Authors' recommendations: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder characterized by impaired muscle coordination affecting the lower limbs, which progresses to the upper limbs. Speech in individuals with FRDA is typically slow and slurred (dysarthria). FRDA is inherited in an autosomal recessive manner, and is one of the most common heritable ataxias, occurring in approximately 1 in 50,000 white individuals. The mean age at onset of FRDA is between 10 and 15 years old. Difficulty walking is the first apparent symptom in the majority of FRDA patients. Most individuals with FRDA experience dysarthria, loss of lower limb reflexes, lower extremity muscle weakness, and some loss of peripheral sensation and vibration sensation within 5 years of disease onset; scoliosis and lower limb spasticity are also common as disease progresses. In 30% of cases, FRDA is associated with the development of diabetes mellitus, and two thirds of patients suffer from heart disease. A smaller proportion of patients experience vision loss, hearing loss, and bladder dysfunction. The rate of disease progression is variable, but the average FRDA patient is wheelchair-bound within 10 years of diagnosis, and many ultimately become incapacitated. Other symptoms experienced by FRDA patients besides those related to lack of muscle coordination include chest pain, heart palpitations, and shortness of breath related to heart disease, which is a common cause of death in FRDA. The average time of survival from diagnosis is 36 years, although cases of longer-term survival have been reported. FRDA is caused by expansion of a GAA trinucleotide repeat in the frataxin (FXN) gene located on chromosome 9 at band q13. The GAA repeat is located in a noncoding portion of the gene and causes a loss of normal frataxin protein function. Normal FXN alleles contain from 5 to 33 GAA repeats. Disease-causing alleles typically contain from 66 to 1700 uninterrupted GAA repeats. No overlap has been reported between normal and disease-causing alleles. Approximately 96% to 98% of individuals with FRDA are homozygous for the expansion (meaning they carry expansions in both copies of FXN), while 2% to 4% of FRDA patients are compound heterozygotes, carrying a GAA trinucleotide repeat expansion in FXN on one chromosome and an inactivating FXN variant on the other. Penetrance of homozygous GAA trinucleotide repeat expansions and compound heterozygous repeat expansions accompanied by an inactivating FXN variant is complete. No affected individuals with two inactivating FXN variants have been reported. As FRDA is a recessive disorder, carriers who have the trinucleotide repeat expansion or an FXN point variant on only one allele are clinically unaffected. Carrier frequency ranges from 1 in 60 to 1 in 100 in the general population. Disease-causing variants in FXN result in low levels of frataxin protein. Frataxin is important in mitochondrial iron metabolism, and deficiency of frataxin leads to maldistribution of iron, resulting in reduction of mitochondrial function and an increase in oxidative damage. The extent of frataxin deficiency is proportional to the length of FXN repeat expansion. Treatment of FRDA is focused on managing manifestations of disease and preventing secondary complications, and may include various therapies, equipment, medication, and dietary or lifestyle modifications. Research is ongoing in the area of potential drug treatments for FRDA.

Project Status: Completed

Year Published: 2011

URL for published report: http://www.hayesinc.com/hayes/crd/?crd=12965

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: HAYES, Inc.

Contact Address: 157 S. Broad Street, Suite 200, Lansdale, PA 19446, USA. Tel: 215 855 0615; Fax: 215 855 5218

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Contact Email: saleinfo@hayesinc.com

Copyright: 2011 Winifred S. Hayes, Inc