Trinucleotide Repeat Disorders

Etiology

The familial inheritance of trinucleotide repeat disorders is well known. The primary inciting event for this expansion has been studied extensively. Various environmental factors have been postulated to trigger complex cellular responses that activate mechanisms aimed at increasing cell survival. One effect, in response to cold, heat, hypoxic, and oxidative stresses, is the compromise of DNA repair fidelity, which inadvertently increases mutagenesis. This process occurs in microsatellite regions, which are highly mutable and respond with rereplication in the form of trinucleotide repeat expansions.[3]

Epidemiology

The epidemiological characteristics of trinucleotide repeat disorders depend on the specific type. Importantly, the distribution and prevalence of these disorders vary across different populations, reflecting genetic, environmental, and historical factors.

Friedreich Ataxia

Friedreich ataxia is the most commonly encountered autosomal recessive ataxia in clinical settings and accounts for 50% of all cases of hereditary ataxia. The incidence ranges from 1 in 22,000 to 2 in 100,000, with most studies yielding an incidence of approximately 1.5 per 100,000 per year among Europeans and North Americans of European descent. The Friedreich ataxia carrier rate is estimated to be between 1 in 60 and 1 in 90, with a disease prevalence of 1 per 29,000.[4]

Fragile X Syndrome

Studies on the full mutation of Fragile X syndrome in male patients demonstrate that the number of Fragile X cases among Tunisian Jews is 10 times the number in the White population. A lower prevalence of the syndrome has been documented among Native Americans due to fewer CGG repeat sequences. Similar results have been reported among the Spanish Basque population.

Elbaz et al studied the Afro-Caribbean population, and Crawford et al examined an African-American population in metropolitan Atlanta, Georgia, USA. Both investigations suggested a point estimate of disease prevalence of 1 in 2,500 in the general population, which is higher than that observed among White individuals.[5][6] Research indicates that the prevalence of full mutations among White male individuals in the general population is approximately 1 in 4,000. For female individuals affected by Fragile X syndrome, the prevalence is about 1 in 8,000 to 1 in 9,000 in the general population.[7]

Spinocerebellar Ataxia

SCA has a global prevalence of 3 in 100,000, with a wide regional variation. While SCA3 is the most common subtype globally, SCA2 is more prevalent in Cuba than SCA3. SCA7 is the most frequent subtype in Venezuela, and SCA6 is one of the most common autosomal dominant cerebellar ataxias in Northern England. Other similar studies in Germany, the United Kingdom, France, the United States, Japan, and Taiwan confirm the relative rarity of SCA, with prevalence rates of 8, 23, 35, 36, and 42 per 100,000. SCA subtypes are each responsible for less than 1% of undiagnosed autosomal dominant cerebellar ataxia.[8]

Huntington Disease

Huntington disease is an autosomal dominant disorder that results from CAG repeat expansions, usually of paternal origin. The frequency of these expansions is highest in Hispanic Americans and Northern Europeans and lowest in black Africans and East Asians. The prevalence of Huntington disease in these populations could be correlated with the frequency of intermediate or "borderline" alleles.[9]

Myotonic Dystrophy

The frequency of the myotonic dystrophy (DM) gene in the Finnish population is 1 in 1,100, with an equal distribution between myotonic dystrophy types 1 (DM1) and 2 (DM2). A study indicated that DM1 is the most common genetic disease affecting skeletal muscle in England. In the European population, the gene frequency is estimated at 1 in 7,400. DM1 is notably more prevalent in certain populations, such as residents of Northeastern Quebec, where the frequency is 1 in 550. Epidemiological data on DM1 in the United States remains inconclusive. Unlike DM1, DM2 does not exhibit a strong bias for intergenerational expansion, and weak correlations exist between disease severity and expansion size, resulting in less anticipation in DM2 than in DM1.[10]

Pathophysiology

The expression of the mutated phenotype depends on several factors, with 2 key elements being the gender of the parent transmitting the repeat and the stage of development when the genetic sequence is introduced into the genome.

Disease manifestations depend on specific repeat thresholds in both coding and noncoding regions. Disease symptoms appear when the expansion surpasses these thresholds. The larger the repeat sequence in the parent, the higher the likelihood of anticipation.

Anticipation occurs when the repeat expansion in the offspring is larger than in the parent, leading to earlier and more severe disease onset. This cycle continues across generations.

The transmission mechanism is influenced by the affected region of the gene. La Spada et al classified trinucleotide repeat disorders into 2 types: type 1, which are polyglutamine (polyQ) disorders with abnormal CAG repeats in the coding region, and type 2, or nonpolyglutamine (nonpolyQ) disorders, which involve triplet expansions in noncoding regions.[11] The 5 most common disorders in these categories are classified and studied, as explained below.

Noncoding Region Repeats

• Fragile X syndrome: This condition results from CGG repeats in the noncoding region of the Fragile X mental retardation 1 (FMR1) gene. The Fragile X CGG repeat exists in 4 forms: common mutation (6–40 repeats), intermediate mutation (41–60 repeats), premutation (61–200 repeats), and full mutation (>200–230 repeats), with transmission primarily occurring through the maternal line. Significant noncoding expansions are generally less problematic when transmitted paternally. During sperm formation, these expansions can occur up until the primary spermatocyte stage. However, large deletions in pathological expansions, known as "contractions," occur at the spermatogonia stage, which reduces the size of the transmitted expansion. In female individuals, primary germ cells are arrested in the M1 phase and complete meiosis during fertilization. This arrested expansion in primary oocytes is passed on to the offspring during maternal transmission.
• DM1: The inheritance pattern is very similar to Fragile X syndrome in that the abnormal gene is transmitted maternally and in an X-linked dominant manner. However, the length of the CTG expansion and, ergo, the severity of the disease correlate with maternal age, suggesting that the expansion occurs in the quiescent M1 phase of the primary oocyte. Paternal transmission in this condition is also forgiving due to the phenomenon of contraction, as explained above.
• SCA: This class comprises SCAs caused by DNA repeat expansions falling outside the protein-coding region of the respective disease genes. In other words, the pathogenic expansion does not encode glutamine or any other amino acid in the disease protein. Ataxias included in this category are SCAs 8, 10, and 12, although some uncertainty exists about the pathogenic mechanism in SCA8.[12]
• Friedrich ataxia: This condition arises from an autosomal recessive disorder involving GAA triplet expansion in the 1st intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-amino acid protein, frataxin, located in the mitochondria and severely reduced in patients with this condition. An average individual has 8 to 30 copies of this trinucleotide, while patients with Friedrich ataxia have as many as 1,000. The main sites of pathology in Friedrich ataxia are the dorsal root ganglia, posterior columns of the spinal cord, corticospinal tracts, and the heart. A gross examination reveals a small spinal cord, with the posterior and lateral columns particularly affected. Demyelination is seen in the posterior columns. The large fibers arising in the dorsal root ganglia, Clarke column, and dentate nucleus are specifically affected. Iron deposits in the myocardium and, consequently, hypokinetic heart failure have been reported.

Coding Region Expansion

• Huntington disease: The pathological CAG expansion sequence in Huntington disease is most likely due to paternal transmission. The offspring of maternal transmission is largely normal due to a contraction in CAG repeat expansion size. A 3- to 175-fold increase in the number of repeats is favored over contraction once the mutation in the coding region reaches the threshold in male individuals with premutation alleles in the germ cells.
• SCA: This condition follows an autosomal dominant inheritance pattern and is transmitted paternally, typically involving up to 28 repeats. The offspring of an affected younger mother is likely to show a contraction of the CAG repeats. However, in older mothers, the CAG repeats tend to expand in the arrested primary oocyte. Somatic changes in the length of the trinucleotide repeat tract occur in patients with SCA, but heterogeneity does not increase significantly with increasing repeat length.

History and Physical

The 5 main trinucleotide repeat disorders manifest differently. Their typical presentations are discussed below.

Friedrich Ataxia

The cardinal clinical features of Friedrich ataxia include progressive gait and limb ataxia, absent lower limb reflexes, extensor plantar responses, dysarthria, and reduced or absent vibration sense and proprioception, the sensory modalities mediated by posterior column neurons. Cardiomyopathy, scoliosis, and foot deformity are common but nonessential features.

Strict diagnostic criteria (see Image. Friedrich Ataxia Diagnostic Criteria.) were essential to confirm that patients included in studies on the natural history of Friedrich ataxia and molecular research definitely had Friedrich ataxia. Cases that meet these criteria are classified as typical Friedrich ataxia, while those that do not are labeled atypical.

Nerve conduction studies characteristically show the absence of both sensory nerve action potentials and spinal somatosensory evoked potentials, although these values may be reduced or normal early in the disease course. Motor nerve conduction velocities are reduced to a lesser extent than sensory nerve action potentials.

Fragile X Syndrome

The facial features are often less noticeable, particularly in affected women and children. Macroorchidism usually develops during or after puberty and is frequently absent in young patients. Seizures are observed in approximately 20% of affected young boys, with a lower prevalence in adults. Infants with Fragile X syndrome often have relative macrocephaly persisting into adult life. However, the height of affected male adults is below normal. A few patients are either overweight or have persistent overgrowth, potentially leading to misdiagnosis as Prader-Willi or Sotos syndrome. Connective tissue abnormalities, such as congenital hip dislocations and inguinal hernia, may be present during infancy. Connective tissue dysplasia may lead to scoliosis, flat feet, and mitral valve prolapse in later life.

Syndromic associations like the Robin sequence (micrognathia, glossoptosis, and soft cleft palate), FG syndrome (congenital hypotonia, macrocephaly, distinctive face, and imperforate anus), and DiGeorge anomaly (defects of the thymus, parathyroids, and great vessels) have been reported. However, no definite evidence proves any association between these conditions and FMR1 gene aberrations. 

Spinocerebellar Ataxia

The symptoms of SCA include gait ataxia and incoordination, nystagmus or visual problems, and dysarthria. Specific features vary by subtype and may include pyramidal and extrapyramidal signs, ophthalmoplegia, and cognitive impairment. These additional features help distinguish between subtypes.[8] Refer to the table for further classification based on symptoms (see Image. Clinical Features of Different Spinocerebellar Ataxia Subtypes).

Huntington Disease

The classic clinical triad in Huntington disease consists of the following:

• Progressive movement disorder, most commonly chorea
• Progressive cognitive disturbance culminating in dementia
• Various behavioral disturbances that often precede diagnosis and can vary depending on the state of the disease

Although the range of movement disorders in Huntington disease is wide, chorea remains the classic motor sign of this condition. Overt chorea involving larger muscle groups becomes evident over the course of the disease. Patients often incorporate chorea into purposeful movements, known as parakinesia. As this symptom progresses, disabling flailing can manifest in these patients.

Subtle cognitive impairment is among the earlier manifestations in the disease process and is associated with progressive caudate atrophy. Most subjects with Huntington disease have significant cognitive impairment at the time of diagnosis, readily measurable by neuropsychological testing.

Behavioral disorders range from affective illness, most notably depression and apathy, to delusional behavior that can include, rarely, hallucinations. As is true of other progressive neurodegenerative pathologies, the behavioral disorders of Huntington disease evolve during illness. Most Huntington disease gene carriers experience some behavioral symptoms before establishing the diagnosis.[13]

Myotonic Dystrophy

The clinical presentation of myotonic dystrophy varies widely in severity, ranging from a lethal disorder in infancy to a mild form in late adulthood. Prenatal manifestations include reduced fetal movement, polyhydramnios, and ultrasound findings of talipes equinovarus or borderline ventriculomegaly. After birth, neonatal hypotonia, along with feeding and respiratory difficulty, is common. The diagnosis of DM1 must be considered in these patients even when the condition is not reported in the family history, as mothers who carry full mutations and can transmit the condition may be asymptomatic.

The onset of DM1 in childhood myotonic dystrophy occurs after the 1st year but before age 10. The condition often presents with predominant cognitive and behavioral features unaccompanied by conspicuous muscle disease.

Classical or adult-onset DM1 occurs between the 2nd and 4th decades. The most common presenting symptom is myotonia, which is more pronounced after rest and improves with muscle activity—a manifestation known as the warm-up phenomenon. In contrast to relative generalized myotonia, the action myotonia in DM1 selectively involves specific muscle groups of the forearm, hand, tongue, and jaw. The cardinal finding on examination is myotonic myopathy, consisting of action and percussion myotonia, weakness, and muscle wasting in a characteristic distribution.

Evaluation

Clinical suspicion of a repeat disorder is paramount for a successful diagnosis and should not be determined solely based on family history. Trinucleotide disorders may develop sporadically, and patients showing suggestive clinical features should be further evaluated with a genetic test to confirm or exclude the diagnosis.

Polymerase chain reaction (PCR) was traditionally used for genetically isolating repeat expansions. However, multiple shadows observed while sizing these repeats prompted the advent of small-pool PCRs, which allowed for precise quantification of repeat change frequencies. Meanwhile, CGG repeats in these disorders, even today, are measured using a Southern blot. The polymerases have difficulty traversing long CG-rich tracts, making Southern blotting a more accurate diagnostic test. Together, these methods account for 99% of the clinical accuracy.[14]

Treatment / Management

The approved management for trinucleotide repeat disorders is mainly conservative and varies due to the diverse presenting features of these conditions. The treatment approaches are summarized below.

Friedrich Ataxia

Antioxidants are biological and chemical compounds that reduce oxidative damage. Antioxidants commonly used in patients with Friedrich ataxia include coenzyme Q, vitamin E, high-dose ascorbic acid, idebenone (a synthetic coenzyme Q), N-acetylcysteine, selegiline, dehydroepiandrosterone, and pioglitazone.

Pioglitazone is a peroxisome proliferator-activated receptor γ (PPAR-γ) that induces the expression of enzymes involved in mitochondrial metabolism, including superoxide dismutase, which is an important antioxidant defense in nearly all cells exposed to oxygen.[15](A1)

Fragile X syndrome

Careful medical follow-up and, sometimes, intervention are required, as the physical and behavioral problems of patients with Fragile X syndrome are related to their stage of development.

Neuropsychiatric manifestations

Seizures are observed in approximately 20% of male and 5% of female individuals and necessitate a timely diagnosis and treatment. Influencing behavioral problems is difficult, although behavioral therapy and avoidance of overwhelming stimuli may alleviate some of the symptoms. Some physicians recommend pharmacological intervention for behavioral problems. The need for special education and training, especially in younger children, is of primary importance. Speech therapists and physiotherapists can help with language and motor development.

Connective tissue manifestations

During infancy, associated connective tissue abnormalities may present as congenital hip dislocations and inguinal hernias that need surgical correction. Some children fail to thrive due to gastroesophageal reflux, tactile defensiveness, or sucking difficulties.

Problems with sucking require attention from a specialized speech therapist or physiotherapist. Dietary modifications, with or without pharmacotherapy, can help with reflux symptoms.

Head and neck manifestations

Frequent otitis media and sinusitis in approximately 50% of affected children require antibiotics, polyethylene tubes, or both. Approximately 30% to 50% of affected individuals need ophthalmological help for strabismus, myopia, or hyperopia.[16]

Spinocerebellar Ataxia

Gene testing can confirm the diagnosis of SCA. However, the US Food and Drug Administration (FDA) has not approved any specific treatments for this condition.

Although incurable, establishing a specific diagnosis can end the quest for an etiology and facilitate discussions about the prognosis and other family members' genetic risk. The psychological lift of simply putting a name to a previously mysterious disease, even if no cure is available, should not be underestimated for some patients.

Further advancements in treatment are currently in the pipeline. A 24-week neurorehabilitation program with neurorehabilitation therapy, focusing on balance, coordination, and muscle strengthening, has been found to be beneficial for reducing cerebellar symptoms in SCA2.[17] The management of other types of SCA is being studied in detail.(A1)

Huntington Chorea

The current management of Huntington chorea focuses primarily on addressing the symptoms rather than the underlying pathology. Clinicians have increasingly turned to newer atypical antipsychotic drugs for individuals with severe chorea, particularly when accompanied by psychiatric symptoms, such as delusions, that require antipsychotic treatment. Depression, which commonly accompanies Huntington disease, is treated with newer antidepressants. Limited trials of cognitive-enhancing agents, such as memantine, rivastigmine, and donepezil—used primarily in Alzheimer disease—have shown only modest benefits. Bradykinesia and rigidity in younger patients may respond to dopaminergic agents typically used for parkinsonism.

Muscular Dystrophy

The management of muscular dystrophy primarily includes genetic counseling, preserving function and independence, and preventing complications. In DM1, the combined effects of disordered breathing and weakness in the diaphragm and oropharyngeal muscles often lead to respiratory impairment and nocturnal hypoventilation. Monitoring changes in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) from a sitting to a supine position during clinic visits may help. Many patients eventually require noninvasive nighttime ventilatory support. Placing a pacemaker or cardiac defibrillator can be lifesaving for individuals with DM1. An annual ECG should be performed to monitor heart function.

Differential Diagnosis

The differential diagnosis of trinucleotide repeat disorders includes various neurologic conditions with associated systemic symptoms. The list below categorizes these diseases by their resemblance to specific trinucleotide repeat disorders.

Differential Diagnosis of Friedreich Ataxia

• Abetalipoproteinemia
• Ataxia with isolated vitamin E deficiency
• Dentatorubropallidoluysian atrophy
• Hereditary motor and sensory neuropathies
• Refsum disease
• SCA types 1, 2, 3 [18]

Differential Diagnosis of Fragile X Syndrome

• Autism spectrum disorders
• Genetics of Marfan syndrome
• Gigantism and acromegaly
• Pediatric attention deficit hyperactivity disorder
• Pervasive developmental disorder
• Prader-Willi syndrome
• Rett syndrome
• Asperger syndrome [19]

Differential Diagnosis of Spinocerebellar Ataxia 

• Abetalipoproteinemia
• Ataxia with isolated vitamin E deficiency
• Dentatorubropallidoluysian atrophy
• Hereditary motor and sensory neuropathies
• Refsum disease [20]

Differential Diagnosis of Myotonic Dystrophy

• Recessive generalized myotonia
• Limb-Girdle muscular dystrophy
• Duchenne muscular dystrophy
• Myotonia congenita (Thomsen disease)
• Paramyotonia congenita (Eulenburg disease) [21]

Differential Diagnosis of Huntington Disease

• Autosomal dominant disorders
  • Polyglutamine diseases
  • Dentatorubral-pallidoluysian atrophy
  • SCA17
  • Huntington disease-like 2
  • Neuroferritinopathy.
• Recessive and x-linked disorders
  • Neuroacanthocytosis family of diseases

Although Huntington disease presents a distinctive phenotype, mimickers are occasionally encountered in clinical practice. Many of these conditions can be excluded based on the patient’s history or findings from the physical examination. When in doubt, molecular testing may be used to confirm or exclude Huntington disease.

Pertinent Studies and Ongoing Trials

So far, the treatment of trinucleotide repeat disorders has been mainly complication-oriented, with no actual cure for the underlying pathology itself. However, upcoming treatment modalities are being studied at length and are explained in this section.

Treatments That Limit the Expression of Trinucleotide Repeats

Several promising clinical trials are underway to identify effective methods for blocking the translation of aberrant proteins. Pharmacological approaches for treating trinucleotide repeat disorders target 3 levels of genetic expression: DNA, RNA, and protein.

A common pathogenic mechanism in trinucleotide repeat disorders involves protein or RNA toxicity, which leads to neuronal dysfunction and death. Emerging therapies focus on reducing the expression of the mutated gene by targeting messenger RNA (mRNA) using techniques such as antisense oligonucleotide (ASO) binding and RNA interference (RNAi).

Polyglutamate-related disorders, such as Huntington disease and SCA, are at the forefront of trinucleotide repeat disorder research. These efforts aim to lower target mRNA levels either nonspecifically or in an allele-specific manner. Therapeutic agents, including microRNAs (miRNA) or ASOs, inhibit mRNA expression by binding to CUG repeat RNA, thereby blocking pathogenic RNA-protein interactions. This process releases expanded CUG transcripts from nuclear foci, allowing their transport to the cytoplasm for rapid degradation. This reduction in mRNA levels decreases aberrant protein production and cytotoxicity.

As for DNA, research is exploring strategies to prevent pathological repeat expansion by inhibiting DNA repair proteins involved in the expansion process. This approach could help regulate repeat length, though preserving normal DNA repair remains a significant challenge. Further studies are ongoing to refine these strategies.[22]

Therapies Targeting Pathways Promoting Neuronal Loss

Major pathways contributing to potential neuronal loss involve molecular chaperone activity, ubiquitin-proteasome degradation, and autophagy. All 3 pathways have been implicated in polyglutamate-related disorders, and targeting them for treatment may be of value. The target molecules in each path are interrelated. For example, a quality-control protein recently shown to modulate polyglutamate toxicity is the carboxy-terminus of the Hsc70 interacting protein (CHIP), which functions both as a cochaperone and a ubiquitin ligase, thereby linking the chaperone and proteasome pathways. Numerous molecular chaperones, including Hsp70, Hsp40, and the cytosolic chaperonin TRiC, have been shown to suppress polyglutamate aggregation or toxicity in various model systems.

Potential Non-Antioxidant Friedrich Ataxia Treatments

Emerging modalities in this category include the following: 

• Deferiprone is a small molecule that preferentially binds iron, preventing the accumulation of reactive oxygen species and thereby reducing oxidative stress.
• Erythropoietin plays a significant role in the brain's response to neuronal injury and contributes to the wound-healing process.
• Histone deacetylase inhibitors modulate the acetylation levels of chromosomal proteins and other cellular targets, converting silent heterochromatin into active chromatin to restore normal function to silenced genes.
• Interferon γ1b has been shown to increase frataxin expression in dorsal root ganglion neurons in treated mouse models, which also demonstrated improved sensorimotor performance.

Treatment for Normal Aging in Patients with Fragile X Syndrome

FXAP is a protein required in the normal aging process in all individuals. This normal process is hampered in patients with Fragile X syndrome. New targeted treatments for Fragile X syndrome, including mGluR5 antagonists, γ-aminobutyric acid (GABA) A and B agonists, and minocycline, are being studied to that effect.[23] 

Stem Cell Therapy

Marrow stromal cells (MSCs) are under investigation as a treatment for neurodegenerative trinucleotide repeat disorders that are often fatal, particularly Huntington disease. The therapy is being tested in FDA-approved phase I to III clinical trials for various disorders following promising results from extensive preclinical studies on neurodegenerative conditions.

Potential benefits arise from the innate trophic properties of MSCs or the delivery of enhanced growth factors, such as brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). These factors, introduced into the brain using MSCs as delivery vehicles, reduce free radical damage through paracrine actions, support synaptic connections, and promote neuronal survival and regeneration. Current protocols highlight the applicability of MSC-based cellular therapies for treating trinucleotide repeat disorders.[24]

Prognosis

Dilated cardiomyopathy significantly increases morbidity in patients with Friedrich ataxia, as it often necessitates a heart transplant. In contrast, patients with Friedreich ataxia who have only ataxia and diabetes experience debilitating but nonlethal complications.[25]

Patients with Fragile X syndrome generally have a near-normal lifespan. The average age of death is approximately 12 years lower than that of the general population for both men and women, though this difference is likely influenced by ascertainment bias. The primary causes of death are cardiovascular, cerebrovascular, and malignant diseases, which mirror those in the general population. FMRP is a key protein in aging across all individuals, and patients with Fragile X syndrome may experience age-related issues due to its absence. However, further research is necessary to identify the specific subgroups of patients with Fragile X syndrome who are more vulnerable to aging-related problems and how they could benefit from targeted treatments.

Total physical dependency is not the norm in patients with SCA. Although the condition often shortens lifespans, accurate prediction of life expectancy is impossible due to significant variations in the condition's presentation and severity. In some severe cases, the last stages of illness may require continuing care by professionals in a facility.[26]

Huntington disease causes extensive depression that leads to a high suicide rate among affected individuals. The suicide rate in these patients can reach up to 4 times that in the normal population.[27]

Patients with adult-onset myotonic dystrophy have a markedly reduced survival rate, with an observed rate of 18% compared to the expected 78%. A weak positive correlation was found between the length of the CTG repeat and younger age at death. The most common causes of death documented were pneumonia and cardiac arrhythmias.[28]

Complications

Most trinucleotide repeat disorders have a wide spectrum of complications, ranging from debilitating physical disabilities like ataxia, chorea, severe muscle weakness, and connective tissue defects to lethal complications like cardiomyopathy, diaphragmatic weakness, and severe depression, depending on the underlying pathology. Specific associations are as follows: 

• Fragile X syndrome: seizures, otitis media, behavioral disorders, and speech disorders [29]
• Friedreich ataxia: diabetes mellitus, scoliosis, dilated cardiomyopathy, foot deformity, and sensory impairment [30]
• SCA: fatigue, pain, dysautonomia, and rapid eye movement (REM) sleep behavioral disorder
• Huntington disease: manic-depressive disorder, swallowing difficulties, choking, and incontinence [31]
• Myotonic dystrophy: muscle weakness, myotonia, dysphagia, hyperglycemia, female infertility, male pattern baldness, dysphagia, hypogonadotropic hypogonadism, cataracts, learning disabilities, QT lengthening, atrioventricular block, and immune deficiency [32][33]