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Friedreich's ataxia: clinical aspects and pathogenesis.
Semin Neurol. 1999; 19(3):311-21.SN

Abstract

Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.

Authors+Show Affiliations

Département de Médecine, Université de Montréal, Department of Neurology and Neurosurgery, McGill University, Québec, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

12194387

Citation

Pandolfo, M. "Friedreich's Ataxia: Clinical Aspects and Pathogenesis." Seminars in Neurology, vol. 19, no. 3, 1999, pp. 311-21.
Pandolfo M. Friedreich's ataxia: clinical aspects and pathogenesis. Semin Neurol. 1999;19(3):311-21.
Pandolfo, M. (1999). Friedreich's ataxia: clinical aspects and pathogenesis. Seminars in Neurology, 19(3), 311-21.
Pandolfo M. Friedreich's Ataxia: Clinical Aspects and Pathogenesis. Semin Neurol. 1999;19(3):311-21. PubMed PMID: 12194387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Friedreich's ataxia: clinical aspects and pathogenesis. A1 - Pandolfo,M, PY - 2002/8/27/pubmed PY - 2002/9/18/medline PY - 2002/8/27/entrez SP - 311 EP - 21 JF - Seminars in neurology JO - Semin Neurol VL - 19 IS - 3 N2 - Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death. SN - 0271-8235 UR - https://www.unboundmedicine.com/medline/citation/12194387/Friedreich's_ataxia:_clinical_aspects_and_pathogenesis_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1055/s-2008-1040847 DB - PRIME DP - Unbound Medicine ER -