Friedreich's ataxia

Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease.

"Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insular covering on all nerve cells that helps conduct nerve impulses).

Delatycki et al. (2000) provided an overview of the clinical features, pathology, molecular genetics, and possible therapeutic options in Friedreich's ataxia.^[1]

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Eponym

It is named after the German physician Nicholaus Friedreich, who first described the condition in the 1860s. ^[2]

Prevalence

Friedreich's ataxia is the most prevalent inherited ataxia, affecting about 1 in 50,000 people in the United States. Males and females are affected equally.

A 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 French-Canadian kindreds previously thought to be unrelated to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin. ^[3]

Genetics

Friedreich's ataxia is an autosomal recessive congenital ataxia and is caused by a mutation in gene FXN (formerly known as X25) that codes for frataxin, located on chromosome 9. This protein is essential for proper functioning of mitochondria (it has been shown to be connected with the removal of iron from the cytoplasm surrounding the mitochondria, and in the absence of frataxin, the iron builds up and causes free radical damage). Nerve and muscle cells appear to be particularly sensitive to the deleterious effects of this type of mitochondrial dysfunction.

The classic form of Friedreich's ataxia has been mapped to 9q13-q21. In most cases, the mutant gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have been detected. Because the defect is located on an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing (i.e., the mutation decreases the transcription of the gene)through induction of a heterochromatin structure in a manner similar to position-effect variegation.

Relationship to muscular dystrophy

Friedreich's ataxia and muscular dystrophy, though often compared, are different diseases. Muscular dystrophy is the result of muscle tissue degeneration, whereas Friedreich's ataxia is the result of nerve degeneration caused by a trinucleotide repeat expansion mutation. Research on both disorders is supported by funding from the Muscular Dystrophy Association.

Symptoms

Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the 20's or 30's. Symptoms include any combination, but not necessarily all of the following:

• Muscle weakness in the arms and legs
• Loss of coordination
• Vision impairment
• Hearing loss
• Slurred speech
• Curvature of the spine (scoliosis)
• High plantar arches
• Diabetes
• Heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy (enlargement of the heart))

It presents before 25 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved.

These symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood. Because of many of these symptoms, a person suffering from Friedrich's Ataxia may require some surgical interventions (mainly for the spine and heart). Often a metal rod is inserted in the spine to help prevent or slow the progression of scoliosis. As progression occurs, assistive devices such as a cane or walker or a wheelchair are required for mobility (independence).

Signs

• Cerebellar: Nystagmus, fast saccadic eye movements, truncal titubation, dysarthria, dysmetria.
• Pyramidal: absent deep tendon reflexes, extensor plantar responses, and distal weakness are commonly found.
• Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
• Cardiac involvement occurs in 90% of patients, including cardiomegaly (up to dilated cardiomyopathy), symmetrical hypertrophy, murmurs, and conduction defects. Median age of death is 35 years, while females have better prognosis with a 20-year survival of 100% as compared to 63% in men.^{[citation needed]}

20% cases are found in association with diabetes mellitus type 1 or 2 or pancreatic β cell dysfunction.

Pathogenesis

The primary site of pathology is spinal cord and peripheral nerves. Sclerosis and degeneration of spinocerebellar tracts, lateral corticospinal tracts, and posterior columns. In peripheral nerves there is a loss of large myelinated fibres.

Treatment

The symptoms can be treated but there is no treatment for Friedrich's Ataxia at this time. There are several clinical trials taking place, including one for idebenone, in the United States. Assistive Technology, such as a standing frame, can help reduce the secondary complications of prolonged use of a wheelchair. In many cases, patients experience significant heart conditions as well. These conditions, fortunately, are much more treatable, and are often countered with ACE inhibitors such as Lisinopril and other heart medications such as Digoxin.

See also

• Ataxia

References

1. ^ Delatycki M, Williamson R, Forrest S (2000). "Friedreich ataxia: an overview". J Med Genet 37 (1): 1-8 As. PMID 10633128.
2. ^ synd/1406 at Who Named It
3. ^ Barbeau A, Sadibelouiz M, Roy M, Lemieux B, Bouchard JP, Geoffroy G (1984). "Origin of Friedreich's disease in Quebec". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 11 (4 Suppl): 506-9. PMID 6391645.

Patient Recruitment for Friedreich's Ataxia Upcoming Clinical Research Trials: to sign up

• http://www.cureFA.org/registry/

FARA Electronic News Bulletin for latest research and news relevant to Friedreich's ataxia: To sign up

• http://visitor.constantcontact.com/email.jsp?m=1101190303489

• FARA What is Friedreich's Ataxia? at www.cureFA.org
• Babel FAmily Multilingual mailing-list about Friedreich's ataxia. Includes latest news about research and fundraising to help defeat this neurodegenerative disease. at Yahoo! Groups
• friedreichs_ataxia at NINDS
• Asks the Experts - Responses: Friedreich's Ataxia at Muscular Dystrophy Association
• Friedreich's Ataxia Enters 'the Treatment Era' at Muscular Dystrophy Association
• NCBI Genes and Disease: Friedreich's ataxia at National Center for Biotechnology Information
• friedreich at NIH/UW GeneTests
• Ataxia Forums at ataxiaforums.co.uk
• Muscular Dystrophy Association's website in Greece at mdahellas.gr
• http://www.curefa.org/news/pr_2007-04-11.asp
• http://www.lacaf.org/en/ Canadian Association for Familial Ataxias - Claude St-Jean Foundation