Friedreich ataxia and hereditary ataxias

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Hereditary ataxias are genetically diverse and can be autosomal dominant, autosomal recessive, X-linked or mitochondrial. The same gene may produce a variable phenotype, and the same clinical syndrome can arise from many genes. A three-generation pedigree should record age at onset, gait, neuropathy, eye movement, hearing, cognition, epilepsy, autonomic symptoms, cardiomyopathy and unexplained early deaths. Apparent absence of family history does not exclude recessive inheritance, de novo change, adoption, non-paternity, limited family size or late-onset dominant disease.

Friedreich ataxia is the archetypal recessive multisystem ataxia. Degeneration of dorsal-root ganglia and posterior columns causes sensory loss; spinocerebellar and corticospinal tracts add incoordination and pyramidal signs; peripheral neuropathy reduces reflexes. Cardiomyopathy and diabetes need active surveillance even when gait dominates the consultation. Most affected people have GAA expansions on both alleles, while a minority have an expansion and another pathogenic FXN variant, so laboratory strategy and phenotype correlation matter.

Other useful patterns include dominant polyglutamine spinocerebellar ataxias with anticipation, ataxia-telangiectasia with immunodeficiency and malignancy risk, ataxia with vitamin E deficiency, Wilson disease, mitochondrial syndromes, episodic ataxias and RFC1 disease. Some have targeted treatment or surveillance. Genomic diagnosis should therefore follow exclusion of acquired causes and be accompanied by consent covering uncertain results, incidental or familial implications, reproductive options and the limits of a negative test.

Key points

Friedreich ataxia is usually autosomal recessive and caused by biallelic GAA repeat expansions in FXN, reducing frataxin and impairing mitochondrial iron–sulfur biology.
Typical disease begins in childhood or adolescence with progressive gait and limb ataxia, dysarthria, impaired vibration and joint position, absent lower-limb reflexes and extensor plantar responses.
Look beyond neurology: hypertrophic or fibrotic cardiomyopathy, arrhythmia, scoliosis, pes cavus, diabetes, hearing impairment and optic neuropathy materially affect surveillance and prognosis.
The combination of areflexia from peripheral neuropathy and upgoing plantar responses from corticospinal disease is a classic localisation clue in Friedreich ataxia.
Autosomal dominant spinocerebellar ataxias often show vertical transmission and age-related anticipation, but de novo disease, reduced penetrance and small families can obscure the pedigree.
RFC1 biallelic repeat expansion commonly underlies late-onset sensory ataxia, bilateral vestibular areflexia and chronic cough, sometimes grouped as CANVAS.
Routine exome or panel sequencing may miss repeat expansions, mitochondrial variants and structural changes; select the assay through an NHS genomic laboratory and ataxia specialist.
No single rehabilitation or medicine plan fits every inherited ataxia: treat reversible mimics and syndrome complications, offer genetic counselling and review emerging disease-modifying eligibility through a specialist centre.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Friedreich ataxia

Biallelic GAA repeat expansions in FXN reduce frataxin and usually cause a recessive childhood or adolescent-onset multisystem ataxia.

Dominant spinocerebellar ataxias

Repeat expansions and other pathogenic variants can cause vertically transmitted progressive ataxia, sometimes with anticipation, eye, pyramidal, neuropathic or cognitive features.

RFC1-related ataxia

Biallelic RFC1 repeat expansions commonly cause later-onset sensory ataxia with bilateral vestibular failure and chronic cough, sometimes described as CANVAS.

Mitochondrial and other recessive disease

Energy-production, DNA-repair, vitamin-transport and metabolic disorders produce varied ataxia phenotypes and may require assays not captured by routine sequencing.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Frataxin and mitochondrial dysfunction
In Friedreich ataxia, reduced frataxin impairs mitochondrial iron–sulfur biology and contributes to progressive neurological and multisystem disease.
2
Selective pathway degeneration
Cerebellar, dorsal-column, spinocerebellar and peripheral sensory pathways progressively fail, producing coordination loss with mixed reflex and pyramidal findings.
3
Accumulating motor disability
Inaccurate sensory feedback and cerebellar timing destabilise gait, speech, swallowing and eye movements as neuronal reserve declines.
4
Systemic organ involvement
Some variants affect myocardium, endocrine organs, hearing, vision and skeleton alongside neurological tissue, making syndrome-specific surveillance essential.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Friedreich neurological pattern

Progressive gait and limb ataxia combines with dysarthria, lost proprioception, absent ankle and knee jerks and extensor plantar responses, often beginning before adulthood.

Friedreich systemic pattern

Scoliosis, pes cavus, cardiomyopathy, arrhythmia, diabetes, hearing difficulty and optic atrophy should be sought rather than waiting for symptoms to declare them.

Dominant spinocerebellar ataxia

Successive affected generations, variable onset and anticipation may accompany cerebellar, pyramidal, extrapyramidal, retinal, cognitive or neuropathic features.

RFC1 spectrum

Late-onset sensory neuronopathy with bilateral vestibular failure, oscillopsia, cerebellar ataxia and a longstanding spasmodic cough is a strong CANVAS-pattern clue.

Ataxia-telangiectasia

Childhood gait disorder with oculomotor apraxia, conjunctival or cutaneous telangiectasia, recurrent respiratory infection and cancer susceptibility suggests ATM-related disease.

Red flags requiring action

Syncope, exertional chest pain, palpitations or breathlessness in suspected Friedreich ataxia requires urgent cardiac assessment for cardiomyopathy or arrhythmia.
Rapid deterioration over weeks, constitutional symptoms or new encephalopathy is atypical for most hereditary ataxias and needs urgent acquired-cause investigation.
Dysphagia, recurrent aspiration, weak cough or weight loss requires prompt swallowing, nutrition and respiratory assessment.
A child with ataxia, recurrent infections and telangiectasia may have a radiosensitive DNA-repair disorder; involve specialist immunology and genetics before avoidable ionising exposure.
A variant of uncertain significance must not be used as a predictive diagnosis in relatives or as sole justification for irreversible treatment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
FXN repeat-expansion analysisFirst step
Why
Confirm the common molecular cause of Friedreich ataxia and identify biallelic expanded alleles.
Interpretation and limitations
A compatible phenotype with only one expansion may require sequencing or deletion analysis for a second pathogenic allele through the genomic laboratory.
02
NHS hereditary ataxia genomic testing
Why
Detect dominant, recessive, RFC1, mitochondrial or other genetic causes using phenotype-appropriate assays.
Interpretation and limitations
Review the current Genomic Test Directory because eligibility and panels evolve; confirm whether repeat expansions and mitochondrial DNA are included rather than assuming sequencing covers them.
03
MRI brain and spinal cord when indicated
Why
Define cerebellar, brainstem or cord atrophy and exclude acquired structural or inflammatory disease.
Interpretation and limitations
Friedreich ataxia may show spinal cord atrophy without striking early cerebellar atrophy; imaging pattern supports but does not replace molecular diagnosis.
04
Neurophysiology and vestibular testing
Why
Characterise sensory neuronopathy, peripheral neuropathy and bilateral vestibular hypofunction in mixed ataxia.
Interpretation and limitations
Absent sensory responses with relatively preserved motor conduction supports neuronopathy; combine with bedside head impulse and formal vestibular results.
05
ECG and echocardiography
Why
Detect hypertrophic remodelling, systolic dysfunction and rhythm abnormalities associated with Friedreich ataxia.
Interpretation and limitations
Cardiac severity can diverge from neurological disability; specialist follow-up frequency follows findings, symptoms and the inherited-disease protocol.
06
Glucose and HbA1c
Why
Screen for diabetes and impaired glucose regulation in Friedreich ataxia and selected mitochondrial syndromes.
Interpretation and limitations
Repeat at the syndrome-defined interval and investigate symptoms promptly; treatment should consider nutrition, mobility and cardiomyopathy.
07
Treatable-cause biochemical screen
Why
Assess vitamin E, B12, thyroid, coeliac, copper, caeruloplasmin and other phenotype-directed metabolic causes before declaring a degenerative genetic disorder.
Interpretation and limitations
Interpret concentrations against supplementation, inflammation and age; use specialist confirmation where a result leads to lifelong treatment or family testing.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Toxic or nutritional ataxia

Alcohol, medicines, thiamine, vitamin B12, vitamin E and copper disorders may be treatable and should be assessed before progressive symptoms are assumed genetic.

Immune or paraneoplastic ataxia

Subacute evolution over weeks, systemic inflammation or cancer context favours autoimmune, demyelinating or paraneoplastic disease rather than slow inherited degeneration.

Multiple-system atrophy

Rapid adult progression with severe autonomic failure, parkinsonism or stridor supports MSA, though genetic late-onset ataxia can include autonomic symptoms.

Functional gait disorder

Positive inconsistency and preserved automatic movement support functional dysfunction, while a coherent progressive neurological phenotype and abnormal neurophysiology favour inherited disease.

Additional chapter-specific clues

Treatable inherited mimic

Retinopathy, neuropathy, dystonia, liver disease, malabsorption or very low vitamin E may indicate a metabolic or nutritional disorder where targeted treatment can alter progression.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SUSPECT FAYoung progressive ataxiaFirst stepA child or young adult has progressive gait ataxia with areflexia, sensory loss or skeletal features.

1Document onset, milestones, school and function, perform full cerebellar, sensory, reflex and plantar examination and construct a three-generation pedigree.
2Arrange specialist neurology and clinical genetics referral and request FXN repeat-expansion analysis through the NHS genomic pathway.
3Obtain baseline ECG, echocardiography, glucose assessment, hearing, vision, spine, foot, swallowing and mobility evaluation.
4Give a coordinated diagnosis discussion and rehabilitation plan, and offer carrier and reproductive counselling after molecular confirmation.

02ADULTLate-onset inherited ataxiaProgression over years, family history or sensory–vestibular clues suggests adult hereditary disease.

1Exclude alcohol, medicines, immune, malignancy, nutritional and structural causes and record cough, hearing, neuropathy, eye and autonomic symptoms.
2Use the pedigree and phenotype to prioritise dominant repeat expansions, RFC1, recessive, mitochondrial or broader testing.
3Confirm assay coverage with the genomic laboratory and interpret pathogenic, uncertain and negative results in a specialist clinic.
4Tailor surveillance, symptomatic treatment, rehabilitation and family counselling to the molecular diagnosis rather than the label ataxia alone.

03RESULTGenetic result returnedTesting identifies a pathogenic variant, uncertain variant or no explanatory finding.

1Check that genotype, inheritance and phenotype agree and seek laboratory clarification of phase, repeat size or secondary analysis when needed.
2Explain what the result does and does not predict, including variable onset and severity, and record the discussion in accessible language.
3Offer targeted testing to relatives only when the familial finding is sufficiently classified and consent, autonomy and predictive-testing standards are met.
4For a negative or uncertain result, continue clinical care and consider reanalysis as test technology and gene–disease evidence change.

04SUPPORTMultisystem long-term careA hereditary ataxia diagnosis is established or strongly supported clinically.

1Coordinate neurology, physiotherapy, occupational therapy, speech and language, dietetics, wheelchair and falls services around current function and goals.
2Follow syndrome-specific cardiac, endocrine, respiratory, skeletal, hearing, visual and malignancy surveillance through named teams.
3Treat spasticity, pain, bladder, sleep, mood and tremor cautiously, measuring function and avoiding sedation that worsens balance.
4Review emerging disease-modifying treatments and research eligibility only through specialist centres using current licensing and commissioning criteria.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Can stabilise or improve neurological disease in ataxia with vitamin E deficiency when treatment begins promptly.

Vitamin E for confirmed deficiency ataxia

Use a specialist-prescribed high-dose oral alpha-tocopherol regimen titrated to the specific inherited deficiency, body weight and serum response rather than a routine supplement dose.

Confirm the diagnosis and monitor concentrations and bleeding risk, particularly with anticoagulants; vitamin E does not treat genetically unrelated ataxias.

May reduce painful spasticity in an inherited ataxia with pyramidal features and improve positioning or care.

Baclofen

Start with a low oral dose, commonly 5 mg up to three times daily, and titrate gradually to function and tolerance under the rehabilitation or neurology plan.

Sedation and weakness can worsen transfers and falls; reduce for renal impairment and avoid abrupt withdrawal after established treatment.

Targets disease biology in the limited hereditary ataxias for which an approved or commissioned therapy exists rather than providing generic symptomatic benefit.

Disease-modifying treatment

Use only the licensed dose for a molecularly confirmed eligible syndrome after specialist review of age, organ function, interactions and current NHS commissioning criteria.

Availability and evidence change rapidly; do not extrapolate between genotypes, and complete product-specific hepatic, cardiac or reproductive monitoring.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cardiomyopathy and arrhythmia

Friedreich ataxia can cause hypertrophic or fibrotic cardiac disease, heart failure and rhythm disturbance that may dominate prognosis.

Diabetes and multisystem morbidity

Endocrine, hearing and optic-nerve involvement can add metabolic risk and sensory disability beyond ataxia and complicate long-term care.

Scoliosis and respiratory restriction

Spinal deformity, weakness and impaired cough can reduce respiratory reserve, complicate seating and contribute to pain.

Mobility, speech and swallowing loss

Progressive ataxia causes falls, wheelchair dependence, dysarthria, aspiration and nutrition problems requiring coordinated rehabilitation and communication support.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure gait, falls, upper-limb function, speech, swallowing and activities of daily living with consistent clinical or therapy outcomes.
In Friedreich ataxia, complete regular ECG, echocardiographic and symptom-led rhythm review under cardiology because cardiac progression may be clinically silent.
Screen glucose regulation at the specialist-defined interval and sooner for polyuria, weight loss or infection.
Follow weight, nutrition, scoliosis, foot deformity, pain, respiratory function and aspiration risk across growth and disease progression.
Review hearing and vision rather than assuming communication difficulty is purely dysarthria or cognitive.
After any symptomatic medicine, assess sedation, weakness, balance and actual functional gain before dose escalation.
Update genetic counselling when reproductive plans, family structure, variant classification or testing technology changes.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Reflexes can appear contradictory

Peripheral sensory neuropathy removes tendon reflexes while corticospinal tract disease produces extensor plantar responses in the same patient with Friedreich ataxia.

Pedigrees can look negative

Recessive inheritance, de novo change, reduced penetrance and relatives dying before onset all conceal genuinely inherited disease.

Repeat size is not destiny

FXN expansion length correlates imperfectly with onset and severity and should not be presented as a precise individual prognosis.

CANVAS may begin with cough

A chronic spasmodic cough can precede gait, sensory and vestibular manifestations of biallelic RFC1 disease by many years.

Cardiac disability can be hidden

Reduced mobility can mask exertional symptoms, so surveillance should not depend solely on reported exercise intolerance.

A negative exome is incomplete

Repeat expansions, mitochondrial variation and some structural variants require methods outside standard exome analysis.

11Common pitfallsFrequent interpretation and management errors.

01
Do not diagnose Friedreich ataxia from pes cavus and ataxia alone without molecular confirmation and acquired-cause assessment.
02
Do not forget cardiac and diabetes surveillance because neurological disability dominates the consultation.
03
Do not infer dominant inheritance is absent because only one small generation appears affected.
04
Do not use a routine sequencing panel without checking that relevant repeat expansions, including FXN and RFC1, are tested.
05
Do not offer predictive testing to a healthy relative on the basis of a variant of uncertain significance.
06
Do not treat all inherited ataxias with unregulated supplements; targeted replacement requires a confirmed or strongly supported deficiency.
07
Do not allow genetic testing to delay physiotherapy, swallowing care, mobility equipment and symptom control.