Friedreich Ataxia

Friedreich ataxia (FA) is the most common hereditary ataxia. It is autosomal recessive, caused by a GAA trinucleotide repeat expansion in the FXN gene on chromosome 9, and the deficient product is the protein frataxin.

Who. The incidence is about 1 in 50,000. Onset is usually between 5 and 15 years, and the earlier the onset, the more severe the disease.

The gene is switched down, not mutated. The expanded GAA repeat lies in the first intron of FXN and causes heterochromatin and transcriptional silencing, so the patient makes too little of a structurally normal frataxin. A quantitative deficiency is why the disease is recessive, both alleles being reduced, and why a larger repeat means less frataxin and earlier, more severe disease.

What frataxin does. Frataxin is a mitochondrial protein essential for the biogenesis of iron-sulphur (Fe-S) clusters and for safe mitochondrial iron handling and storage. Its deficiency impairs the Fe-S-cluster-dependent enzymes, mitochondrial aconitase and respiratory-chain complexes I-III, and leads to mitochondrial iron accumulation and oxidative stress. The cell injury is one of energy deficit and oxidation.

Why these tissues. The damage falls on high-energy-demand, iron-handling tissues, which explains the multisystem pattern:

• Large sensory neurons of the dorsal root ganglia, and the dorsal columns, spinocerebellar and corticospinal tracts - ataxia, proprioceptive loss, and areflexia with extensor plantars
• Cardiomyocytes - hypertrophic cardiomyopathy
• Pancreatic beta cells - diabetes
• The optic and auditory pathways

A single mitochondrial energy and iron defect therefore produces the neurological, cardiac, metabolic and skeletal picture. The therapeutic logic follows from it: omaveloxolone, an Nrf2 activator, targets the oxidative stress.

The neurological lesion. Degeneration of the spinocerebellar tracts, dorsal columns and peripheral nerves produces ataxia, sensory loss and weakness. Pyramidal signs come late: the Babinski response is positive despite absent reflexes.

Why scoliosis develops. Truncal weakness and ataxia combine to produce the curve. Scoliosis is reported in 80-100%, although the two-institution Milbrandt series found it in 63%. Curve patterns are variable, unlike neuromuscular scoliosis, and curves often progress rapidly, especially in wheelchair users.

Cavovarus feet. The mechanism is muscle imbalance, similar to CMT, and the foot deformity may precede the neurological symptoms. The foot is where the two diseases overlap:

Neurological. Gait ataxia is often the first symptom, and it is progressive. Limb ataxia brings intention tremor and dysmetria, and dysarthria slurs the speech.

Other features. Diabetes mellitus affects 10-30%, and vision and hearing may be affected. The skeletal deformities are scoliosis and foot deformity.

History. Establish the age of onset and how the ataxia has progressed, ask about cardiac symptoms such as palpitations and syncope, take a family history and record the patient's mobility status.

Examination. Work through the systems the disease reaches:

1. Gait - wide-based and ataxic
2. Reflexes - absent tendon reflexes with a positive Babinski
3. Sensation - reduced proprioception and vibration
4. Spine - assess the scoliosis
5. Feet - cavovarus, claw toes
6. Heart - listen for murmurs

Hypertrophic cardiomyopathy is the most common cardiac feature and the leading cause of death in FA, and it is the reason cardiology clearance is required before surgery. What the cardiomyopathy actually is matters, because it drives both mortality and perioperative risk.

What it is. A concentric, usually non-obstructive hypertrophic cardiomyopathy: unlike sarcomeric HOCM, there is typically no left-ventricular outflow-tract obstruction. It reflects the cardiomyocyte energy deficit, is common and often subclinical early, and correlates with larger GAA repeats and earlier onset.

How it kills. Many hearts later transition to a dilated, "burnt-out" phase with systolic dysfunction. It is the systolic failure and the arrhythmia, especially atrial fibrillation or flutter and ventricular arrhythmias, that cause death. Arrhythmias and heart failure are common: arrhythmias can be fatal, heart failure is progressive, and sudden cardiac death can occur.

Surveillance. Periodic ECG, echocardiography and Holter monitoring for arrhythmia detect the hypertrophy, the falling ejection fraction and the rhythm disturbance before they become symptomatic.

Management. There is no FA-specific cardiac cure; omaveloxolone is for the neurological phenotype. Cardiology monitors regularly and treats symptoms: beta-blockers if needed, standard heart-failure therapy as systolic function declines, anticoagulation and rate or rhythm control for atrial fibrillation, and device therapy in selected cases.

Why the surgeon cares. Because the cardiomyopathy is usually non-obstructive with preserved systolic function early, a fusion is not absolutely contraindicated. A hypertrophied, poorly compliant ventricle depends on adequate filling and on the atrial contribution to that filling, so the two things that decompensate it on the table are hypovolaemia and a fast, irregular rhythm. That is exactly what blood loss and light anaesthesia produce during a long fusion, and the anaesthetic plan must maintain preload and afterload and avoid tachyarrhythmia, with TIVA, intra-operative echo and meticulous fluid management.

Genetic testing for the GAA repeat expansion in FXN confirms the diagnosis. The rest of the work-up surveys the organs the disease reaches:

• Echocardiogram for hypertrophic cardiomyopathy, and ECG for arrhythmias
• HbA1c and glucose to screen for diabetes
• Spine radiographs for the scoliosis, and foot radiographs to assess the cavovarus

Scoliosis: do not import the generic neuromuscular threshold. Friedreich scoliosis behaves as its own entity, and its natural history is bimodal: curves of 40 degrees or less have tended to remain stable, while curves over 60 degrees have progressed. That, not a single cut-off, should drive the decision.

• Observation with serial films is reasonable for curves at or under 40 degrees. Many of these do not progress, so operating on the number alone over-treats.
• Bracing may slow progression but does not prevent it, and is not definitive treatment. It is used for seating and comfort, or to buy time in a growing child.
• Posterior spinal fusion is for curves in the 40 to 60 degree band that are documented to progress, and for curves already beyond 60 degrees. A single film does not make the decision.

Feet. An AFO gives support. A symptomatic deformity is corrected surgically on CMT principles, with soft-tissue or bony procedures chosen according to flexibility (see Surgical Technique).

Medical care. Diabetes is managed in the standard way, and physiotherapy maintains mobility for as long as possible.

Disease-modifying therapy. Omaveloxolone is now approved (FDA 2023, EMA 2024) and slows neurological decline (MOXIe trial). It is not a cure, and it does not address the orthopaedic deformity or established cardiomyopathy.

Posterior spinal fusion: before surgery. The anaesthetic team must be aware of the cardiomyopathy and experienced in managing it; the physiology that governs the anaesthetic is set out under the cardiomyopathy above. The work-up covers three systems:

• Cardiac - cardiology clearance with a recent echocardiogram and ECG, mandatory before any orthopaedic surgery and above all a scoliosis fusion
• Respiratory - pulmonary function tests if needed
• Diabetes - check the glucose

Technique. A posterior approach with pedicle screw constructs. The extent of fusion depends on the curve: often T2-L4, or to the pelvis if the patient sits.

After surgery. The patient is monitored in ICU with cardiac telemetry, and perioperative risk is high because of the cardiac disease. Mobilise early as tolerated, with physiotherapy to maintain function, and continue cardiology follow-up and orthotic use in the long term.

Foot surgery. The indication is a symptomatic cavovarus deformity, and the operation follows CMT practice. The Coleman block test determines whether the foot is supple or rigid:

• Supple - soft-tissue procedures: plantar fascia release, tendon transfers
• Rigid - bony procedures: Dwyer, calcaneal osteotomy, triple arthrodesis

Afterwards the foot goes into a cast or boot, then orthotics.

Survival. Median life expectancy is 30-40 years, and cardiac disease is the main determinant. The disease progresses relentlessly, and there is currently no cure.

Function. Wheelchair dependency usually follows 10-15 years after symptom onset. Scoliosis surgery improves sitting and may prevent respiratory decline.

Global Epidemiology

• Most common inherited ataxia in populations of European, Middle Eastern, South Asian and North African descent; prevalence roughly 1 in 50,000, carrier frequency around 1 in 60-90.
• Effectively absent in populations of Sub-Saharan African and East Asian origin — a useful exam discriminator pointing away from FA.
• Larger GAA expansions broadly correlate with earlier onset, more frequent cardiomyopathy and diabetes, and faster progression to wheelchair use.

Side-by-Side Practice

Registry & Resource Notes

• No dedicated arthroplasty/implant registry captures FA spinal surgery; evidence rests on single-centre and two-centre series, so outcomes data are inherently limited.
• High-resource settings: TIVA, intraoperative echocardiography, multimodal monitoring and ICU/ECMO backup.
• Limited-resource settings: prioritise cardiac risk stratification and a planned wake-up test where advanced neuromonitoring is unavailable; concentrate care in referral centres.
• Patient organisations (e.g. Friedreich's Ataxia Research Alliance, Ataxia UK) support genetic counselling and multidisciplinary care coordination.