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Genetic Disorders

Many human diseases have a genetic component. Some of these conditions are under investigation by researchers at or associated with the National Human Genome Research Institute (NHGRI).

A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes). As we unlock the secrets of the human genome (the complete set of human genes), we are learning that nearly all diseases have a genetic component. Some diseases are caused by mutations that are inherited from the parents and are present in an individual at birth, like sickle cell disease. Other diseases are caused by acquired mutations in a gene or group of genes that occur during a person's life. Such mutations are not inherited from a parent, but occur either randomly or due to some environmental exposure (such as cigarette smoke). These include many cancers, as well as some forms of neurofibromatosis.

List of Genetic Disorders

This list of genetic, orphan and rare diseases is provided for informational purposes only and is by no means comprehensive.

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8.6: Genetic Disorders

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• Page ID 16765

• Suzanne Wakim & Mandeep Grewal
• Butte College

Each hand in Figure \(\PageIndex{1}\) has an extra pinky finger. This is a condition called polydactyly, which literally means "many digits." People with polydactyly may have extra fingers and/or toes, and the condition may affect just one hand or foot or both hands and feet. Polydactyly is often genetic in origin and may be part of a genetic disorder that is associated with other conditions.

What Are Genetic Disorders?

Genetic disorders are diseases, syndromes, or other conditions that are caused by mutations in one or more genes or by chromosomal alterations. Genetic disorders are typically present at birth, but they should not be confused with congenital disorders, which are any disorders, regardless of cause, that are present at birth. Some congenital disorders are not caused by genetic mutations or chromosomal alterations. Instead, they are caused by problems that arise during embryonic or fetal development or during the process of birth. An example of a nongenetic congenital disorder is fetal alcohol syndrome. This is a collection of birth defects, including facial anomalies and intellectual disability, caused by maternal alcohol consumption during pregnancy.

Genetic Disorders Caused by Mutations

Table \(\PageIndex{1}\) lists several genetic disorders caused by mutations in just one gene. Some of the disorders are caused by mutations in autosomal genes, others by mutations in X-linked genes. Which disorders would you expect to be more common in males than females?

Very few genetic disorders are controlled by dominant mutant alleles. A dominant allele is expressed in every individual who inherits even one copy of it. If it causes a serious disorder, affected people may die young and fail to reproduce. Therefore, the mutant dominant allele is likely to die out of the population.

A recessive mutant allele, such as the allele that causes sickle cell anemia or cystic fibrosis, is not expressed in people who inherit just one copy of it. These people are called carriers. They do not have the disorder themselves, but they carry the mutant allele and their offspring can inherit it. Thus, the allele is likely to pass on to the next generation rather than die out.

Genetic Disorders Caused by Chromosomal Alterations

As we learned in the Cell Reproduction chapter , mistakes may occur during meiosis that results in nondisjunction . This is the failure of replicated chromosomes to separate properly during meiosis. Some of the resulting gametes will be missing all or part of a chromosome, while others will have an extra copy of all or part of the chromosome. If such gametes are fertilized and form zygotes, they usually do not survive. If they do survive, the individuals are likely to have serious genetic disorders.

Table \(\PageIndex{2}\) lists several genetic disorders that are caused by atypical numbers of chromosomes. Most chromosomal disorders involve the X chromosome. The X and Y chromosomes are the only chromosome pair in which the two chromosomes are very different in size. This explains why nondisjunction of the sex chromosomes tends to occur more frequently than nondisjunction of autosomes.

Diagnosing and Treating Genetic Disorders

A genetic disorder that is caused by a mutation can be inherited. Therefore, people with a genetic disorder in their family may be concerned about having children with the disorder. A genetic counselor can help them understand the risks of their children being affected. If they decide to have children, they may be advised to have prenatal (“before birth”) testing to see if the fetus has any genetic disorders. One method of prenatal testing is amniocentesis. In this procedure, a few fetal cells are extracted from the fluid surrounding the fetus in utero , and the fetal chromosomes are examined. Down syndrome and other chromosomal alterations can be detected in this way.

The symptoms of genetic disorders can sometimes be treated or prevented. For example, in the genetic disorder called phenylketonuria (PKU) , the amino acid phenylalanine builds up in the body to harmful levels. PKU is caused by a mutation in a gene that normally codes for an enzyme needed to break down phenylalanine. The buildup of PKU can lead to serious health problems, such as intellectual disability and delayed development, among other serious problems. Babies in the United States and many other countries are screened for PKU soon after birth. If PKU is diagnosed, the infant can be fed a low-phenylalanine diet. This prevents the buildup of phenylalanine and the health problems associated with it. With a low phenylalanine diet, most symptoms of the disorder can be prevented.

Curing Genetic Disorders

Cures for genetic disorders are still in the early stages of development. One potential cure is gene therapy. Gene therapy is an experimental technique that uses genes to treat or prevent disease. In gene therapy, normal genes are introduced into cells to compensate for mutated genes. If a mutated gene causes a necessary protein to be nonfunctional or missing, gene therapy may be able to introduce a normal copy of the gene to produce the needed functional protein.

A gene that is inserted directly into a cell usually does not function, so a carrier called a vector is genetically engineered to deliver the gene (Figure \(\PageIndex{3}\)). Certain viruses, such as adenoviruses , are often used as vectors. They can deliver the new gene by infecting cells. The viruses are modified so they do not cause disease when used in people. If the treatment is successful, the new gene delivered by the vector will allow the synthesis of a functioning protein.

Feature: Human Biology in the News

Down syndrome is the most common genetic cause of intellectual disability. It occurs in about 1 in every 700 live births, and it currently affects nearly half a million Americans. Until recently, scientists thought that the changes leading to intellectual disability in people with Down syndrome all happen before birth.

Researchers recently discovered a genetic disorder that affects brain development in people with Down Syndrome throughout childhood and into adulthood. The newly discovered genetic disorder changes communication between nerve cells in the brain, resulting in the slower transmission of nerve impulses. This finding may eventually allow the development of strategies to promote brain functioning in Down syndrome patients and may also be applicable to other developmental disabilities such as autism.

• Define genetic disorder.
• Identify three genetic disorders caused by mutations in a single gene.
• Why are single-gene genetic disorders more commonly controlled by recessive than dominant mutant alleles?
• What is nondisjunction? Why may it cause genetic disorders?
• Explain why genetic disorders caused by a number of chromosomes most often involve the X chromosome.
• How is Down syndrome detected in utero ?
• Use the example of PKU to illustrate how the symptoms of a genetic disorder can sometimes be prevented.
• Explain how gene therapy works.
• Compare and contrast genetic disorders and congenital disorders.
• Explain why parents that do not have Down syndrome can have a child with Down syndrome.
• Hemophilia A and Turner’s syndrome both involve problems with the X chromosome. What is the major difference between these two types of disorders in terms of how the X chromosome is affected?
• Can you be a carrier of Marfan syndrome and not have the disorder? Explain your answer.
• True or False. It is impossible for people to have more than three copies of one chromosome.
• True or False. The gene for sickle cell anemia is on a sex chromosome.

Explore More

Scientists have promised that gene therapy will be the next big leap for medicine, but what is it exactly? Learn more here:

Attributions

• Polydactyly by Baujat G, Le Merrer M. CC BY 2.0 via Wikimedia Commons
• Down Syndrome Karyotype by National Human Genome Research Institute, public domain via Wikimedia Commons
• Brushfield eyes by Erin Ryan, public domain via Wikimedia Commons
• Virus by Darryl Leja at NHGRI public domain via Wikimedia Commons
• Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.0

Genetics Basics

• Glossary of Genomic Terms

Genetics research studies how individual genes or groups of genes are involved in health and disease. Understanding genetic factors and genetic disorders is important in learning more about promoting health and preventing disease.

Some genetic changes have been associated with an increased risk of having a child with a birth defect or developmental disability or developing diseases such as cancer or heart disease. Genetics also can help us understand how medical conditions happen.

How We Get Our Genes

People get (inherit) their chromosomes , which contain their genes , from their parents. Chromosomes come in pairs and humans have 46 chromosomes, in 23 pairs. Children randomly get one of each pair of chromosomes from their mother and one of each pair from their father. The chromosomes that form the 23rd pair are called the sex chromosomes. They decide if a person is born a male or female. A female has two X chromosomes, and a male has one X and one Y chromosome. Each daughter gets an X from her mother and an X from her father. Each son gets an X from his mother and a Y from his father.

Genetic Disorders

Genetic disorders can happen for many reasons. Genetic disorders often are described in terms of the chromosome that contains the gene that is changed in people who have the disorder. If the gene is on one of the first 22 pairs of chromosomes, called the autosomes, the genetic disorder is called an autosomal condition. If the gene is on the X chromosome, the disorder is called X-linked.

Genetic disorders also are grouped by how they run in families. Disorders can be dominant or recessive, depending on how they cause conditions and how they run in families.

Dominant diseases can be caused by only one copy of a gene having a DNA mutation . If one parent has the disease, each child has a 50% chance of inheriting the mutated gene.

For recessive diseases, both copies of a gene must have a DNA mutation in order to get one of these diseases. If both parents have one copy of the mutated gene, each child has a 25% chance of having the disease, even though neither parent has it. In such cases, each parent is called a carrier of the disease. They can pass the disease on to their children, but do not have the disease themselves.

Single Gene Disorders

Chapter 6. Genetic Disorders

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• Autosomal Dominant Disorders
• Autosomal Recessive Disorders
• Lysosomal Storage Disorders
• Glycogen Storage Disorders
• Genetic Conditions with X-Linked Inheritance Pattern
• Genetic Conditions with Mixed Inheritance Patterns
• Additional Genetic Abnormalities
• Sex Chromosome Abnormalities
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There are three major types of mutations: (1) genome mutations, which involve loss or gain of an entire chromosome; (2) chromosomal mutations, which involve alterations in one or more chromosomes that are usually identifiable by karyotyping; and (3) gene mutations, which are partial or complete deletion of the gene or alteration of the base. Genome mutations usually result in death of the fetus, or death during infancy or early childhood.

Many diseases have a genetic component, albeit without a specific identifiable gene mutation. Such conditions are said to have a multifactorial inheritance pattern. Examples of such diseases include coronary artery disease, hypertension, gout, and diabetes mellitus.

When discussing genetic diseases, some definitions are important to remember: (1) hereditary or familial, a condition derived from parents (i.e., a condition that is transmitted in the germ line); and (2) congenital, a condition that is present at birth. Not all hereditary conditions are congenital, and not all congenital conditions are hereditary. Some hereditary conditions are manifested at the time of birth or shortly thereafter, and many manifest later in life.

The overall effects of the mutation of a single gene include (1) an enzyme defect; (2) defects in membrane receptors and/or transport system; (3) alterations in structure, function, or quantity of nonenzymatic protein; or (4) mutations resulting in unusual reactions to drugs. An enzyme defect can cause accumulation of substrate, a metabolic block resulting in a decreased amount of needed end product, or failure to inactivate a tissue-damaging substrate.

Overview: In general, autosomal dominant disorders have reduced penetrance and variable expressivity. They usually do not encode enzymes because a loss of up to 50% of an enzyme's activity can be compensated for by activity of the enzyme encoded by the normal allele ( Table 6-1 ).

LDL, low-density lipoprotein; APC, adenomatous polyposis coli.

Familial Hypercholesterolemia

Mutation: Low-density lipoprotein receptor gene ( LDL ); there are more than 100 known mutations.

Mechanism: The LDL receptor recognizes apolipoprotein B100 or apolipoprotein E; therefore, a mutation of the receptor results in impaired uptake of cholesterol into cells.

Manifestations of familial hypercholesterolemia

• Elevated cholesterol level: Heterozygotes have half the normal amount of LDL receptors and two to three times the normal level of cholesterol; homozygotes have five or more times the normal level of cholesterol.
• Tendon sheath xanthomas, corneal arcus, and xanthelasma.
• Early atherosclerosis and its consequences; homozygotes usually die of cardiovascular disease before the age of 30 years.

Familial Polyposis ...

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• Open access
• Published: 12 April 2024

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods

• Yupeng Liu 1   na1 ,
• Xue Ma 2   na1 ,
• Zhehui Chen 2 ,
• Ruxuan He 3 ,
• Yao Zhang 2 ,
• Hui Dong 2 ,
• Yanyan Ma 4 ,
• Tongfei Wu 2 ,
• Qiao Wang 5 ,
• Yuan Ding 5 ,
• Xiyuan Li 6 ,
• Dongxiao Li 7 ,
• Jinqing Song 2 ,
• Mengqiu Li 2 ,
• Ying Jin 2 ,
• Jiong Qin 1 &
• Yanling Yang   ORCID: orcid.org/0000-0002-0034-0123 2  

Orphanet Journal of Rare Diseases volume  19 , Article number:  159 ( 2024 ) Cite this article

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Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported.

Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D , c.159_164inv and c.1427G > A in SLC25A13 , and c.591 C > G in MTHFR .

Conclusions

Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

In the realm of rare genetic diseases, ensuring effective medical management and genetic counseling hinges on providing precise diagnoses. However, clinical evaluations and conventional genetic testing bring about the diagnosis in < 50% patients [ 1 ]. The capacity to offer molecular diagnostics to patients has witnessed a substantial improvement, rapidly emerging as the most suitable method for those with rare diseases. Consequently, it has become an indispensable process for identifying various genetic diseases in a single patient [ 2 ].

A distinctive facet of the dual molecular diagnostic process is the occurrence of a unique or overlapping clinical diagnosis involving > 1 independently genetically separated locus. Medical literature intermittently features reports on patients with concomitant diagnoses of ≥ 2 genetically related disorders, colloquially known as “double trouble” [ 3 ]. The identification of a significant number of cases with dual genetic diseases is incidental, often occurring during next-generation or whole sequencing procedures [ 2 , 3 , 4 ]. Whole-exome sequencing data indicate that the prevalence of dual molecular diagnosis, contrary to previous assumptions, may be higher, readily detectable in approximately 7% cases [ 2 ]. Herein we present a description of the clinical evaluation of five patients with dual molecular diagnoses of genetic diseases.

From 2013 to 2022, 1,659 patients were diagnosed at our hospitals with inherited metabolic disorders via gene sequencing. In this retrospective study, we aimed to evaluate five pediatric patients exhibiting dual rare genetic diseases observed in our outpatient clinics. The comprehensive data collection encompassed age at onset and diagnosis, clinical manifestations, family history, treatment, and outcomes. In addition, routine blood and urine examination was performed to assess liver, renal, and heart functions.

Dried blood spots were collected for further analyses. As previously described, liquid chromatography–mass spectrometry (Waters MS/MS system A, 1445–002; API3200, Applied Biosystems, CA, USA) was employed to analyze blood amino acids, free carnitine, and acylcarnitines [ 5 , 6 , 7 ]. Metabolite concentrations were computed using ChemoView software. Urinary organic acids were analyzed using gas chromatography–mass spectrometry, which was performed on a Shimadzu GCMS-QP2010 system (Kyoto, Japan) [ 8 , 9 , 10 ]. Fluorescence polarization immunoassay was utilized to analyze plasma total homocysteine levels. Lysosomal enzyme activity in peripheral blood leukocytes was determined using a synthetic fluorescent substrate based on a standard curve.

Genomic DNA from peripheral blood samples was extracted, purified, and subsequently sent to Euler Genomics (Beijing, China), Berry Genomics Corporation (Beijing, China), and GrandOmics (Beijing, China) for next-generation or whole-exon sequencing for variant screening. DNA samples were sequenced on Illumina HiSeq 2500 (Illumina, San Diego, USA). Each variant was compared with information from 1000 Genomics ( www.1000genomes.org ), the ExAC database ( http://exac.broadinstitute.org/ ), and the gnomAD database ( http://gnomad.broadinstitute.org/ ). In silico analysis of variants to predict pathogenicity also involved Mutation Taster, PolyPhen-2, and SIFT. Interpretation of the variants was based on the Human Gene Mutation Database ( http://www.hgmd.cf.ac.uk/ac/index.php ). Pathogenicity assessment followed the American College of Medical Genetics and Genomics guidelines, classifying variants as pathogenic, likely pathogenic, variants of uncertain significance, likely benign, or benign.

Before research commencement, a consent form was signed by all patients or their caregivers, indicating their approval for all aspects of the clinical assessment, including genetic testing, and all ancillary testing (e.g., bone marrow aspiration).

Clinical reports

Case 1: angelman syndrome and krabbe disease.

Case 1, a 7-year-old boy, presented with general developmental delay, irritability, and a distinctive giggle. Physical assessment revealed muscle tension, limb stiffness, thumb buckling, and substandard comprehension proficiency. Brain MRI revealed myelin dysplasia, while blood amino acid and acylcarnitine profiles were normal. Electroencephalogram data indicated slow wave emission from bilateral occipital and temporal spines. Chromosome G banding was 46, XY. Whole-exome sequencing identified a 4.88 Mb deletion in 15q11.2q13.1 (copy number variation, CNV) and compound heterozygous variants, c.1963G > A (p.V655M) and c.1511T > C (p.L504P), in the GALC gene. The CNV was associated with Angelman syndrome, while the two GALC variants were found to originate from his parents (Tables  1 , 2 and 3 ). Peripheral leukocyte galactose cerebrosidase activity showed a significant decrease (3.8 nmol/g/h, normal range 33.4–123.9 nmol/g/h), confirming the diagnosis of Krabbe disease.

Case 2: Citrin deficiency and kabuki syndrome

Case 2, a girl, visited us with developmental delay and liver dysfunction. Born at term (weight, 3.3 kg) after an uncomplicated pregnancy, she exhibited persistent jaundice until 3 months of age. Elevated levels of serum alpha-fetoprotein and blood citrulline (110 µmol/L, normal range 10–50 µmol/L) were observed, along with mild liver dysfunction and hyperammonemia. Ultrasound of the abdomen revealed hepatomegaly, but brain MRI was normal. Treatment with a lactose-free diet led to gradual improvement, with liver function and blood citrulline level returning to normal after 6 months.

Physical examination revealed distinctive features, such as a long cleft on the eyelid, elongated lateral canthus, heavy eyebrows, cleft palate, and increased muscle tension. Chromosome G banding was 46, XX. Whole-exome sequencing identified a de novo variant c.15292de1A (p.T5098Lfs*49) in the KMT2D gene, supporting the diagnosis of Kabuki syndrome. Besides, compound heterozygous variants in the SLC25A13 gene, c.159_164inv (p.N54delinsD*) and c.1427G > A (p.R476Q), were identified. Her parents were heterozygous carriers at the same mutation site in SLC25A13. These findings confirmed the second diagnosis of citrin deficiency.

Case 3: homocysteinemia type 2 and copy number variant

A 10-year-old boy visited our hospital with psychomotor retardation and seizures. He exhibited normalcy during the newborn period. However, developmental delays in major motor skills surfaced after one month of age, with independent walking achieved at 3 years. A progressive deterioration in motor functions emerged at the age of 8 years, characterized by dysarthria, increased muscular tension in both lower limbs, dorsiflexion restriction, and varus of both feet, which were identified upon physical assessment. MRI indicated brain atrophy. Urinary organic acid, blood amino acid, and acylcarnitine profiles were normal, but plasma total homocysteine level was increased to 108.5 µmol/L (normal range 0–15 µmol/L) and 5-methyltetrahydrofolate level in cerebrospinal fluid was significantly decreased to 19.8 nmol/L (normal range 60–210 nmol/L), indicative of secondary cerebral folate deficiency. Compound heterozygous variants, c.591C > G (p.Y197*) and c.584G > A (p.A195V), in the MTHFR gene confirmed the diagnosis of homocysteinemia type 2 due to methylenetetrahydrofolate reductase deficiency. Simultaneously, whole-exome sequencing identified a 0.648 Mb deletion in 16p11.2, confirming the diagnosis of 16p11.2 deletion syndrome. Both parents were found to carry heterozygous MTHFR variants without the deletion in 16p11.2.

Case 4: Isolated methylmalonic acidemia and niemann-pick disease type B

A 3-year-old girl visited our hospital with general developmental delay. Initially considered for cerebral palsy at 1 year of age, she underwent physical rehabilitation. Routine blood test results were normal, but significantly increased levels of urine methylmalonate and methylcitrate were observed. Blood propionyl carnitine level was increased to 15.2 µmol/L (normal range 1.0–5.0 µmol/L), and propionylcarnitine/acetylcarnitine ratio was high at 0.53 (normal range 0.03–0.25). Plasma total homocysteine level was normal. These findings led to the diagnosis of isolated methylmalonic aciduria (MMA). Whole-exome sequencing identified compound heterozygous variants in methylmalonyl-CoA mutase (MMUT, c.1540C > A and c.323G > A), confirming the diagnosis of MMUT deficiency.

Clinical examination also revealed liver abnormalities. Serum alanine aminotransferase (59.4 IU/L) and aspartate aminotransferase (73.7 IU/L) levels showed a slight increase. Abdominal ultrasonography revealed significant enlargement of the liver (lower edge 3.1 cm below the right costal margin) and spleen (lower edge 2.2 cm below the left costal margin). Whole-exome sequencing identified compound heterozygous variants (c.1144C > T and c.1675G > T) in SMPD1 gene. Niemann-Pick cells were found in her bone marrow. Further, peripheral leukocyte acid sphingomyelinase activity was significantly decreased (80.8 nmol/g/min, normal value 216.1–950.9 nmol/g/min), confirming the diagnosis of Niemann-Pick disease type B.

Case 5: Isolated methylmalonic acidemia and 21-hydroxylase deficiency

A boy, aged 1 year and 8 months, visited us with feeding difficulties, diarrhea, metabolic acidosis, and psychomotor retardation following vaccination against polio at 3 months of age. He exhibited a significant increase in urine methylmalonate (34.4 mmol/mol creatinine, normal range 0.2–3.6 mmol/mol creatinine) and methylcitrate levels, while plasma total homocysteine level was normal. Two pathogenic variants (c.866G > C and c.2179C > T) in MMUT gene supported the diagnosis of methylmalonyl-CoA mutase deficiency. Treatment with cobalamin intramuscular injection and L-carnitine supplementation improved his clinical picture. Mental development and upper limb motor function normalized, but spastic paralysis persisted in the lower limbs, necessitating the use of a brace.

At 5 years of age, signs of precocious puberty emerged. His left wrist bone age was 13 years. Serum growth hormone level was normal. Upon gonadotropin-releasing hormone stimulation, the luteinizing hormone/follicle stimulating hormone peak value was < 0.6. Plasma adrenocorticotropic hormone levels showed a marked increase (309 pg/mL, normal range 0–46 pg/mL), while plasma cortisol levels were normal (7.9 µg/dL, normal range 5–25 µg/dL). Testosterone and 17-α-hydroxyprogesterone levels were increased to 5.77 ng/mL (normal range 0.27–0.90 ng/mL) and 495 nmol/L (normal control < 30 nmol/L), respectively. Estradiol level was normal at < 20 pg/mL (normal range 0–56 pg/mL). Aldosterone level was 32.29 ng/dL (normal range 5–17.5 ng/dL in horizontal position and 6.5–30 ng/dL in vertical position). MRI revealed no abnormalities in the pituitary and hypothalamus. Notably, double adrenal ultrasound, along with CT enhancement, depicted bilateral adrenal thickening, particularly on the left. Endocrine examination results indicated congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Two pathogenic variants (c.188A > T and c.518T > A) were found in CYP21A2 gene, confirming the diagnosis.

In clinical training, clinicians are traditionally oriented toward identifying a single explanation for the clinical presentation of a patient. The concept of multiple genetic diseases in a single patient is perceived as complex and challenging [ 1 ]. Conventionally, clinicians abstract a specific phenotype to recognize Mendelian disease patterns, forming the basis for adequate diagnosis. Clinical attributes not aligning with this genetic etiology pattern may be considered phenotypic expressions. However, literature reports several cases of co-occurring genetic disorders [ 2 , 3 , 4 ]. Posey et al. indicated that the occurrence of molecular “double trouble” is not as rare as previously assumed, suggesting up to 7% patients diagnosed by whole-exome sequencing possess a dual or triple genetic diagnosis [ 2 ]. This challenges the hypothesis that a single diagnosis concludes genetic investigations. Complete diagnosis in such cases is challenging, as distinguishing whether atypical clinical features represent a novel primary disease phenotype or a second genetic or acquired disease poses difficulty.

Herein all five patients exhibited clinical features that overlapped with their primary diagnoses. However, the presence of atypical clinical features prompted secondary diagnoses. For instance, in Case 1, a distinctive giggle and general developmental delay could be attributed to Angelman syndrome, but irritability and skeletal/muscle presentations were untypical. In addition to Angelman syndrome, whole-exome sequencing and CNV analyses identified a compound heterozygous variant in the GALC gene; moreover, a significant decrease was observed in galactose cerebrosidase activity. These findings confirmed the diagnosis of Krabbe disease. Similar methods were applied in Cases 2, 3, and 4 for addressing non-specific presentations. As indicated in Table  1 , the examination of a secondary disease for atypical features of the primary disease was systematically initiated. In Case 5, however, because of a variation in clinical symptomatology and a less specific physical assessment, secondary disease examination was relatively complex. At 3 months of age, Case 5 presented with feeding difficulties, diarrhea, metabolic acidosis, and psychomotor retardation following vaccination against polio. Elevated levels of urine methylmalonate and methylcitrate were observed, while total homocysteine level was normal. The diagnosis of isolated MMA was confirmed by Sanger sequencing of the MMUT gene. Clinical condition of this patient improved post-treatment. The emergence of precocious puberty at age 5 raised questions about whether it represented a new phenotype of isolated MMA or resulted from a second genetic or acquired disease. To address this, whole-exome sequencing was employed for a second diagnosis, confirming 21-hydroxylase deficiency. The significance of conducting accurate diagnoses is paramount for patients, families, and caregivers as precise diagnosis offers insights into patient condition from the perspective of natural history and prognosis, enabling the application of tailored therapeutic strategies. In the context of genetic conditions, this also ensures the provision of genetic counseling. When faced with an indistinct phenotype or possibility of various etiologies, comprehensive investigations become imperative. Employing advanced genome-wide techniques, such as chromosomal microarray analysis, can facilitate CNV identification; moreover, whole-exome sequencing can be applied to detect mutations in protein-coding genes.

MMA, a rare inherited disorder, is the most common organic aciduria in Mainland China [ 11 , 12 ]. MMAs encompass a group of genetically heterogeneous autosomal recessive disorders stemming from defective metabolic pathways involving MMUT or its cofactor, cobalamin [ 13 ]. The clinical manifestation of MMA is intricate, ranging from asymptomatic disease to severe multisystem injuries and even death. MMAs tend to occur at any age, from prenatal to adult life [ 14 , 15 ]. From June 1998 to December 2020, our hospital diagnosed 1,266 cases of MMA in Mainland China [ 11 , 16 , 17 ]. Predominant clinical presentations included psychomotor retardation and metabolic crisis [ 11 , 18 ]. Multiorgan damage, including hematological abnormalities, pulmonary hypertension, kidney damage, eye disease, and skin lesion, was evident. Notably, megaloblastic anemia was a primary hematological abnormality [ 11 , 16 ]. Cases 3 and 5 exhibited additional complexities, including liver function abnormalities and precocious puberty. Unfortunately, dual diagnoses were identified in these cases through whole-exome sequencing, underscoring the necessity for detailed history and physical examination in clinical practice.

It is conceivable that clinical signs and symptoms of multiple appropriately characterized disorders may exhibit similar biochemical and radiological attributes. This can lead to the masking and/or overlooking of one disorder if another affecting a similar system is present. Even if an atypical feature or pattern is identified, it is often attributed to the primary diagnosis, with secondary diagnoses potentially being overlooked. Consequently, the atypical feature of one disease may inaccurately reflect another undiagnosed condition, emphasizing the need for careful consideration of the complete assessment.

In cases where the clinical picture is atypical or exhibits more severity than expected, the possibility of a dual diagnosis (“double trouble”) should be contemplated [ 3 ]. Recent cases highlight the ongoing necessity for meticulous clinical evaluation, including a thorough physical examination, particularly in patients with atypical clinical features. The identification of another condition can significantly influence genetic management and counseling [ 2 , 3 ].

In conclusion, this study reports five pediatric cases with dual diagnoses confirmed through whole-exome sequencing. Our findings underscore the importance of considering the possibility of genetic diseases when the overall clinical picture does not align with a single unifying diagnosis. Clinicians are urged to be cognizant of the significance of physical examination and history, drawing on their extensive experience in identifying atypical clinical features.

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All data generated or analyzed during this study are included in this article.

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Acknowledgements

We would like to thank all the patients and their families who participated in this study. We thank the Euler Genomics (Beijing, China), Berry Genomics Corporation (Beijing, China), and GrandOmics (Beijing, China) for their invaluable support in genetic sequencing and analysis. We are greatly indebted to the team of Professor Seiji Yamaguchi (Department of Pediatrics, Shimane Medical University, Japan) for their expert technical assistance in the diagnosis and treatment of methylmalonic acidemia.

This work was supported by grants from the National Key Research and Development Program of China [grant numbers 2021YFC2700903, 2022YFC2703401]; the Beijing Municipal Science and Technology Commission [grant numbers Z141107004414036, Z151100003915126]; and the Foundation of 2018 Beijing Key Clinical Specialty Construction Project-Pediatrics [grant number 2199000726].

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Yupeng Liu and Xue Ma contributed equally.

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Department of Pediatrics, Peking University People’s Hospital, Beijing, China

Yupeng Liu & Jiong Qin

Department of Pediatrics, Peking University First Hospital, Beijing, China

Xue Ma, Zhehui Chen, Yao Zhang, Hui Dong, Tongfei Wu, Jinqing Song, Mengqiu Li, Ying Jin & Yanling Yang

Department of Respiration, Beijing Children’s Hospital, Capital Medical University, Beijing, China

Department of Pediatrics, Qinghai University Affiliated Hospital, Xining, China

Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, Beijing, China

Qiao Wang & Yuan Ding

Department of Precise Medicine, General Hospital of Tianjin Medical University, Tianjin, China

Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, China

Dongxiao Li

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YYL and QJ conceived the study. LYP and MX drafted the manuscript. CZH, HRX, ZY, DH, MYY, WTF, WQ, DY, LDX, SJQ, LMQ, JY participated in the clinical management and patient data collection. LXY checked the genetic data. All authors read and approved the final version of the manuscript.

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Correspondence to Jiong Qin or Yanling Yang .

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This study was approved by the Hospital Institutional Ethics Committee and was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents of the patients for collection of samples and publication of medical data.

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Liu, Y., Ma, X., Chen, Z. et al. Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods. Orphanet J Rare Dis 19 , 159 (2024). https://doi.org/10.1186/s13023-024-03148-3

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DOI : https://doi.org/10.1186/s13023-024-03148-3

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Genetic Diseases

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Achonddroplasia (Dwarfism) Adrenoleukodystrophy Albinism Alkaptonuria Asthma Autosomal Recessive Polycystic Kidney Disease Cystic Fibrosis Duchenne Muscular Dystrophy Fabray Disease Hemophilia Hereditary Breast Cancer Hereditary non-polyposis colorectal cancer Hunter Syndrome

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Achonddroplasia (Dwarfism) Adrenoleukodystrophy Albinism Alkaptonuria Asthma Autosomal Recessive Polycystic Kidney Disease Cystic Fibrosis Duchenne Muscular Dystrophy Fabray Disease Hemophilia Hereditary Breast Cancer Hereditary non-polyposis colorectal cancer Hunter Syndrome Huntington’s Disease Krabbe’s Disease Long QT Syndrome Marfan Syndrome Myotonic Dystrophy Neurofibromatosis Osteogenesis Imperfecta Phenylketonuria Pompe Prader-Willi Syndrome Retinitis Pigmentosa Scprintzen syndrome Sickle Cell Anemia Tay Sachs Usher Syndrome Waardenburg Syndrome Frederichs Ataxia Genetic Diseases

Achondroplasia (Dwarfism) • Associations • Little People of America • Human Growth Foundation • March of Dimes • Books • Human Diseases and Conditions • Diseases • World of Health • Resource File (a folder of information gathered from the Public Library’s database) • Web pages • Short Stature • Mayo Clinic • MedLine Plus • Web MD

Associations The ARC of the United States Australian Leukodystrophy Group CLIMB ELA Fight ALD NIH Office of Rare Diseases United Leukodystrophy Foundation ) Resource File (a folder of information gathered from the Public Library’s database Books World of Health Web pages MedLine Plus Leukodystrophy types Mayo Clinic Adrenoleukodystrophy

Albinism • Associations • NOAH • Books • Diseases • World of Health • Human Diseases and Conditions • Resource Files (a file of articles from the public library’s database) • Web pages • MedLine plus • Mayo Clinic • Scientific American • National Institutes of Health

Alkaptonuria • Associations • Children living with inherited metabolic diseases (CLIMB) • National Institute of diabetes and digestive and kidney diseases • National Organization for rare disorders (NORD) • Books • Human Diseases and Conditions • World of Health • Diseases • Sick • Resource File (a folder of information gathered from the Public Library’s database) • Web pages • National Institutes of Health • Medline Plus

Associations Asthma and Allergy Foundation of America American Lung Association American Academy of Allergy, Asthma, and Immunology Books World of Health Diseases Sick Coping with Asthma Human Diseases and Conditions Resource File (a folder of information from the public library’s database) Web Sites National Heart Blood and Lung Institute MedLine Plus Web MD CDC Mayo Clinic Asthma

Autosomal Recessive Polycystic Kidney Disease • Associations • ARPKD / CHF Alliance • CAGS • Rare Diseases organization • Books • World of Health • Diseases • Kidney Disorders • Human Diseases and Conditions • Resource File (a folder of information from the public library’s database) • Web sites: • National Institutes of Health • NIH • Web MD

Associations Cystic Fibrosis Foundation Boomer Esiason Foundation Kids Health Canadian Cystic Fibrosis Foundation Books World of Health Diseases Sick Genetics and Human Health Human Diseases and Conditions Web sites Medline Mayo Clinic National Heart lung and Blood Institute Genetics Home Reference Resource File (a folder of information from the public library’s database) Cystic Fibrosis

Duchenne Muscular Dystrophy • Organizations • Muscular Dystrophy Association • Parent Project Muscular Dystrophy • Your Genes your health • Books • World of Health • Diseases • Sick • Human Diseases and Conditions • Resource File (a folder of information from the public library’s database) • Web Sites • Medline PlusCDCMayo Clinic • National Institute of Neurological Disorders and Stroke

Fabry Disease • Associations • Alliance of Genetic support groups • Mount Sinai Medical center • Fabry support and information group • National Organization for Rare Disorders • Books • World of Health • Diseases • Sick • Human Diseases and Conditions • Resource File (a folder of information gathered from the Public Library’s database) • Web pages • National Institute for Neurological disorders and stroke • National Institutes of Health • Overview

Gaucher’s Disease • Associations • Center for Jewish diseases, department of Human genetics, Mount Sinai Medical center. • Children’s Gaucher Research Fund • National Gaucher Foundation • Books • World of Health • Diseases • Sick • Human Diseases and Conditions • Genetics and Human Health • Resource File (a folder of information gathered from the Public Library’s database) • Web pages • Mayo Clinic • Medline Plus • National Institute of Neurological Disorders and Stroke

Associations National Hemophilia Organization Bleeding Disorders Association Hemophilia Organization of America Books World of Health Diseases Sick Human Diseases and Conditions Genetics and Human Health Resource File (a folder of information from the public library’s database) Web Sites Medline Plus National Heart lung and blood Institute Mayo Clinic E Medicine Hemophilia

Associations National Breast Cancer Foundation American Cancer Society Susan G. Komen Books World of Health Diseases Sick Breast Cancer The Cancer Dictionary Web Sites National Cancer Institute Medicine Net Web MD Mayo Clinic Resource File (a folder of information from the public library’s database) Hereditary Breast Cancer

Hereditary non-polyposis colorectal cancer • Organizations • Colon Cancer Alliance • Colorectal Cancer Network • Hereditary Colon Cancer Association • Books • World of Health • Sick • The Cancer Dictionary • Human Diseases and Conditons • Resource File (a folder of information from the public library’s database) • Web Sites • Cleveland ClinicNational Institutes of Health • National Cancer InstituteWeb MDMayo Clinic

Hunter Syndrome • Organizations • Rare Diseases • Brave Community • Resource File (a folder of information from the public library’s database) • Web Sites • A list of links • Mayo Clinic • Medline Plus • Web MD • Shire

Huntington’s Disease • Organizations • Hereditary Disease Foundation • Huntington’s Disease Society of America • National Institute of Neurological Disorders and Stroke • Books • World of Health • Disease • Human Diseases and Conditions • Resource File (a folder of information from the public library’s database) • Web Sites • Mayo Clinic • Medline Plus • NCBI • Web MD

Krabbe’s Disease • Organizations • United Leukodystrophy Foundation • Hunter’s Hope Foundation • National Organization for Rare Disorders • Resource File (a folder of information from the public library’s database) • Web Sites • Mayo Clinic • Medline Plus • National Institute of Neurological Disorders and Stroke • University of Maryland Medical Center

Long QT Syndrome • Organizations • CARE • American Heart Association • Heart rhythm Society • Resource File (a folder of information from the public library’s database) • Web sites • Mayo Clinic • Cleveland Clinic • National Heart Lung and Blood Institute

Marfan Syndrome • Organizations • National Marfan Foundation • A list of Associations from around the world • Books • Diseases • Human Diseases and Conditions • Resource File (a folder of information from the public library’s database) • Web sites • Mayo Clinic • Medline Plus • Web MD

Myotonic Dystrophy • Organizations • Muscular Dystrophy Association • Mytonic Dystrophy Foundation • Books • World of Health • Diseases • Sick • Human Diseases and Conditions • Resource File (a folder of information from the public library’s database) • Web sites • Genetics Home Reference • Mayo Clinic • NCBI

Neurofibromatosis • Organizations • Acoustic Neuroma Association • Acoustic Neuroma Association of Canada • Books • World of Health • Human Diseases and Conditions • Resource File (a folder of information from the public library’s database) • Web Sites • National Institute for Neurological Disorders and Stroke • Kids Health • Medline Plus • Mayo Clinic

Osteogenesis Imperfecta • Organizations • Children’s Brittle Bone Foundation • Resource File (a folder of information from the public library’s database) • Books • World of Health • Diseases (Look under bone diseases) • Web Sites • Medline Plus • Web MD • Net Doctor • University of Maryland Medical Center

Phenylketonuria • Resource File (a folder of information from the public library’s database) • Books • World of Health • Human Diseases and Conditions • Web Sites • Mayo Clinic • Medline Plus • Web MD • Rare Diseases

Pompe • Associations • Acid Maltase Deficiency Association (ADMA) • Association for Glycogen Storage Disease • Books • World of Health • Diseases • Sick • Human Diseases and Conditions • Resource File (a folder of information gathered from the Public Library’s database) • Web pages • National Association for Neurological disorders and stroke • National Institutes of Health

Prader-Willi Syndrome • Resource File (a folder of information from the public library’s database) • Organizations • Prader-Willi Association • Books • World of Health • Web sites • Medline Plus • University of Michigan • Mayo Clinic • Rare Diseases

Retinitis Pigmentosa • Resource File (a folder of information from the public library’s database) • Organizations • Foundation Fighting Blindness • Low Vision Organization • American Optometric Association • Books • World of Health • Diseases • Web Sites • Medline Plus • Web MD • Natural Eye Care

Shprintzen Syndrome • Resource File (a folder of information from the public library’s database) • Organizations • Coalition for Heritable Disorders of Connective Tissue • Hydrocephalus Association • Web sites • Genetics Home Reference • CCDD • Web MD

Sickle Cell Anemia • Resource File (a folder of information from the public library’s database) • Organizations • Sickle Cell Disease Association • Sickle Cell Information Center • Books • Sickle Cell Anemia • Sick • Diseases • World of Health • Human Diseases and Conditions • Web Sites • Mayo ClinicMedline PlusWeb MD • Kids HealthCDC

Tay Sachs • Resource File (a folder of information from the public library’s database) • Organizations • National Institute of Neurological Disorders and Stroke • National Tay Sachs and Allied Diseases • Rare Diseases • Books • Diseases • World of Health • Human Diseases and Conditions • Web sites • Genetics Home Reference • Mayo Clinic • Medline Plus

Usher Syndrome • Resource File (a folder of information from the public library’s database) • Organizations • Usher Syndrome Foundation • American Council of the Blind • Foundation Fighting Blindness • Helen Keller National Center for Deaf-Blind youths and Adults • Web Sites • NIDCD • Genetics Home Reference • National Institutes for Health • Web MD

Waardenburg Syndrome • Resource File (a folder of information from the public library’s database) • Organizations • National Organization of Rare Diseases • Web Sites • Medline Plus • Web MD • Rare diseases

Frederichs Ataxia • Web sites: • Mayo Clinic • Medline Plus • Web MD • Organizations • The Frederichs Ataxia Research Alliance • Muscular Dystrophy Association

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How can I plan what to eat or drink when I have diabetes?

How can physical activity help manage my diabetes, what can i do to reach or maintain a healthy weight, should i quit smoking, how can i take care of my mental health, clinical trials for healthy living with diabetes.

Healthy living is a way to manage diabetes . To have a healthy lifestyle, take steps now to plan healthy meals and snacks, do physical activities, get enough sleep, and quit smoking or using tobacco products.

Healthy living may help keep your body’s blood pressure , cholesterol , and blood glucose level, also called blood sugar level, in the range your primary health care professional recommends. Your primary health care professional may be a doctor, a physician assistant, or a nurse practitioner. Healthy living may also help prevent or delay health problems  from diabetes that can affect your heart, kidneys, eyes, brain, and other parts of your body.

Making lifestyle changes can be hard, but starting with small changes and building from there may benefit your health. You may want to get help from family, loved ones, friends, and other trusted people in your community. You can also get information from your health care professionals.

What you choose to eat, how much you eat, and when you eat are parts of a meal plan. Having healthy foods and drinks can help keep your blood glucose, blood pressure, and cholesterol levels in the ranges your health care professional recommends. If you have overweight or obesity, a healthy meal plan—along with regular physical activity, getting enough sleep, and other healthy behaviors—may help you reach and maintain a healthy weight. In some cases, health care professionals may also recommend diabetes medicines that may help you lose weight, or weight-loss surgery, also called metabolic and bariatric surgery.

Choose healthy foods and drinks

There is no right or wrong way to choose healthy foods and drinks that may help manage your diabetes. Healthy meal plans for people who have diabetes may include

• dairy or plant-based dairy products
• nonstarchy vegetables
• protein foods
• whole grains

Try to choose foods that include nutrients such as vitamins, calcium , fiber , and healthy fats . Also try to choose drinks with little or no added sugar , such as tap or bottled water, low-fat or non-fat milk, and unsweetened tea, coffee, or sparkling water.

Try to plan meals and snacks that have fewer

• foods high in saturated fat
• foods high in sodium, a mineral found in salt
• sugary foods , such as cookies and cakes, and sweet drinks, such as soda, juice, flavored coffee, and sports drinks

Your body turns carbohydrates , or carbs, from food into glucose, which can raise your blood glucose level. Some fruits, beans, and starchy vegetables—such as potatoes and corn—have more carbs than other foods. Keep carbs in mind when planning your meals.

You should also limit how much alcohol you drink. If you take insulin  or certain diabetes medicines , drinking alcohol can make your blood glucose level drop too low, which is called hypoglycemia . If you do drink alcohol, be sure to eat food when you drink and remember to check your blood glucose level after drinking. Talk with your health care team about your alcohol-drinking habits.

Find the best times to eat or drink

Talk with your health care professional or health care team about when you should eat or drink. The best time to have meals and snacks may depend on

• what medicines you take for diabetes
• what your level of physical activity or your work schedule is
• whether you have other health conditions or diseases

Ask your health care team if you should eat before, during, or after physical activity. Some diabetes medicines, such as sulfonylureas  or insulin, may make your blood glucose level drop too low during exercise or if you skip or delay a meal.

Plan how much to eat or drink

You may worry that having diabetes means giving up foods and drinks you enjoy. The good news is you can still have your favorite foods and drinks, but you might need to have them in smaller portions  or enjoy them less often.

For people who have diabetes, carb counting and the plate method are two common ways to plan how much to eat or drink. Talk with your health care professional or health care team to find a method that works for you.

Carb counting

Carbohydrate counting , or carb counting, means planning and keeping track of the amount of carbs you eat and drink in each meal or snack. Not all people with diabetes need to count carbs. However, if you take insulin, counting carbs can help you know how much insulin to take.

Plate method

The plate method helps you control portion sizes  without counting and measuring. This method divides a 9-inch plate into the following three sections to help you choose the types and amounts of foods to eat for each meal.

• Nonstarchy vegetables—such as leafy greens, peppers, carrots, or green beans—should make up half of your plate.
• Carb foods that are high in fiber—such as brown rice, whole grains, beans, or fruits—should make up one-quarter of your plate.
• Protein foods—such as lean meats, fish, dairy, or tofu or other soy products—should make up one quarter of your plate.

If you are not taking insulin, you may not need to count carbs when using the plate method.

Work with your health care team to create a meal plan that works for you. You may want to have a diabetes educator  or a registered dietitian  on your team. A registered dietitian can provide medical nutrition therapy , which includes counseling to help you create and follow a meal plan. Your health care team may be able to recommend other resources, such as a healthy lifestyle coach, to help you with making changes. Ask your health care team or your insurance company if your benefits include medical nutrition therapy or other diabetes care resources.

Talk with your health care professional before taking dietary supplements

There is no clear proof that specific foods, herbs, spices, or dietary supplements —such as vitamins or minerals—can help manage diabetes. Your health care professional may ask you to take vitamins or minerals if you can’t get enough from foods. Talk with your health care professional before you take any supplements, because some may cause side effects or affect how well your diabetes medicines work.

Research shows that regular physical activity helps people manage their diabetes and stay healthy. Benefits of physical activity may include

• lower blood glucose, blood pressure, and cholesterol levels
• better heart health
• healthier weight
• better mood and sleep
• better balance and memory

Talk with your health care professional before starting a new physical activity or changing how much physical activity you do. They may suggest types of activities based on your ability, schedule, meal plan, interests, and diabetes medicines. Your health care professional may also tell you the best times of day to be active or what to do if your blood glucose level goes out of the range recommended for you.

Do different types of physical activity

People with diabetes can be active, even if they take insulin or use technology such as insulin pumps .

Try to do different kinds of activities . While being more active may have more health benefits, any physical activity is better than none. Start slowly with activities you enjoy. You may be able to change your level of effort and try other activities over time. Having a friend or family member join you may help you stick to your routine.

The physical activities you do may need to be different if you are age 65 or older , are pregnant , or have a disability or health condition . Physical activities may also need to be different for children and teens . Ask your health care professional or health care team about activities that are safe for you.

Aerobic activities

Aerobic activities make you breathe harder and make your heart beat faster. You can try walking, dancing, wheelchair rolling, or swimming. Most adults should try to get at least 150 minutes of moderate-intensity physical activity each week. Aim to do 30 minutes a day on most days of the week. You don’t have to do all 30 minutes at one time. You can break up physical activity into small amounts during your day and still get the benefit. 1

Strength training or resistance training

Strength training or resistance training may make your muscles and bones stronger. You can try lifting weights or doing other exercises such as wall pushups or arm raises. Try to do this kind of training two times a week. 1

Balance and stretching activities

Balance and stretching activities may help you move better and have stronger muscles and bones. You may want to try standing on one leg or stretching your legs when sitting on the floor. Try to do these kinds of activities two or three times a week. 1

Some activities that need balance may be unsafe for people with nerve damage or vision problems caused by diabetes. Ask your health care professional or health care team about activities that are safe for you.

Stay safe during physical activity

Staying safe during physical activity is important. Here are some tips to keep in mind.

Drink liquids

Drinking liquids helps prevent dehydration , or the loss of too much water in your body. Drinking water is a way to stay hydrated. Sports drinks often have a lot of sugar and calories , and you don’t need them for most moderate physical activities.

Avoid low blood glucose

Check your blood glucose level before, during, and right after physical activity. Physical activity often lowers the level of glucose in your blood. Low blood glucose levels may last for hours or days after physical activity. You are most likely to have low blood glucose if you take insulin or some other diabetes medicines, such as sulfonylureas.

Ask your health care professional if you should take less insulin or eat carbs before, during, or after physical activity. Low blood glucose can be a serious medical emergency that must be treated right away. Take steps to protect yourself. You can learn how to treat low blood glucose , let other people know what to do if you need help, and use a medical alert bracelet.

Avoid high blood glucose and ketoacidosis

Taking less insulin before physical activity may help prevent low blood glucose, but it may also make you more likely to have high blood glucose. If your body does not have enough insulin, it can’t use glucose as a source of energy and will use fat instead. When your body uses fat for energy, your body makes chemicals called ketones .

High levels of ketones in your blood can lead to a condition called diabetic ketoacidosis (DKA) . DKA is a medical emergency that should be treated right away. DKA is most common in people with type 1 diabetes . Occasionally, DKA may affect people with type 2 diabetes  who have lost their ability to produce insulin. Ask your health care professional how much insulin you should take before physical activity, whether you need to test your urine for ketones, and what level of ketones is dangerous for you.

Take care of your feet

People with diabetes may have problems with their feet because high blood glucose levels can damage blood vessels and nerves. To help prevent foot problems, wear comfortable and supportive shoes and take care of your feet  before, during, and after physical activity.

If you have diabetes, managing your weight  may bring you several health benefits. Ask your health care professional or health care team if you are at a healthy weight  or if you should try to lose weight.

If you are an adult with overweight or obesity, work with your health care team to create a weight-loss plan. Losing 5% to 7% of your current weight may help you prevent or improve some health problems  and manage your blood glucose, cholesterol, and blood pressure levels. 2 If you are worried about your child’s weight  and they have diabetes, talk with their health care professional before your child starts a new weight-loss plan.

You may be able to reach and maintain a healthy weight by

• following a healthy meal plan
• consuming fewer calories
• being physically active
• getting 7 to 8 hours of sleep each night 3

If you have type 2 diabetes, your health care professional may recommend diabetes medicines that may help you lose weight.

Online tools such as the Body Weight Planner  may help you create eating and physical activity plans. You may want to talk with your health care professional about other options for managing your weight, including joining a weight-loss program  that can provide helpful information, support, and behavioral or lifestyle counseling. These options may have a cost, so make sure to check the details of the programs.

Your health care professional may recommend weight-loss surgery  if you aren’t able to reach a healthy weight with meal planning, physical activity, and taking diabetes medicines that help with weight loss.

If you are pregnant , trying to lose weight may not be healthy. However, you should ask your health care professional whether it makes sense to monitor or limit your weight gain during pregnancy.

Both diabetes and smoking —including using tobacco products and e-cigarettes—cause your blood vessels to narrow. Both diabetes and smoking increase your risk of having a heart attack or stroke , nerve damage , kidney disease , eye disease , or amputation . Secondhand smoke can also affect the health of your family or others who live with you.

If you smoke or use other tobacco products, stop. Ask for help . You don’t have to do it alone.

Feeling stressed, sad, or angry can be common for people with diabetes. Managing diabetes or learning to cope with new information about your health can be hard. People with chronic illnesses such as diabetes may develop anxiety or other mental health conditions .

Learn healthy ways to lower your stress , and ask for help from your health care team or a mental health professional. While it may be uncomfortable to talk about your feelings, finding a health care professional whom you trust and want to talk with may help you

• lower your feelings of stress, depression, or anxiety
• manage problems sleeping or remembering things
• see how diabetes affects your family, school, work, or financial situation

Ask your health care team for mental health resources for people with diabetes.

Sleeping too much or too little may raise your blood glucose levels. Your sleep habits may also affect your mental health and vice versa. People with diabetes and overweight or obesity can also have other health conditions that affect sleep, such as sleep apnea , which can raise your blood pressure and risk of heart disease.

NIDDK conducts and supports clinical trials in many diseases and conditions, including diabetes. The trials look to find new ways to prevent, detect, or treat disease and improve quality of life.

What are clinical trials for healthy living with diabetes?

Clinical trials—and other types of clinical studies —are part of medical research and involve people like you. When you volunteer to take part in a clinical study, you help health care professionals and researchers learn more about disease and improve health care for people in the future.

Researchers are studying many aspects of healthy living for people with diabetes, such as

• how changing when you eat may affect body weight and metabolism
• how less access to healthy foods may affect diabetes management, other health problems, and risk of dying
• whether low-carbohydrate meal plans can help lower blood glucose levels
• which diabetes medicines are more likely to help people lose weight

Find out if clinical trials are right for you .

Watch a video of NIDDK Director Dr. Griffin P. Rodgers explaining the importance of participating in clinical trials.

What clinical trials for healthy living with diabetes are looking for participants?

You can view a filtered list of clinical studies on healthy living with diabetes that are federally funded, open, and recruiting at www.ClinicalTrials.gov . You can expand or narrow the list to include clinical studies from industry, universities, and individuals; however, the National Institutes of Health does not review these studies and cannot ensure they are safe for you. Always talk with your primary health care professional before you participate in a clinical study.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

NIDDK would like to thank: Elizabeth M. Venditti, Ph.D., University of Pittsburgh School of Medicine.

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• v.15(8); 2023 Aug
• PMC10494960

Unraveling Huntington’s Disease: A Report on Genetic Testing, Clinical Presentation, and Disease Progression

Moutushi ahmed.

1 Internal Medicine, Khulna Medical College, Khulna, BGD

Debasish Mridha

2 Neurology, Michigan Advanced Neurology Center, Saginaw, USA

This study presents the clinical features and disease progression of a 39-year-old male patient diagnosed with Huntington's disease (HD). The diagnosis was confirmed by direct genetic testing, using DNA obtained from a blood sample that revealed expanded cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HD gene). The patient exhibited motor symptoms, including chorea, muscle rigidity, coordination difficulties, and speech and swallowing impairments. Cognitive symptoms comprised impaired judgment, planning difficulties, slowed thinking, memory lapses, and attention problems. The patient's progressive deterioration resulted in wheelchair dependency and increased reliance on supportive care. This report highlights the significance of genetic testing in confirming HD diagnosis and emphasizes the need for a multidisciplinary approach to manage the symptoms and improve the patient's quality of life.

Introduction

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms [ 1 ]. It arises from an abnormal amplification of CAG trinucleotide repeats in the huntingtin gene. This genetic anomaly gives rise to mutant huntingtin protein, instigating a gradual breakdown of various areas within the brain [ 2 ]. Huntington's disease (HD) is a severe condition that causes significant challenges for patients and their families. It requires comprehensive and compassionate care to manage the various symptoms and functional limitations caused by the disease.

HD typically becomes symptomatic in mid-adulthood; however, in some cases, the disease can manifest much earlier in life, known as Juvenile Huntington's disease (JHD). JHD refers to the onset of symptoms before the age of 20 years and accounts for approximately 5-10% of all HD cases. Juvenile HD presents unique challenges compared to the adult-onset form of the disease, with a more aggressive and rapidly progressive disease course. Children with JHD may experience a more severe decline in motor and cognitive functions, leading to profound disability and increased reliance on supportive care [ 3 ].

The clinical presentation of HD includes a wide range of motor symptoms, such as involuntary jerky movements, muscle stiffness, and walking difficulties, which significantly impact daily activities and mobility. Additionally, cognitive impairments, including forgetfulness, trouble concentrating, challenges in planning and organizing, and difficulties in decision-making, ultimately add to the burden of the disease. Psychiatric symptoms, such as mood swings, restlessness, irritability, apathy, lack of interest, impulsivity, and lack of emotion, further contribute to the complexity of managing HD [ 4 - 6 ].

This study aimed to describe HD’s clinical presentation and disease progression in a 39-year-old male patient diagnosed with confirmed expanded CAG repeats in the huntingtin gene through genetic testing.

Case presentation

This study involves a 39-year-old married male who was diagnosed with Huntington's disease (HD) in his late 20s after undergoing genetic testing. The patient has a significant family history of HD, as both his father and sister tragically lost their lives to this devastating condition. His father succumbed to HD, while his sister experienced Juvenile HD and passed away. These familial occurrences highlight the genetic nature of HD and underscore the crucial role of genetic testing in confirming the diagnosis.

The patient married at the age of 25 years, had no children, and worked as an accountant. As time passed, he developed symptoms that affected his concentration and experienced abnormal, uncontrollable movements. His coordination deteriorated, and irritability became a constant struggle. Upon undergoing genetic testing, the diagnosis was confirmed, and his condition continued to worsen. Regrettably, the progression of the disease forced him to give up his job, as its impact on his daily life became too significant to manage. As the disease progressed, the patient's motor symptoms worsened, leading to severe disability, complete wheelchair dependency, and eventual loss of speech.

The patient's neurological examination revealed prominent chorea, generalized rigidity, and dystonia, confirming the motor manifestations of HD. Alongside these motor symptoms, significant cognitive impairments were evident, including attention difficulties, memory lapses, and executive function deficits. Behavioral changes, such as irritability, apathy, and impulsivity, further complicated the disease presentation. Due to the progressive nature of HD, the patient requires constant monitoring and assistance from two caregivers, and he relies on a liquid nutritional supplement (Ensure) with a daily intake of eight servings. The patient has been taking antiepileptic medications, valproic acid (250 mg/5 mL twice daily) and levetiracetam (500 mg twice daily), but the seizures persist, necessitating ongoing management. In addition, he has been taking Austedo (12 mg twice daily), Seroquel (50 mg thrice daily), and Ativan (1 mg) as needed. He has been seeing a psychiatrist, as regular psychiatric follow-up is crucial to address the associated mental health challenges. The patient also undergoes physical therapy (PT) and occupational therapy (OT) thrice a week to manage functional limitations. The family, especially the patient's mother and wife, experiences distress witnessing the continual decline in his health. This study underscores the intricate nature of comprehensive HD management, highlighting the importance of a multidisciplinary approach in managing diverse symptoms and enhancing the patient's overall well-being.

Depending on the patient's family history and any associated signs or symptoms, there are different types of tests used to detect HD, including prenatal, pre-symptomatic, and confirmatory. The diagnosis of HD in this patient was confirmed through confirmatory genetic testing, specifically the detection of expanded CAG repeats in the huntingtin gene.

HD is an autosomal dominant neurodegenerative disorder caused by abnormal expansion of CAG trinucleotide repeats in the huntingtin gene on chromosome 4p16.3. The expanded CAG repeats result in the production of mutant huntingtin protein, leading to progressive neurodegeneration in various regions of the brain.

Genetic testing for HD plays a crucial role in identifying at-risk individuals, confirming the diagnosis, and providing genetic counseling. The most common method for genetic testing involves polymerase chain reaction (PCR) amplification of the CAG repeat region in the huntingtin gene, followed by fragment analysis or DNA sequencing to determine the number of CAG repeats. In individuals with HD, the CAG repeat expansion typically exceeds 36 repeats, whereas a normal allele generally has 10 to 35 CAG repeats (Figure 1 ).

The image is adapted from New NIST SRM helps improve diagnosis of Huntington's disease (April 12, 2011) (https://shorturl.at/gIZ23; public domain).

The number of CAG repeats in the huntingtin gene can provide valuable information about disease prognosis and age of onset. There is an inverse correlation between the number of CAG repeats and the age at which symptoms first appear, known as the age of onset. Individuals with a higher number of CAG repeats tend to experience an earlier onset of symptoms. However, it is important to note that there can be considerable variability in the age of onset, even among individuals with a similar number of CAG repeats [ 7 ].

Conclusions

This study provides crucial insights into the clinical features and progression of Huntington's disease (HD) in a patient diagnosed through genetic testing. It emphasizes the pivotal role of genetic testing in confirming HD diagnosis, especially for individuals with a family history of the disease. Early detection is highlighted, underscoring the importance of timely intervention and comprehensive symptom management to enhance the overall quality of life for affected individuals. An interdisciplinary approach involving specialists from neurology, psychiatry, physical therapy, and occupational therapy is essential in addressing the diverse manifestations of this debilitating neurodegenerative disorder. Through collaboration, healthcare professionals can optimize symptom control, provide support for the patient's well-being, and offer understanding and assistance to families facing the challenges of HD. Ultimately, this collaborative approach aimed to improve HD management and the quality of life for patients and their loved ones, offering hope and compassion throughout the journey of dealing with HD.

Acknowledgments

This study was conducted under the supervision of Debasish Mridha, M.D., and Michigan Advanced Neurology Center.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study