Review articleFriedreich’s ataxia
Introduction
Friedreich’s ataxia (FRDA) was first reported in 1863 by Nicholaus Friedreich in Heidelberg, Germany. He described the essential findings of the disease: degenerative atrophy of the posterior columns of the spinal cord leading to progressive ataxia, sensory loss, and muscle weakness, often associated with scoliosis, foot deformity, and heart disease [1]. Although it was initially reported more than 150 years ago, the complete clinical spectrum of FRDA and the features that distinguished this disease from other ataxia syndromes have been controversial. The Québec Collaborative Group in 1976 [2] and Harding in 1981 [3] defined the essential clinical criteria for diagnosis of FRDA.
By application of molecular genetic methods, the loci and mutations for many hereditary ataxias have been identified. The FRDA gene was localized to chromosome 9q, and the most common mutation was defined as an unstable expansion of a GAA trinucleotide repeat sequence. Since this discovery, the molecular diagnosis of atypical cases has become possible and the phenotypic spectrum of FRDA has been broadened.
Section snippets
Epidemiology
FRDA is the most common hereditary ataxia. It is an autosomal-recessive neurodegenerative disorder with an estimated prevalence of 1:50000-1:29000 [4], [5], [6], [7]. The incidence is much lower in Asians and those of African descent [8]. The carrier rate has been estimated at 1:120-1:60 [5,9,10].
Clinical features: “core” features and variants
Progressive, unremitting ataxia is the principal feature of this disease. Most commonly, it begins with clumsiness in gait. The onset is usually around puberty, but it may vary from 2-3 years of age to later than 25 years of age [6]. According to Harding [3] the essential clinical features are (1) autosomal-recessive inheritance, (2) onset before 25 years of age, (3) progressive limb and gait ataxia, (4) absent tendon reflexes in the lower extremities, (5) electrophysiologic evidence of axonal
Identification of the gene defect in FRDA
FRDA is inherited as an autosomal-recessive disorder. Families were identified that included multiple individuals affected because of consanguinity. There were pockets of high incidence in southern Italy (concentration of consanguineous marriages), in Cyprus, in French-Canadian families from Quebec, and in the Acadian population of Louisiana. By linkage analysis in these families, in 1988 the FRDA gene was mapped to chromosome 9 [26]. The locus was finely mapped in relation to the closely
Genotype-phenotype correlation
Several studies have described the relationship between length of the GAA repeat and the severity of the disease [9], [12], [14], [16], [24]. Each of these studies has revealed an inverse correlation between GAA repeat length and certain clinical characteristics.
Filla (1996) analyzed 75 patients; 67 patients were homozygous for the expanded GAA sequence [9]. Five patients were compound heterozygous (GAA expansion and point mutation), and three patients manifested no genetic abnormality (they
Role of frataxin in mitochondria
Frataxin has been described to be a mitochondrial protein conserved through evolution [5], [23]. It is thought that frataxin plays a role either in mitochondrial iron transport or in iron-sulphur (Fe-S) assembly and transport [36]. Studies of yeast strains deficient in YFH1, a yeast frataxin homologue, demonstrated that the frataxin is involved in mitochondrial iron homeostasis [37]. Fibroblasts from FRDA patients manifested higher mitochondrial iron levels than controls did [38]. Endocardial
Therapeutic advances
Oxidative stress appears to play a key role in the pathogenesis of FRDA, whether the mitochondrial iron accumulation is primary or secondary. Initial therapeutic trials were with iron chelators such as desferrioxamine, which reduces intracellular iron, but its ability to remove mitochondrial iron is unknown. Normal serum iron and ferritin concentrations have been demonstrated in FRDA patients [43]. Besides, in vitro studies revealed that desferrioxamine caused decreased aconitase activity in
Summary
FRDA is yet another example of diseases caused by trinucleotide repeat expansion. FRDA is caused by expansion of a GAA triplet located within the first intron of the frataxin gene. There is a clear correlation between size of the expanded repeat and severity of the phenotype in FRDA. Frataxin is a mitochondrial protein that plays a role in iron homeostasis. Deficiency of frataxin results in mitochondrial iron accumulation, defects in specific mitochondrial enzymes, enhanced sensitivity to
References (47)
- et al.
Hereditary ataxias
Mayo Clin Proc
(2000) - et al.
Molecular genetics of the hereditary ataxias
Adv Genet
(1998) - et al.
Confirmation of linkage of Friedreich ataxia to chromosome 9 and identification of a new closely linked marker
Genomics
(1989) - et al.
The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure
Am J Hum Genet
(1998) - et al.
Effect on idebenone on cardiomyopathy in Friedreich’s ataxiaA preliminary study
Lancet
(1999) Molecular pathogenesis of Friedreich ataxia
Arch Neurol
(1999)- et al.
Clinical description and roentgenologic evaluation of patients with Friedreich ataxia
Can J Neurol Sci
(1976) Friedreich’s ataxiaA clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features
Brain
(1981)- et al.
Friedreich’s ataxiaAutosomal recessive disease caused by an intronic GAA triplet repeat expansion
Science
(1996) - et al.
Friedreich ataxiaAn overview
J Med Genet
(2000)
Prenatal diagnosis of Friedreich Ataxia
Prenat Diagn
The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia
Am J Hum Genet
Differential stability of the (GAA)n tract in Friedreich ataxia (STM7) gene
Hum Genet
Clinical features and classification of inherited ataxias
Adv Neurol
Phenotypic variability in Friedreich ataxiaRole of the associated GAA triplet repeat expansion
Ann Neurol
Clinical and genetic abnormalities in patients with Friedreich’s ataxia
N Engl J Med
Clinical and genetic study of Friedreich ataxia in an Australian population
Am J Med Genet
Friedreich’s ataxiaRevision of phenotype according to molecular genetics
Brain
Late onset Friedreich’s diseaseClinical features and mapping of mutation to the FRDA locus
J Neurol Neurosurg Psychiatry
Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich’s ataxia locus on chromosome 9q
Ann Neurol
Friedreich’s ataxia with retained tendon reflexesMolecular genetics, clinical neurophysiology, and magnetic resonance imaging
Neurology
“Acadian” and “classical” forms of Friedreich ataxia are probably caused by mutations at the same locus
Am J Med Genet
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