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Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder classically characterized by progressive gait and limb ataxia, dysarthria, dysphagia, oculomotor dysfunction, loss of deep tendon reflexes, pyramidal tract signs, scoliosis, and in some, cardiomyopathy, diabetes mellitus, visual loss and defective hearing.
ORPHA:95Classification level: Disorder
The prevalence of FRDA in Caucasians is estimated at 1/20,000 to 1/50,000.
The classical presentation of FRDA begins in childhood or adolescence. General clumsiness and gait ataxia are usually the first signs to appear, often followed by pyramidal signs, upper-limb ataxia and dysarthria. Oculomotor manifestations present early and include fixation instability (square wave jerks) and nystagmus. Visual loss may occur later. Auditory neuropathy (8-39% of cases), leads to hearing difficulties. Intelligence seems unaffected. Areflexia and distal sensory loss is present in most cases. Dysphagia is mild at first but in advanced disease can lead to choking on foods and liquids. Scoliosis and foot deformities (pes cavus and talipesequinovarus) can be mild or debilitating. Spasticity, seen later in the disease course, can lead to discomfort, pain, positioning problems and contractures in some. Cardiac involvement (typically hypertrophic cardiomyopathy) usually develops later in the disease course, but may rarely precede neurological manifestations. Diabetes mellitus, seen in up to 30% of cases, often presents later. Bladder hyperactivity has been reported in some. The average time from symptom onset to wheelchair dependence is 15.5 years (range 3 to 44). Several atypical phenotypes have been described but overlap is significant.
FRDA is caused by an unstable GAA expansion situated in intron 1 of the FXN gene (9q21.11) encoding frataxin. The function of this protein is currently unknown, but the most accepted theory is that it has a role in the biogenesis of iron-sulfur clusters. A deficiency in this protein leads to the progressive central and peripheral nervous system damage seen in FRDA. The length of the shorter allele is inversely correlated to both age of onset and time between onset and wheelchair confinement, and positively with the prevalence of cardiomyopathy.
Motor nerve conduction studies reveal a velocity of greater than 40m/s with absent or reduced sensory nerve action potential. ECG reveals inferolateral or widespread T-wave inversion. MRI may show spinal and cerebellar atrophy. Molecular genetic testing identifies mutations in the FXN gene, confirming diagnosis.
Differential diagnoses include Charcot-Marie-Tooth type 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1 and 2 and other early-onset ataxias.
Prenatal diagnosis is possible in families with a known mutation.
FRDA is inherited autosomal recessively. Genetic counseling is possible.
Management and treatment
There is no cure for FRDA and management is multidisciplinary. Physical therapy and the use of walking aids, prostheses and wheelchairs help maintain an active lifestyle. A speech therapist may be necessary. Stretching programs and the use of frame splints and pharmacologic agents (baclofen and botulinum toxin) help with spasticity. Treatment of cardiac disease includes anti-coagulants, anti-arrhythmic agents and pacemakers. Patients with diabetes mellitus usually require insulin. In later stages, a percutaneous endoscopic gastrostomy tube may be needed. Psychological counseling can be offered. Annual follow-up should include ECG, echocardiography and testing of blood glucose and glycated hemoglobin (HbA1c).
Prognosis has improved but quality of life is still significantly affected. Mean life expectancy is about 40 years, depending on age of onset and presence of diabetes and cardiomyopathy. Death is mainly due to heart disease (cardiac failure or arrhythmia) and bronchopneumonia.
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