic stroke before giving him an anti-thrombolitic. He is thirsty and has dysphagia., 2.
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Effects of the added sugar labeling on consumers' willingness to pay
Cranberry products make an interesting case study to analyze the effectiveness of labeling policies, specifically the added sugar rule. ... This study uses a 1-10 scale of ... (−$0.18). Health and nutrition-conscious respondents (36% of the sample) also assigned significantly lower WTP for added sugars (−$0.38) relative to their ...
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1 | P a g e. Questions for Medical Nutrition Therapy: A Case Study Approach 5 th ed. Case Study C - Chronic Kidney Disease (CKD) Treated with Dialysis (Case 19 in text) Instructions: Answer the questions below. You may print your answers or e-mail them to your instructor. Describe the basic physiological functions of the kidneys.
Genetic exploration of Dravet syndrome: two case report
Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and comorbidities including intellectual disability, behavioral problems, sleep disturbances, gait disturbances, and an increased risk of sudden unexpected death in epilepsy [1, 2].
"I am incompetent—I just can't cope"—A case study in depression
This chapter describes the treatment of a 41-year-old female (Naomi) with major depressive disorder and symptoms of anxiety and stress following a stressful workplace event. Naomi endorsed a range of dysfunctional appraisals which contributed to the maintenance of her symptoms; they centred around themes of her incompetence and inability to cope at work, and beliefs that she should be able to ...
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Nutrition Chapter 1; Case study 1 NUT100; NUT 100 Hw1 - HW #1; Nutrition HW #4 (GI Disorder Case Study) Studocu; Community Food Supply and Health Case Study; Nutritional Therapy Homework 3; Related documents. Community Food Supply and Health Case Study; HW 2 - homework 2; Thera Exam 1 - notes;
Sudden unexpected postnatal collapse and BUB1B mutation ...
Sudden unexpected postnatal collapse (SUPC) is a sudden collapse of the clinical conditions of the full-term or almost full-term newborn, within the first 7 days of life, who requires resuscitation with positive ventilation and who either dies, presents hypoxic-ischemic encephalopathy, or requires therapy intensive [].The incidence of SUPC is very low and very often has a negative prognosis [2 ...
Scoping review of hearing loss attributed to congenital syphilis
Background There are no narrative or systematic reviews of hearing loss in patients with congenital syphilis. Objectives The aim of this study was to perform a scoping review to determine what is known about the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis. Eligibility criteria PROSPERO, OVID Medline, OVID EMBASE ...

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Medical Nutrition Therapy: A Case Based Approach

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Medical Nutrition Therapy | 6th Edition

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Genetic exploration of Dravet syndrome: two case report

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Journal of Medical Case Reports

Sudden unexpected postnatal collapse and BUB1B mutation: first forensic case report

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