Friedreich’s ataxia (also called FA or FRDA) is a rare, debilitating, degenerative neuro-muscular disorder with a mean age of onset between 10 and 15 years.
The disorder is named after Nicholaus Friedreich, a German doctor who first described the condition in 1863 and it was the first form of hereditary ataxia to be distinguished from other forms of ataxia. It is also the most common of the autosomal recessive ataxias, accounting for at least 50% of cases of hereditary ataxias in most large series.
In Friedreich’s ataxia the spinal cord and peripheral nerves degenerate, becoming thinner. The cerebellum, part of the brain that coordinates balance and movement, also degenerates to a lesser extent. FA symptoms include loss of arm and leg coordination, thick or slurred speech (dysarthria), fatigue, impaired sensory functions, aggressive scoliosis (curvature of the spine), diabetes (occurs in about 10-20% of individuals with FA) and heart conditions including hypertrophic cardiomyopathy and arrthymias. The progressive loss of coordination and muscle strength leads to motor incapacitation and the full-time use of a wheelchair. Most young people diagnosed with FA require mobility aids such as a cane, walker, or wheelchair by their teens or early 20s. The disorder does not affect thinking and reasoning abilities (cognitive functions).
FA is inherited in an autosomal recessive manner meaning both biological parents must be a carrier of the disease for a child to be affected. FA is caused by an unstable GAA expansion situated in intron 1 of the FXN gene encoding frataxin. The gene mutation restricts the production of Frataxin, which is an important protein that functions in the mitochondria (the energy producing factories) of the cell. This iron-binding protein plays a role in the biogenesis of iron-sulfur clusters and iron-trafficking in the mitochondria. A deficiency in this protein leads to the progressive central and peripheral nervous system damage seen in FA.
Estimates of incidence range anywhere from 1 in 22,000 to 2 in 100,000, with most studies yielding an incidence among Europeans and North Americans of European descent of approximately 1.5 per 100,000 per year; a slightly higher incidence has been reported in Quebec. About one in 40-50,000 people in the United States have Friedreich’s ataxia.
Diagnosis of FA typically begins with a clinical examination and detailed neuromuscular exam. The diagnosis is generally confirmed by molecular genetic testing to look for mutations in the FXN gene that causes the disease. Specialized tests may be ordered to evaluate the function of muscles and nerves like Electromyography (EMG) – to record electrical signals it generates during contraction, a nerve conduction velocity test (NCV), CT scan or MRI might be performed to look for changes in the cerebellum.
There is no cure for Friedreich’s Ataxia 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. Surgical procedures can correct foot deformities and scoliosis. 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.
There are several treatment approaches under investigation:
- Decrease oxidative stress and/increase mitochondrial function
- Modulation of frataxin controlled metabolic pathways
- Frataxin stabilizers, enhancers and replacements
- Increase in FA gene expression
- Gene therapy
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