title: Friedreich's ataxia: pathology, pathogenesis, and molecular genetics.
abstract: The pathogenic mutation in Friedreich's ataxia (FRDA) is a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. This autosomal recessive disease affects central and peripheral nervous systems, heart, skeleton, and endocrine pancreas. Long expansions lead to early onset, severe clinical illness, and death in young adult life. Patients with short expansions have a later onset and a more benign course. Some are not diagnosed during life. The neurological phenotype reflects lesions in dorsal root ganglia (DRG), sensory peripheral nerves, corticospinal tracts, and dentate nuclei (DN). Most patients succumb to cardiomyopathy, and many become diabetic during the course of their disease. This review seeks to reconcile the diverse clinical features with pathological and molecular data. In the pathogenesis of the lesion in DRG, dorsal spinal roots, and sensory peripheral nerves, developmental defects and atrophy occur in combination. The progressive lesion of the DN lacks a known developmental component. Destruction of the DN, optic atrophy, and degeneration of the corticospinal tracts are intrinsic central nervous system lesions. Fiber loss in dorsal columns and spinocerebellar tracts, and atrophy of the neurons in the dorsal nuclei of Clarke are secondary to the lesion in DRG. The role of frataxin deficiency in the pathogenesis of FRDA is still unclear because the protein has multiple functions in the normal state, including biogenesis of iron-sulfur clusters; iron chaperoning; iron storage; and control of iron-mediated oxidative tissue damage.
authors.affiliation: VA Medical Center, 113 Holland Ave, and Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA. arnulf.koeppen@med.va.gov
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Koeppen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D005621:Friedreich Ataxia / Q000209:etiology / Q000235:genetics* / Q000266:history / Q000473:pathology*; D049672:History, 19th Century; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D007223:Infant; D033862:Iron-Binding Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin