Friedreich Ataxia

FRDA is a progressive spinocerebellar disorder typically having prepubertal onset between ages 5 and 15 years, although exceptions occur, with up to 25% having delayed onset into adulthood. Because of spinal cord, peripheral nerve, and, to a lesser extent, cerebellar atrophy, the initial signs are principally ataxia involving gait and limb function (spinocerebellar tracts) and muscle weakness followed by progressive loss of muscle stretch reflexes at the knees and ankles, contrasting with spasticity and extensor plantar responses (pyramidal tracts). In addition, progressive diminution of proprioception and vibratory sensation (posterior columns) occurs. With steady progression of gait and lower limb dysfunction with foot deformities, that is, equinovarus, pes cavus, and clawed toes, wheelchair dependency occurs as early 10 years after onset.

Progressive dysarthria is typical. Abnormal visual and auditory function occurs, particularly in later stages. Abnormal oculomotor function is quite common; optic atrophy occurs in 25%. Although cognitive function is not affected overall, the speed of information processing is often slowed, with increasing difficulty in complex reasoning. Scoliosis is present in virtually all individuals, requiring constant surveillance for progression, bracing to retard progress, and surgical intervention in up to 20%.

Systemic involvement is also prominent in the form of cardiomyopathy and progressive cardiac conduction defects (arrhythmia and heart block), representing the most common cause of death. In addition, diabetes mellitus and glucose intolerance, requiring glucose monitoring, occur in at least one third of patients.

Assessment of neurologic function involves neuroimaging, clinical electrophysiology (electromyography [EMG]), radiologic evaluation for scoliosis, and testing for visual and audiometric function. Magnetic resonance imaging (MRI) of cerebral hemispheres is normal, but atrophy of the spinal cord, brainstem, and cerebellum are progressive. Motor nerve conduction velocities are generally normal, but sensory nerve studies reveal reduced or absent function. Electrocardiogram (ECG) is recommended at diagnosis and annually thereafter, and echocardiography is recommended with onset of cardiomyopathy.

FRDA has an incidence in Indo-European populations of approximately 1 : 50,000, although isolates have been described at 1 : 25,000. Lower frequencies are reported in Native Americans and residents of sub-Saharan Africa and Southeast Asia.

The normal range of GAA repeats in FXN is 5 to 33, with greater than 80% having less than 12. Affected individuals have at least 70 GAA repeats, although expansions up to 1,700 are described. Most commonly, repeat length is 600 to 1,200. The intermediate range is regarded as a premutation, although the percentage of affected individuals is less than 1%. In the 25% with delayed FDRA onset, the GAA expansion is generally smaller (100-600 repeats), but factors such as genetic background and environmental influences are important variables. FRDA is due to abnormal expansion (equal or different lengths) in both alleles of FXN in approximately 98% of cases. The remainder represents individuals with abnormal expansion in one allele and a point mutation or deletion inactivating the gene in the other allele. No individual has been described lacking an expansion in at least one FXN allele.

Diagnosis of FDRA depends on assessment of FXN in blood by deoxyribonucleic acid (DNA) sequencing methodology capable of detecting GAA expansion and direct assessment of inactivating mutations of nonexpanded regions for the small percentage with a point mutation or deletion. Carrier detection and prenatal diagnosis is recommended for individuals in a family with known disease-producing expansion. Frataxin is a relatively small (210 amino acids) protein that is prevalent in the inner mitochondrial membrane. Required in the formation of iron-sulfur clusters that occur in respiratory chain complexes I to III and aconitase, frataxin deficiency results in defective mitochondrial function, increased mitochondrial free iron, and abnormal energy production in spinal cord and skeletal and cardiac muscle. Differential diagnosis includes peripheral neuropathy (Charcot-Marie-Tooth), spinocerebellar ataxia, ataxia telangiectasia, abetalipoproteinemia, mitochondrial DNA mutations (myoclonus epilepsy with ragged-red fibers [MERF]), and late-onset hexosaminidase deficiency.

In general, survival is significantly shortened in FRDA, with an average longevity of 30 to 40 years after onset. Although no cure exists at present, a number of pharmacologic agents are under investigation. Specific gene therapy is not currently available.

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