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PubMed1995

Friedreich ataxia.

Friedreich ataxia is an autosomal recessive ataxia with onset usually before puberty whose characteristic clinical features include progressive ataxia of gait and limbs, dysarthria, loss of joint position and vibratory sense, absent knee and ankle jerks, and Babinski signs. Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are common and characteristic. Patients survive until about age 30 years although longer survivals occur. A later onset, more slowly progressive form seems to be an allelic variant. The basic process seems to be a dying-back of neuronal processes. Using linkage mapping techniques, the classical form of Friedreich ataxia has been localized to 9q13-q21, a region on the long arm of chromosome 9. Haplotype analysis, analysis of recombinants, and physical mapping techniques, including construction of a YAC contig, have narrowed the interval for the Friedreich ataxia gene, FRDA, to a few hundred thousand base pairs. Candidate genes in the region are being studied by techniques of mutation analysis. It is likely that the Freidreich ataxia gene will be cloned soon. A condition resembling Friedreich ataxia with decreased vitamin E levels has been localized to chromosome 8 and is discussed elsewhere.

Child↗

PubMed2006

Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedreich ataxia.

Friedreich ataxia is a human neurodegenerative and myocardial disease caused by decreased expression of the mitochondrial protein frataxin. Proteomic analysis of the mutant yeast model of Friedreich ataxia presented in this paper reveals that these cells display increased amounts of proteins involved in antioxidant defenses, including manganese-superoxide dismutase. This enzyme shows, however, lower activity than that found in wild type cells. Our results indicate that this lack of activity is a consequence of cellular manganese deficiency, because in manganese-supplemented cultures, cell manganese content, and manganese-superoxide dismutase activity were restored. One of the hallmarks of Friedreich ataxia is the decreased activity of iron/sulfur-containing enzymes. The activities of four enzymes of this group (aconitase, glutamate synthase, succinate dehydrogenase, and isopropylmalate dehydratase) have been analyzed for the effects of manganese supplementation. Enzyme activities were recovered by manganese treatment, except for aconitase, for which, a specific interaction with frataxin has been demonstrated previously. Similar results were obtained when cells were grown in iron-limited media suggesting that manganese-superoxide dismutase deficiency is a consequence of iron overload. In conclusion, these data indicate that generalized deficiency of iron-sulfur protein activity could be a consequence of manganese-superoxide dismutase deficiency, and consequently, it opens new strategies for Friedreich ataxia treatment.

Aconitate Hydratase↗

PubMed1998

Molecular genetics and pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most frequent cause of inherited ataxia, is due in most cases to a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. The autosomal recessive inheritance of the disease gives this triplet repeat mutation some unique features of natural history and evolution. Frataxin is a mitochondrial protein that has homologues in yeast and even in gram negative bacteria. Yeast deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich ataxia is caused by mitochondrial dysfunction and free radical toxicity.

Friedreich Ataxia↗

PubMed1999

Molecular pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most common type of inherited ataxia, is itself caused in most cases by a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. The autosomal recessive inheritance of the disease gives this triplet repeat mutation some unique features of natural history and evolution. Frataxin is a mitochondrial protein that has homologues in yeast and even in gram-negative bacteria. Yeast organisms deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich ataxia is caused by mitochondrial dysfunction and free radical toxicity.

Friedreich Ataxia↗

PubMedDate not supplied

Iron metabolism and mitochondrial abnormalities in Friedreich ataxia.

Friedreich ataxia is an autosomal recessive disease causing degeneration in the central and peripheral nervous system, cardiomyopathy, skeletal abnormalities and increased risk of diabetes. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded mitochondrial protein. The genetic mutation found in 98% of Friedreich ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the gene. The expanded GAA repeat, by adopting an abnormal triple helical structure, impairs frataxin transcription. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Yeast cells deficient in the frataxin homologue (Deltayfh1) become unable to carry out oxidative phosphorylation, lose mitochondrial DNA, accumulate iron in mitochondria, show unregulated high expression of high affinity iron uptake, and have an increased sensitivity to oxidative stress. Loss of respiratory competence in Deltayfh1 is iron-dependent. Additional properties of these cells include a deficiency of iron-sulfur cluster containing proteins (ISPs) and impaired iron efflux out of mitochondria. Evidence of oxidative stress, mitochondrial dysfunction, deficiency of multiple ISPs and iron deposits are also found in the human disease and in mouse models. The primary function of frataxin is still unknown, however much recent evidence suggests that it enhances iron-sulfur cluster synthesis and protects iron from free radical-generating reactions. The search for frataxin function stimulated more investigations on the role of mitochondria in cellular iron homeostasis. Their results suggest that these organelles may play a central role in controlling iron homeostasis, which is not surprising considering that they are the major cellular site where this metal is utilized. I propose a model, valid in yeast as well as in higher eukaryotes, in which iron transport into mitochondria is directly coupled to its uptake at the cell membrane and iron transport out of mitochondria depends on adequate iron-sulfur cluster synthesis. Regulatory mechanisms in the cytosol would then sense a post-mitochondrial iron pool. Much circumstantial evidence from genetically manipulated yeast and from human diseases supports this model.

Animals↗

PubMed1989

Prenatal diagnosis of Friedreich ataxia.

Friedreich ataxia is a progressive neurodegenerative disorder affecting the peripheral and central nervous systems. One in 50,000 of the population are affected by this recessively inherited disorder, with onset usually before puberty. The recent localization of the disease locus to chromosome 9 has made it possible to provide genetic counselling to families with at least one affected child. Tight linkage of the disease mutation to an anonymous DNA marker MCT112 (D9S15) has been shown with a pairwise lod score of 36.1 at 0 = 0. We report here the first prenatal diagnosis in Friedreich ataxia. Using MCT112 and the confidence interval approach, we have calculated risks for a fully informative family with one affected sib.

Amniocentesis↗

PubMed2004

Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia.

Friedreich ataxia is caused by the expansion of a polymorphic and unstable GAA triplet repeat in the FRDA gene, but the mechanisms for its instability are poorly understood. Replication of (GAA*TTC)n sequences (9-105 triplets) in plasmids propagated in Escherichia coli displayed length- and orientation-dependent instability. There were small length variations upon replication in both orientations, but large contractions were frequently observed when GAA was the lagging strand template. DNA replication was also significantly slower in this orientation. To evaluate the physiological relevance of our findings, we analyzed peripheral leukocytes from human subjects carrying repeats of similar length (8-107 triplets). Analysis of 9400 somatic FRDA molecules using small-pool PCR revealed a similar mutational spectrum, including large contractions. The threshold length for the initiation of somatic instability in vivo was between 40 and 44 triplets, corresponding to the length of a eukaryotic Okazaki fragment. Consistent with the stabilization of premutation alleles during germline transmission, we also found that instability of somatic cells in vivo and repeats propagated in E.coli were abrogated by (GAGGAA)n hexanucleotide interruptions. Our data demonstrate that the GAA triplet repeat mutation in Friedreich ataxia is destabilized, frequently undergoing large contractions, during DNA replication.

DNA↗

PubMed2003

Dominant ataxias and Friedreich ataxia: an update.

PURPOSE OF REVIEW: The present review covers recent developments in inherited ataxias. The discovery of new loci and genes has led to improved understanding of the breadth and epidemiology of inherited ataxias. This has resulted also in more rational classification schemes. Research on identified loci has begun to yield insights into the pathogenesis of neuronal dysfunction and neurodegeneration in these diseases. RECENT FINDINGS: There are a plethora of inherited ataxias due to a variety of mutational mechanisms involving numerous loci. While ataxia and other aspects of cerebellar dysfunction are the core features of these diseases, rational classification has been impeded by the simultaneous variety of associated clinical features and considerable overlap in clinical features among diseases involving different loci. Inherited ataxias can be classified according to mode of inheritance and mechanism of mutations. Dominantly inherited ataxias (spinocerebellar ataxias) are one major group of ataxias. Spinocerebellar ataxias can be subdivided into expanded exonic CAG repeat (polyglutamine; polyQ) disorders, dominantly inherited ataxias with mutations in non-coding regions, and dominantly inherited ataxias with chromosomal localizations but unidentified loci. Another group of dominantly inherited ataxias are episodic ataxias due to ion channel mutations. Recessive ataxias constitute a more heterogeneous group due to loss-of-function effects in numerous loci. A number of these loci have now been identified. Progress has been made in investigating the pathogenesis of neuronal dysfunction/neurodegeneration in several inherited ataxias. Convergent evidence suggests that transcriptional dysregulation is an important component of neurodegeneration in polyQ disorders. Mitochondrial dysfunction is central to pathogenesis of the most common recessive ataxia, Friedreich ataxia. SUMMARY: Mapping of additional ataxia loci and identification of novel ataxia genes continues unabated. Genetic classification enables typology of inherited ataxias. Identification of the affected loci and the mutational mechanisms has allowed the first glimmers of understanding of the pathogenesis of several inherited ataxias.

Ataxia↗

PubMed1999

Clinical and molecular studies in five Brazilian cases of Friedreich ataxia.

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in 94% of cases by homozygous expansions of an unstable GAA repeat localised in intron 1 of the X25 gene. We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes. The GAA expansion was detected in all these patients. The confirmation of FRDA diagnosis in the atypical case may be pointing out, as in other reports, that clinical spectrum of Friedreich's ataxia is broader than previously recognised and includes cases with intact tendon reflexes.

Adult↗

PubMed1997

Deciphering the cause of Friedreich ataxia.

Friedreich ataxia (FA), the most frequent cause of recessive ataxia, is attributable, in most cases, to a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. This gene encodes a novel mitochondrial protein that has homologues of unknown function in yeast and even in gram-negative bacteria. Yeast deficient in the frataxin homologue accumulate iron in their mitochondria and show increased sensitivity to oxidative stress. This finding suggests that FA patients suffer from a mitochondrial dysfunction that causes free-radical toxicity, reminiscent of the clinically similar ataxia caused by inherited isolated vitamin E deficiency.

Animals↗

PubMed2000

Age of the intronic GAA triplet repeat expansion mutation in Friedreich ataxia.

Friedreich ataxia (FRDA), the most frequently inherited ataxia, is due in the vast majority of cases to a large expansion of an intronic GAA repeat. Using linkage disequilibrium analysis based on haplotype data of seven polymorphic markers close to the frataxin gene, the age of FRDA founding mutational event(s) is estimated to be at least 682+/-203 generations (95% confidence interval: 564-801 g), a dating which is consistent with little or no negative selection and provides further evidence for an ancient spread of a pre-mutation (at-risk alleles) in western Europe.

Europe↗

PubMed2006

Iron dysregulation in Friedreich ataxia.

Friedreich ataxia is the most common hereditary ataxia. The signs and symptoms of the disorder derive from decreased expression of the protein frataxin, which is involved in iron metabolism. Frataxin chaperones iron for iron-sulfur cluster biogenesis and detoxifies iron in the mitochondrial matrix. Decreased expression of frataxin is associated with impairments of iron-sulfur cluster biogenesis and heme synthesis, as well as with mitochondrial dysfunction and oxidative stress. Compounds currently in clinical trials are directed toward improving mitochondrial function and lessening oxidative stress. Iron chelators and compounds that increase frataxin expression are under evaluation. Further elucidation of frataxin's function should lead to additional therapeutic approaches.

Amino Acid Sequence↗

PubMed2001

Idebenone in patients with Friedreich ataxia.

Friedreich ataxia (FA), the most common form of degenerative ataxia, is thought to be caused by respiratory deficiency due to mitochondrial iron accumulation and oxidative stress. Idebenone, a free-radical scavenger, protects mitochondrial function in in vitro models of FA. In a placebo-controlled crossover trial we studied the effect of idebenone on respiratory function in nine ambulant FA patients. (31)P magnetic resonance spectroscopy demonstrated mitochondrial impairment in vivo in skeletal muscle of all FA patients, but no recovery with idebenone. No effects were seen in clinical scores. Echocardiography did not confirm a preliminary study reporting improvement of FA-associated cardiomyopathy with idebenone.

Antioxidants↗

PubMed1999

Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia.

Friedreich ataxia (FRDA) is due to mutations in the FRDA gene (FRDA). When the gene homologous to FRDA is knocked out in yeast, there is accumulation of iron in mitochondria and reduced respiratory function. So far, there is only indirect evidence to support the hypothesis that FRDA is due to accumulation of mitochondrial iron leading to increased production of free radicals. We show here that mitochondrial iron is significantly higher in fibroblasts from patients with FRDA than in control fibroblasts. This is the first direct evidence that the findings in yeast are reproducible in cells from patients with FRDA.

Fibroblasts↗

PubMed2000

Recent advances in the molecular pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most frequent cause of recessive ataxia, is due in most cases to a homozygous intronic expansion resulting in the loss of function of frataxin. Frataxin is a mitochondrial protein conserved through evolution. Yeast knock-out models and histological data from patient heart autopsies have shown that frataxin defect causes mitochondrial iron accumulation. Biochemical data from patient heart biopsies or autopsies have revealed a specific deficiency in the activities of aconitases and of mitochondrial iron-sulfur proteins. These results suggest that frataxin may play a role either in mitochondrial iron transport or in iron-sulfur cluster assembly or transport. Iron abnormalities suggest a pathogenic mechanism involving free radical production and oxidative stress, a process that might be sensitive to antioxidant therapies.

Friedreich Ataxia↗

PubMed2006

Iron and Friedreich ataxia.

Friedreich ataxia is due to insufficient levels of frataxin, a mitochondrial iron chaperone that shields this metal from reactive oxygen species (ROS) and renders it bioavailable as Fe II. Frataxin participates in the synthesis of iron-sulfur clusters (ISCs), cofactors of several enzymes, including mitochondrial and cytosolic aconitase, complexes I, II and III of the respiratory chain, and ferrochelatase. It also plays a role in the maintenance of ISCs, in particular for mitochondrial aconitase. A role of frataxin in heme synthesis has been postulated, but is controversial. Insufficient frataxin leads to deficit of ISC enzymes and energy deficit. Iron levels increase in mitochondria. Oxidative stress may result from respiratory chain dysfunction and from direct reaction between iron and ROS. Stress pathways are activated that may lead to apoptosis or other forms of cell death. The basis for the selective vulnerability of specific neurons, like sensory neurons, is still unknown.

Animals↗

PubMed1997

Locus heterogeneity in Friedreich ataxia.

Friedreich ataxia (FRDA) is the most common form of autosomal recessive ataxia. The disease locus was assigned to chromosome 9 and the disease gene, STM7/X25, has been isolated. To date most data suggest locus homogeneity in FRDA. We now provide strong evidence of a second FRDA locus. Studying two siblings with FRDA from two families we did not detect a mutation in STM7/X25. Haplotype analysis of the STM7/X25 region of chromosome 9 demonstrated that the relevant portion of chromosome 9 differs in the patients. Although the patients studied had typical FRDA, one sibpair had the uncommon symptom of retained tendon reflexes. In order to investigate whether retained tendon reflexes are characteristic of FRDA caused by the second locus, FRDA2, we studied an unrelated FRDA patient with retained tendon reflexes. The observation of typical mutations in STM7/X25 (GAA expansions) in this patient demonstrates that the two genetically different forms of FRDA cannot be distinguished clinically.

Adaptor Proteins, Signal Transducing↗

PubMed1996

The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia.

Friedreich ataxia (FA) is associated with the expansion of a GAA trinucleotide repeat in the first intron of the X25 gene. We found both alleles expanded in 67 FA patients from 48 Italian families. Five patients from three families were compound heterozygotes with expansion on one allele and an isoleucine-->phenylalanine change at position 154 on the other one. We found neither expansions nor point mutations in three patients. The length of FA alleles ranged from 201 to 1,186 repeat units, with no overlap with the normal range, and showed a negatively skewed distribution with a peak between 800 and 1,000 repeats. The FA repeat showed meiotic instability with a median variation of 150 repeats. The lengths of both larger and smaller alleles in each patient inversely correlated with age at onset of the disorder. Smaller alleles showed the best correlation, accounting for approximately 50% of the variation of age at onset. Mean allele length was significantly higher in patients with diabetes and in those with cardiomyopathy.

Adolescent↗