Trinucleotide repeat and inherited neurological disorders

• A trinucleotide repeat disorder is caused by an unstable short repeat of DNA that grows, generation after generation, beyond a threshold that the gene or its RNA and protein can tolerate.
• The same mechanism produces very different diseases depending on which gene, which repeat, and where in the gene the repeat sits: fragile X syndrome, Friedreich ataxia, Huntington disease and myotonic dystrophy are the classic examples.
• These conditions often show anticipation: an affected parent passes on a larger repeat, so a child can become ill younger and more severely than the parent.
• Testing is molecular, not biochemical, and standard sequencing can miss the diagnosis; the clinician has to name the gene and ask for the repeat specifically.
• There is no cure for most of these disorders, so management is early recognition, symptom control, cardiac and respiratory surveillance, reproductive counselling and support for the family.

By the end of this page you should be able to:

1. Explain what a repeat expansion is and why the same mutation mechanism can silence a gene, create a toxic protein or poison RNA processing.
2. Relate repeat size and location to the clinical picture in fragile X syndrome, Friedreich ataxia, Huntington disease and myotonic dystrophy.
3. Recognise the bedside patterns that point to each of these four disorders.
4. Choose the correct molecular test, interpret normal, intermediate, premutation and full-mutation ranges, and explain reduced penetrance.
5. Describe the multisystem complications that are treatable or preventable (cardiomyopathy, diabetes, arrhythmia, seizures, sleep and respiratory problems).
6. Counsel an at-risk relative about inheritance, anticipation, predictive testing and reproductive options in honest, non-directive terms.

A medical student meets this family of disorders in paediatrics, neurology and genetics clinics. A boy with unexplained learning difficulty and a long face; a girl in a wheelchair with a progressive scoliosis and an abnormal electrocardiogram; a middle-aged man with chorea whose father had something similar; a woman with grip myotonia and premature cataracts. The grouping of two of them under paediatrics is a reminder that these are childhood-onset conditions in many patients, but the mechanism unites all four: a short stretch of DNA, repeated a handful of times in health, expands into hundreds or thousands of copies in disease. ^[1]

These are grouped under "inherited neurodevelopmental disorders" because most are present or begin in the developing nervous system, even when the adult presentation dominates the literature. The molecular cause was understood only after 1991, when the first such expansion was shown in spinal and bulbar muscular atrophy. Since then about 60 repeat expansion disorders have been described, and most of them cause neurological or neurodevelopmental disease. ^[1]

This page teaches the mechanism first, then works through the four named disorders, then pulls them together in a table and a diagnostic flowchart. It ends with the questions a clinician asks every family: who else is at risk, what should be tested, and how is the information given.

A short tandem repeat (STR) is a stretch of DNA made of a short motif, up to six base pairs long, repeated in tandem. Everyone has thousands of these polymorphic stretches; they vary in length between individuals and are the basis of forensic DNA profiling. A repeat expansion disorder occurs when one particular repeat grows, beyond a gene-specific threshold, and that expansion is what causes disease. ^[1]

The repeat can sit anywhere in the gene: in an exon that codes for protein, in an intron, or in an untranslated region (UTR) at either end. Location determines size. Pathogenic repeats in non-coding regions are usually much larger than those in exons. For example, the FMR1 gene is silenced when its 5' untranslated CGG repeat exceeds 200, while an exon CAG repeat of only about 36 to 39 can begin to cause Huntington disease. ^[1]

Four broad molecular mechanisms are recognised, and more than one can operate in the same disease: ^[1]

• Loss of function by silencing. The expanded repeat attracts methylation or compacting proteins that switch the gene off. Fragile X syndrome and Friedreich ataxia are the examples here.
• Toxic gain of function at the protein level. The repeat is transcribed and translated into an abnormal protein with an expanded polyglutamine or polyalanine track that misfolds and kills neurons. Huntington disease belongs to this group.
• RNA toxicity. The repeat is transcribed into an RNA that binds and traps regulatory proteins, disturbing splicing and cell function. Myotonic dystrophy type 1 and type 2 are the prototypes.
• Repeat-associated non-AUG translation. The expanded repeat is translated out of frame, producing toxic peptides even without a normal start codon. This contributes to amyotrophic lateral sclerosis and frontotemporal dementia linked to C9orf72 expansions.

Anticipation is the clinical version of this instability. The repeat is meiotically unstable: it tends to grow when it is passed to the next generation, so the child inherits a larger expansion than the parent and becomes ill earlier and more severely. Minor contractions occur too, especially on the maternal line, but paternal transmission is the one most likely to produce a dramatically larger repeat. ^[1]

A useful classification for the bedside is by inheritance:

• X-linked: fragile X syndrome and the fragile X tremor/ataxia syndrome.
• Autosomal recessive: Friedreich ataxia and most of the spinocerebellar ataxias of this group.
• Autosomal dominant: Huntington disease, myotonic dystrophy types 1 and 2, and most spinocerebellar ataxias.

Friedreich ataxia is the most common inherited ataxia in Caucasian populations, affecting approximately 1 in 29,000 individuals in one consensus guideline and 1 in 50,000 to 100,000 people in United States series. ^[3][4] Friedreich ataxia is autosomal recessive, so most affected children have no family history of ataxia. ^{[4] [7]}

Huntington disease is fully penetrant with more than 39 CAG repeats and shows a strong geographic pattern: prevalence in populations descended from Europe is roughly 10 to 100 times higher than in East Asia. ^[5] In the United Kingdom Huntington disease affects about 1 in 8,000 people. ^{[6] [1]}

Across all repeat expansion disorders epidemiological studies suggest a prevalence of about 1 in 3,000 people worldwide, rising to roughly 1 in 283 individuals when population sequencing data are used, because many carriers never receive a diagnosis and phenotypes are heterogeneous. ^{[1] [7]}

Fragile X syndrome is the most commonly recognised inherited single-gene cause of intellectual disability and of autism spectrum disorder in many series. It occurs in all ethnic groups. Myotonic dystrophy type 1 affects between 1 in 3,000 and 1 in 8,000 people worldwide. ^[2][7]

Inheritance follows the gene's chromosomal location. Fragile X syndrome is X-linked: a mother who carries a premutation has a high chance, for each child, of passing on the fragile X chromosome, and a son who inherits a full mutation develops the syndrome while a daughter is usually less severely affected because of the second, usually normal, X chromosome. ^[2]

Friedreich ataxia is autosomal recessive. The expansion is in the first intron of the FXN gene on chromosome 9. In 96% of patients both mutations are expanded GAA repeats; the remaining 4% have one expanded allele and one point mutation or deletion. ^[3]

Huntington disease is autosomal dominant. Each child of an affected person has a 50% chance of inheriting the mutation, and Huntington disease behaves as a highly penetrant dominant disorder, with both heterozygous and homozygous individuals showing a similar age of onset. ^[6][5]

Myotonic dystrophy type 1 is autosomal dominant. An expansion of over 35 repeats is usually unstable and capable of growing; 50 or more CTG repeats is consistent with the diagnosis. ^[7]

Repeat size is modified by the sex of the transmitting parent. In Huntington disease, paternal transmission is the main cause of anticipation, because spermatogenesis is more prone to repeat growth; juvenile onset has been associated with more than 55 CAG repeats in Chen et al. 2025, usually inherited from the father. ^[1] In myotonic dystrophy type 1 the situation is reversed: a child with severe or congenital disease is much more likely to have inherited a large expansion from the mother, although anticipation can occur with transmission from either parent. ^[1]

Additional risk factors are uncommon and mostly non-modifiable. Intermediate alleles, in the 27 to 35 CAG range for Huntington disease, are not disease-causing in the carrier but can expand into the pathogenic range in offspring. ^[5] Female sex is protective in fragile X, not because the mutation is absent but because FMRP production depends on which X chromosome is active in each tissue. ^[2]

A family history may be absent even when the disorder is inherited. Intergenerational instability can produce generation skipping, a mild or late presentation can be unrecognised in a grandparent, and reduced-penetrance alleles may never have caused symptoms. A clinician should not let a negative family history override a classic phenotype. ^[1]

The path from DNA to illness follows the same three steps in every disorder: transcription, then translation (or not), then the effect on the cell.

Fragile X syndrome. The CGG repeat sits in the 5' untranslated region of FMR1 and is transcribed but not translated. Once the repeat exceeds about 200 copies, the promoter becomes methylated and the gene is effectively switched off. ^[1] The product, fragile X mental retardation protein (FMRP), is an RNA-binding protein that regulates the translation of many other genes, especially those involved in synaptic plasticity. Its absence disrupts brain development, which is why every aspect of fragile X—autism traits, sensory overload, intellectual disability, anxiety—can be traced back to disordered neuronal signalling rather than to structural malformation. ^[2]

Friedreich ataxia. The GAA repeat in the first intron of FXN also acts as a transcriptional silencer. A mixture of heterochromatin formation and R-loop trapping reduces frataxin to a small fraction of normal. Frataxin is a mitochondrial protein required for iron-sulphur cluster assembly; without it, mitochondrial and cytosolic iron-sulphur enzymes fail, iron accumulates in mitochondria, and oxidative stress accumulates. Large sensory neurons in the dorsal root ganglia and the spinocerebellar tracts are the earliest casualties, followed by cardiomyocytes and pancreatic beta cells. ^[3][4]

Huntington disease. The CAG repeat lies in exon 1 of HTT and is translated into a huntingtin protein with an expanded polyglutamine track. The mutation behaves as a toxic gain of function: mutant huntingtin is cleaved, aggregates, and disrupts transcription, axonal transport, mitochondrial function and the ubiquitin-proteasome system. Striatal medium spiny neurons are selectively vulnerable early, which is why chorea, not weakness, dominates the first decade of illness. ^[5]

Myotonic dystrophy type 1. The CTG repeat in the 3' untranslated region of DMPK is transcribed into RNA but not translated in the usual way. The repeat-containing RNA accumulates in the nucleus and sequesters splicing regulators such as MBNL, so that a whole set of downstream genes are spliced incorrectly. This explains the multisystem pattern: chloride channel splicing produces myotonia, insulin receptor splicing produces diabetes, and cardiac sodium and calcium channel splicing produces arrhythmia. ^[7][1]

The meiotic and somatic instability of these repeats is itself part of the disease. In neurons and other tissues the repeat continues to grow during life, which is why symptoms can worsen independently of the inherited size. This also means that the repeat length reported on a diagnostic test is only an estimate of the true size in the brain. ^[1]

Fragile X syndrome is X-linked and usually becomes apparent in the second and third years of life, when speech and language delay become obvious. The mean age of diagnosis in the United States is 36 months. ^[2]

Males are more severely affected than females, because females retain a second X chromosome that can compensate. Only 25 to 30% of females with fragile X syndrome have intellectual disability, although another 30% have a borderline intelligence quotient and many with a normal intelligence quotient have learning or emotional problems. ^[2] More than 90% of boys show developmental delay and 50 to 60% are diagnosed with autism spectrum disorder. ^[2]

Physical features are often subtle in infancy and become more distinctive with age: a long narrow face, large or prominent ears, a high-arched palate, hypermobile joints and macro-orchidism after puberty. Over 80% of individuals have one or more of these features. Boys with more extreme physical findings are not necessarily more severely affected cognitively; the two dimensions overlap but are not identical. ^[2]

Behavioural problems are usually the most disabling part of the syndrome: attention deficit hyperactivity disorder, social anxiety, sensory hyperarousal, shyness, perseverative speech and sometimes self-injurious behaviour. A 15 to 20% seizure rate is reported, more often in those with autism traits. ^[2] Sleep disturbance, recurrent otitis media and gastrointestinal problems (gastro-oesophageal reflux, constipation) are common and treatable. Over 30% of patients suffer from obesity and gastrointestinal dysfunction. ^[2]

A diagnostic pearl: fragile X rarely declares itself in the first year unless there is hypotonia or a family history of learning difficulty. When a toddler has delayed speech with poor eye contact, hand flapping and hyperactivity, fragile X belongs in the differential even if the face looks normal. ^[2]

Friedreich ataxia typically presents between ages 5 and 20 years with gait instability and general clumsiness, and it is slowly progressive. The core neurological picture is an afferent and cerebellar ataxia with dysarthria, loss of vibration and position sense, absent lower-limb reflexes and pyramidal weakness. ^[3][4]

Several features separate Friedreich ataxia from most other ataxias:

• Absent ankle reflexes early, together with extensor plantar responses.
• Position and vibration loss before temperature and pain loss, because large sensory fibres are affected first.
• Scoliosis and foot deformity (pes cavus) in many children.
• Onset in childhood in the classic form; later-onset forms exist and can be missed in adults.

The heart is involved in most patients, although the degree varies. Hypertrophic cardiomyopathy with thickened ventricular walls is the typical lesion, and measures of systolic function may stay normal until late in the disease. Dynamic left ventricular outflow obstruction is uncommon. ^[4] Sixty percent of individuals die of cardiac disease, the main cause of premature mortality in this condition; clinically important cardiac disease is almost always limited to people whose neurological onset was before age 18, who carry larger expansions. ^[3]

Diabetes is a late and variable feature. Estimates of diabetes incidence range from 10 to 65% depending on definition, with abnormal glucose tolerance included. Early-onset patients can present like type 1 diabetes, with ketosis and low insulin and C-peptide, while later-onset patients develop a mixed picture with insulin resistance as the patient ages. ^{[3] [1]}

Huntington disease is classically described as a triad: movement disorder, cognitive decline and psychiatric change, progressing over 15 to 20 years. Chorea is the hallmark: non-suppressible, non-rhythmic jerking that affects the face, trunk and limbs, continuously present while awake and worse with stress. Rigidity, dystonia, incoordination and later dysarthria and dysphagia gradually replace the chorea with a Parkinsonian picture. ^[5][6]

Cognitive change is not memory loss in the Alzheimer sense. It begins with loss of mental flexibility, planning and sequential organisation, and only later involves broader memory and visuospatial function. Psychiatric problems (depression, anxiety, irritability, apathy, obsessive behaviour, psychosis) often begin before the motor diagnosis and are the part of the illness that families remember most. ^[5][6]

Other, less well known but common and disabling features include unintentional weight loss, sleep and circadian disruption, autonomic disturbance and peripheral manifestations in muscle, liver and heart. ^[5]

Juvenile Huntington disease begins before age 20 with a phenotype dominated by rigidity, akinesia and seizures rather than chorea, and is associated with more than 55 CAG repeats in Chen et al. 2025, more than 53 in Andhale et al. 2022 and more than 60 in Massey et al. 2024. ^{[1] [5] [6]}

Myotonic dystrophy type 1 is described as one of the more variable diseases in medicine. Its hallmarks are distal muscle weakness and myotonia, with characteristic involvement of the face, neck and hands, but the same mutation produces disease in the heart, lung, eye, endocrine system, gut and brain. ^[7]

• Muscle. Weakness typically begins distally: grip, ankle dorsiflexion and neck flexion. Myotonia is the delayed relaxation after contraction, often noticed as difficulty releasing a handshake or turning a doorknob. Percussion myotonia can be elicited by tapping the thenar eminence.
• Eye. Posterior subcapsular cataracts develop early and may be the first clue in mild or late-onset cases.
• Heart. Conduction abnormalities and arrhythmia are the principal life-shortening complications; fatal arrhythmias can precede other symptoms.
• Endocrine and metabolism. Insulin resistance, diabetes, hypogonadism in men and thyroid dysfunction are common.
• Respiratory. Weakness of respiratory and bulbar muscles leads to basal atelectasis, hypoventilation and sleep apnoea, which are a common cause of death.
• Gut and brain. Dysphagia, constipation, excessive daytime sleepiness and cognitive or executive changes are frequent.

Myotonic dystrophy type 2 (proximal myotonic myopathy) is caused by a CCTG expansion in CNBP (ZNF9). It produces more proximal weakness and myalgia, without the congenital form and with less central nervous system involvement, and anticipation is not described. ^[1]

The differential depends on which system leads. Table 2 lists the common traps.

The single most important concept is that the clinician must name the gene. Repeat expansions are invisible to standard exome or genome sequencing, which does not reliably size tandem repeats. If Friedreich ataxia is plausible, the laboratory must be asked for FXN GAA repeat analysis first, not whole-exome sequencing; if more testing is needed, sequencing of FXN follows, because 4% of patients need it. ^[3]

Use targeted testing guided by phenotype:

• Fragile X syndrome: CGG repeat sizing of FMR1 by PCR, with Southern blot or methylation analysis when the expansion is large. Repeat size alone is not enough in a male: methylation status determines whether FMRP is produced at all.
• Friedreich ataxia: FXN GAA repeat sizing first; if only one expanded allele is found, sequence FXN for point mutations or deletions. ^[3]
• Huntington disease: HTT CAG repeat sizing on blood DNA. This is a diagnostic test in a person with characteristic features and a positive family history, and a predictive test in an asymptomatic at-risk adult.
• Myotonic dystrophy type 1: DMPK CTG repeat sizing. Best-practice guidelines recommend reporting the size range rather than an exact count, because sizing error is substantial near the borders. ^[1] Specialised assays for variant repeats are needed when the routine result does not fit the clinical picture.
• Other repeat disorders: each has its own assay. A repeat-expansion panel is increasingly available and is the sensible first step when a family shows anticipation and a variable neurological phenotype.

Interpret the result by category rather than by a single cut-off: ^[1][2][5][7]

• Normal: fragile X 5 to 44 CGG (gray zone 45 to 54) in most technical sources, and 6 to 52 CGG in the Chen et al. 2025 repeat table; Friedreich 7 to 22 GAA; Huntington normal alleles are 26 CAG or fewer, with 27 to 35 intermediate (26 or fewer normal, and 27 to 35 intermediate, in Andhale et al. 2022; review tables list 6 to 34 or up to 35); myotonic dystrophy type 1: 5 to 37 CTG. ^{[1] [2] [5]}
• Intermediate or unstable: Huntington 27 to 35 CAG (the carrier is unaffected but the repeat may grow in offspring); myotonic dystrophy type 1: over 35 CTG, an unstable allele. ^[1][7]
• Premutation or reduced penetrance: fragile X 55 to 200 CGG; Friedreich more than 66 GAA repeats; Huntington 36 to 39 CAG; myotonic dystrophy type 1: 50 or more CTG, consistent with a diagnosis. ^[1][5]
• Full mutation or pathogenic: fragile X more than 200 CGG; Friedreich expansions vary widely in length; Huntington 40 or more CAG with near-complete penetrance; myotonic dystrophy type 1 more than 50 CTG. ^[1][5]

Ancillary tests follow the disorder:

• Friedreich ataxia: electrocardiogram, echocardiography and cardiac magnetic resonance imaging for hypertrophic cardiomyopathy; fasting glucose and HbA1c; spinal radiographs for scoliosis; audiology and vision testing.
• Myotonic dystrophy type 1: electrocardiogram in specialist centres; fasting glucose and HbA1c; ophthalmological examination for cataracts; polysomnography if sleep is disordered; lung function. ^[7]
• Huntington disease: Unified Huntington's Disease Rating Scale, cognitive testing and neuroimaging to exclude other causes. ^[5]
• Fragile X syndrome: autism and ADHD assessment, speech therapy evaluation, electroencephalography if seizures are suspected, hearing and vision review.

These are not arbitrary scores; they are repeat ranges with named consequences.

Huntington disease. The offspring who inherit 36 to 39 repeats are at risk, but penetrance is reduced and some never develop symptoms. Forty or more repeats are near-fully penetrant and, given a normal lifespan, produce disease with very high certainty. The intermediate range of 27 to 35 repeats does not cause disease in the carrier but can expand in the next generation, which is why a result in this range still matters for the family even though the individual is unaffected. ^[5] Juvenile-onset disease is associated with large CAG expansions, reported as more than 55 repeats (Chen et al. 2025), more than 53 repeats (Andhale et al. 2022) and more than 60 repeats (Massey et al. 2024). ^{[1] [5] [6]}

Fragile X syndrome. Males with a full mutation (more than 200 CGG repeats with methylation) are affected; females are variably affected depending on the X-activation ratio in the brain. Unmethylated full mutations, which produce residual FMRP, produce a milder phenotype; this is one source of the wide spectrum in females. ^[2]

Friedreich ataxia. More than 66 GAA repeats is the accepted pathogenic threshold, and longer expansions are common in affected children. There is a broad correlation between repeat length and age of onset, with larger expansions associated with earlier, more severe disease and cardiomyopathy, but the correlation is loose enough that repeat number should not be used to predict an individual child's outcome. ^{[4] [1]}

Myotonic dystrophy type 1. An expansion of over 35 repeats is usually unstable and capable of growing, and 50 or more CTG repeats is consistent with a diagnosis. Longer repeat lengths are associated with more severe symptoms and an earlier age of onset. ^[7] Because sizing varies between laboratories, repeat ranges should be interpreted alongside the clinical picture and not read as exact boundaries. ^[7]

No reliable staging system exists for any of these disorders at the individual level. The Unified Huntington's Disease Rating Scale is used to track Huntington disease in research, and the Friedreich Ataxia Rating Scale is used in clinical trials, but neither changes individual management. ^[5]

Management is mostly supportive and multidisciplinary, centred on preserving function, preventing complications and supporting the family. Honesty matters here: no therapy has been shown to stop the progression of Friedreich ataxia, Huntington disease or myotonic dystrophy in the sources used here, and trials of disease-modifying approaches remain ongoing. ^[4]

• Start early. Developmental support, speech therapy and behavioural intervention for fragile X, and physiotherapy and orthopaedic surveillance for Friedreich ataxia, change outcomes even though they do not change the mutation.
• Surveil the at-risk organs. In Friedreich ataxia the organs that kill are the heart and, later, the pancreas; in myotonic dystrophy type 1 the heart and the respiratory muscles; in Huntington disease the consequences of immobility and dysphagia.
• Keep the family in the loop. At-risk relatives often attend the same clinic as the patient. Separate appointments and clear confidentiality agreements prevent the patient's diagnosis from being revealed without their consent.
• Refer early. Cardiology for cardiomyopathy, respiratory medicine and sleep medicine for myotonic or Huntington patients, orthopaedics for scoliosis, genetics for cascade testing.

Interventions are behavioural and educational rather than pharmacological. Special education, speech and language therapy, occupational therapy and sensory integration support are the core, with functional behavioural assessment for aggression, self-injury or anxiety. ADHD and sleep problems can be treated pragmatically with behavioural strategies first and, where necessary, pharmacotherapy directed at symptoms rather than at the syndrome, following the child's developmental profile. Seizures, when they occur, usually respond to standard anti-seizure medicines. ^[2]

There is no established disease-modifying therapy, and reviews stress that the chronic progressive nature of the condition is not slowed by any currently available agent. ^[4] Management therefore targets:

• Cardiac. Follow the generic guidelines for cardiomyopathy. Hypertrophic Friedreich cardiomyopathy does not behave like hypertrophic obstructive cardiomyopathy: negative inotropic agents are not routinely effective, and outflow obstruction is rarely a dominant problem. Beta-blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists and newer agents are used once systolic dysfunction or fluid overload develops. ^[4]
• Diabetes screening. Annual HbA1c and fasting glucose at minimum, with education about symptoms; additional testing or tolerance tests if results are equivocal. Treating as type 1 or type 2 diabetes depends on age of onset and insulin reserve. ^[3]
• Scoliosis and feet. Early bracing and timing of surgery matter; left unchecked, severe scoliosis compounds both respiratory and cardiac impairment.
• Physiotherapy and mobility. Mobility aids should be introduced before falls become frequent. Speech and swallowing assessment should not wait for weight loss.

There is no disease-modifying treatment, and care centres on multidisciplinary support and symptom relief. Chorea is treated when it causes distress, weight loss or injury; tetrabenazine and newer vesicular monoamine transporter-2 inhibitors are used, with awareness of depression and akathisia as adverse effects. Depression, anxiety and psychosis are treated on their merits. Nutrition, swallowing safety and physiotherapy maintain independence for longer than the motor scores predict. ^[6]

Genetic testing is offered in two contexts: diagnostic testing for a person with signs consistent with Huntington disease, and predictive testing for an asymptomatic adult. Predictive testing requires pre-test counselling, time to consider the consequences, and assessment of the person's support and psychological readiness. It is not offered to children for an adult-onset condition unless there is a specific clinical indication. ^[6][5]

Management recommendations are consensus-based rather than evidence-based, because no guidelines of the highest quality exist for this disorder. The essentials are:

• Cardiac. Annual or biennial electrocardiogram in specialist centres, because sudden death from conduction disease can be the first manifestation; Ashizawa et al. 2018 accept either interval. Cardiac pacemakers or implantable defibrillators can prevent life-threatening arrhythmias. ^[7]
• Respiratory. Sleep studies and non-invasive ventilation when indicated; anaesthetic planning is critical—succinylcholine is avoided, and agents and neuromuscular blockade are chosen to minimise myotonic complications. ^[7]
• Myotonia. Mexiletine has been used in small studies, but the evidence is limited and the decision should be made with the neuromuscular team.
• Metabolic. Annual fasting glucose and HbA1c, with treatment of diabetes if required.
• Eyes. Ophthalmological review for cataracts.
• Exercise and lifestyle. Obesity, smoking, inactivity and excess alcohol are associated with more severe disease; regular aerobic and resistance exercise improves function and quality of life. ^[7]

For myotonic dystrophy type 2, the cardiac and respiratory approach is similar, but respiratory muscle weakness is milder and the focus is more on myalgia, proximal weakness and cataract management.

• Cardiac: cardiomyopathy (Friedreich ataxia, myotonic dystrophy), arrhythmia and sudden death (myotonic dystrophy), outflow obstruction rarely (Friedreich ataxia).
• Metabolic: diabetes and glucose intolerance (Friedreich ataxia, myotonic dystrophy).
• Neurological: epilepsy in fragile X syndrome and juvenile Huntington disease; posterior fossa and craniovertebral abnormalities in Friedreich ataxia; dementia and psychiatric disease in Huntington disease.
• Musculoskeletal: scoliosis (Friedreich ataxia), facial and limb deformity in congenital myotonic dystrophy, skeletal dysplasia.
• Sensory: cataracts (myotonic dystrophy), hearing and vision loss (Friedreich ataxia), swallowing and speech problems in advanced Huntington disease and myotonic dystrophy.
• Respiratory and sleep: apnoea, hypoventilation, aspiration pneumonia.
• Reproductive and endocrine: primary ovarian insufficiency in fragile X premutation carriers, hypogonadism in myotonic dystrophy.

Prognosis depends on the disorder and on repeat size, modified by care of the treatable complications. Friedreich ataxia is life-shortening, and cardiac disease is the main cause. ^[3][4] Huntington disease lasts 15 to 20 years after motor onset, with death most often from intercurrent infection or aspiration. ^[5] Myotonic dystrophy type 1 varies from severe congenital disease to mild late-onset cataract and baldness; life expectancy is shortened mainly by cardiac and respiratory complications. ^[7] Fragile X syndrome is not a fatal condition, and life expectancy is essentially normal, but outcomes in cognition, independence and behaviour depend on early intervention and on the family's environment. ^[2]

There is no primary prevention for any of these disorders, because the expansion arises de novo in a minority and is otherwise inherited. What is possible is cascade identification and informed reproductive choice:

• Fragile X. Women with a family history of unexplained intellectual disability, premature menopause or fragile X in relatives should be offered FMR1 carrier testing. Carrier status should be discussed before conception. ^[2]
• Huntington disease. Asymptomatic adults can request predictive testing. Prenatal diagnosis and pre-implantation genetic diagnosis are available for families who want a pregnancy that is not at risk. Each adult decides whether to be tested; children are not tested for an adult-onset condition without clinical need. ^[6]
• Myotonic dystrophy type 1. Testing is offered to relatives of an affected individual, and prenatal testing is available; counselling should emphasise that repeat size predicts poorly for the individual fetus. ^[7]
• Friedreich ataxia. Carrier testing is offered to relatives when the mutation is known. Prenatal diagnosis is possible but unusual, because most families have no previous history. ^[4]

Newborn or population screening is not established for any of these disorders in the sources used here.

Children and adolescents. Fragile X often presents in preschool speech delay; Friedreich ataxia in mid-childhood. Juvenile Huntington disease can begin in childhood with delayed developmental milestones. Congenital myotonic dystrophy presents at birth with hypotonia and respiratory difficulty, usually inherited from the mother. ^[1][2]

Older adults. Premutation carriers, particularly men with 55 to 200 CGG repeats, can develop fragile X-associated tremor/ataxia syndrome decades later, with intention tremor, cerebellar ataxia and cognitive decline. Women with premutations are at risk of primary ovarian insufficiency. ^[1][2]

Pregnancy. There is no specific obstetric protocol in the sources used. Management should be led by a multidisciplinary team. Women with myotonic dystrophy type 1 need careful anaesthetic and respiratory planning, and Friedreich cardiomyopathy may need cardiac optimisation. Genetic counselling and testing decisions for the partner or the fetus belong to the genetics service.

Much of the care for these disorders is clinical; the single most important step is recognition, because the tests, once available, are specific.

• Fragile X syndrome is a clinical diagnosis of suspicion long before genetics. Developmental delay, hand stereotypies, poor eye contact and social anxiety in a boy should trigger a CGG repeat test when it becomes available, and family support and special education in the meantime. ^[2]
• Friedreich ataxia can be recognised from gait ataxia with absent ankle reflexes and extensor plantars, long before genetic testing. Functional mobility, scoliosis care and cardiac auscultation are low-cost interventions. Where echocardiography and cardiac magnetic resonance imaging are unavailable, clinical follow-up for heart failure and avoidance of excessive fluid or salt may reduce harm. ^[4]
• Huntington disease requires no investigation to diagnose in a family with a known history, and supportive care (nutrition, swallowing, physiotherapy, psychiatric care) is the main treatment everywhere. Genetic testing should be done through an official laboratory, not a direct-to-consumer kit, because of the ethical weight of the result. ^[6]
• Myotonic dystrophy type 1 gives itself away at the bedside: grip myotonia, percussive myotonia, distal weakness and cataracts. An electrocardiogram is inexpensive and often reveals the arrhythmia risk before a patient has cardiac symptoms. ^[7]
• General resource-sparing steps: confirm a diagnosis before cascade testing so that limited testing funds are used well; train nurses and physiotherapists to recognise early signs; keep the family informed; and avoid the pitfall of ordering whole-exome sequencing for ataxia when a targeted FXN repeat test is the right first step. ^[3]

Genetic counselling; intellectual disability evaluation; cerebellar ataxia approach; cardiomyopathy; neuromuscular weakness; cataract in systemic disease.