Elsevier

Pediatric Neurology

Volume 28, Issue 5, May 2003, Pages 335-341
Pediatric Neurology

Review article
Friedreich’s ataxia

https://doi.org/10.1016/S0887-8994(03)00004-3Get rights and content

Abstract

Friedreich’s ataxia, the most common hereditary ataxia, is caused by expansion of a GAA triplet located within the first intron of the frataxin gene on chromosome 9q13. There is a clear correlation between size of the expanded repeat and severity of the phenotype. 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 oxidative stress, and eventually free-radical mediated cell death. Friedreich’s ataxia is considered a nuclear encoded mitochondrial disease.

This review discusses the major and rapid progress made in Friedreich’s ataxia from gene mapping and identification of the gene to pathogenesis and encouraging therapeutic implications.

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

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      Friedreich ataxia (FRDA, OMIM: 229300) is a debilitating, life-shortening, neurodegenerative disorder affecting mainly the nervous system and the heart. It is classified as a rare disease; however, it is the most common form of inherited ataxia, with an estimated prevalence of 1 in 50,000 individuals in the Caucasian population (Alper and Narayanan, 2003; Delatycki et al., 2000). Symptoms are progressive and usually begin around puberty, although late-onset cases have been described.

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