Friedreich Ataxia

Monogenic (Mendelian): 100%, FXN GAA-repeat expansion^[1]

Inheritance: Autosomal recessive, both parents are obligate carriers of a GAA expansion or pathogenic FXN variant.^[1]

Familial proportion: Nearly 100% of cases are inherited (de novo cases exceptionally rare). Siblings of an affected individual have a 25% risk of being affected; parents are carriers (unaffected). Carrier frequency ~1 in 85–100 in European populations.^[1]

Gene: FXN (frataxin), homozygous GAA trinucleotide repeat expansion in intron 1 in ~96% of cases; ~4% are compound heterozygotes (one expansion + one point mutation)

Pathophysiology: Frataxin deficiency → mitochondrial iron accumulation → oxidative stress → cardiomyocyte and neuronal injury

Estimated prevalence 1 in 50,000, the most common inherited ataxia in European populations.^[1]

Carrier frequency approximately 1 in 85–100 in European populations.^[1]

Cardiomyopathy develops in 60–75% of affected individuals and is the leading cause of premature death.^[2]

Onset typically in childhood or adolescence (mean age ~10–15 years).

Confirming the diagnosis: genetic testing for a homozygous GAA trinucleotide-repeat expansion in FXN is diagnostic (a minority are compound heterozygous with a point variant). Larger repeat lengths correlate with earlier onset and a higher risk of cardiomyopathy.^[1]

Neurological: Progressive ataxia, dysarthria, areflexia, proprioception loss

Cardiac (~60-75% have cardiomyopathy):

• Concentric LVH (symmetric, non-obstructive)
• Diastolic dysfunction
• Arrhythmias (atrial fibrillation, ventricular ectopy)
• Progressive to dilated phase in some (poor prognosis)

Other: Diabetes, scoliosis, pes cavus

ECG: LVH, T-wave inversion, short PR interval (in some cases)^[1]

Echo: Concentric LVH (non-obstructive), diastolic dysfunction, annual screening from diagnosis^[2]

Cardiac MRI: Hypertrophy pattern, late gadolinium enhancement (fibrosis marker, prognostic significance)^[2]

Genetic testing: FXN GAA repeat analysis (diagnostic)^[1]

Disease-modifying therapy:

• Omaveloxolone (Skyclarys): Nrf2 activator; FDA-approved February 2023, EMA-approved June 2024; indicated for patients ≥16 years with Friedreich ataxia; slows neurological progression

Cardiac:

• Standard HCM/HF therapy as appropriate
• Treat arrhythmias, heart failure

Supportive: Physiotherapy, occupational therapy, diabetes management

• Hypertrophic (usually concentric) cardiomyopathy: which may transition to a dilated, hypokinetic phase leading to heart failure, a leading cause of death^[1]
• Atrial fibrillation and other arrhythmia.
• Multisystem context: progressive ataxia, diabetes and scoliosis

Cardiac disease major cause of death (~60% of deaths)

Prognosis: Progressive neurological disability, median survival 30s-40s

Based on ESC 2023 Cardiomyopathy guidelines and Friedreich ataxia reviews^[2][1].

Advanced / complicated = LVEF decline or systolic dysfunction, AF, or symptomatic heart failure.

	Uncomplicated / Stable	Advanced / Complicated
Frequency	Annual	Every 6 months
Clinical review	Symptoms, HF signs (may be limited by ataxia)	As above
ECG	Annual 12-lead (widespread T-wave changes)	Each visit
Echocardiography	Annual (LV mass, function)	6-monthly
Holter / ambulatory	Periodic (AF common with LV dysfunction)	As indicated

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Annual cardiac screening (ECG, echo) from diagnosis^[1]
• Cardiomyopathy may precede neurological symptoms^[1]
• Distinguish from HCM - neurological features, family history, genetic testing