Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.
Friedreich's ataxia is the most common inherited ataxia. Ninety‐six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy‐terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino‐terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early‐onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele. Ann Neurol 1999;45:200–206
Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder of motor neurons, leading to a severe muscle weakness and atrophy. 1 Several mutated genes (e.g., Cu/Zn SOD1, FUS/TLS, TARDBP, C9ORF72) have been demonstrated to be implicated in the disease. [1][2][3][4] A recent work demonstrated that TDP-43, a TARDBP gene product, and ataxin-2 (ATXN-2) form a complex that depends on RNA binding and that a small number of patients with ALS are carriers of ATXN-2 intermediate expansions (27-33 glutamines). 5 This finding led to a number of studies from America, Europe, and China that have now demonstrated that ATXN-2 intermediate poly-CAG expansions with CAA interruptions are indeed a risk factor for ALS. [5][6][7][8][9][10][11][12] This effect appears to be specific, as ATXN-2 repeat length intermediate expansions in Alzheimer disease, Parkinson disease, and frontotemporal degeneration were not significantly more frequent than in controls.
13Clinical signs and symptoms of motor neuron degeneration, with bulbar and distal neurogenic muscle atrophy, have been described in spinocerebellar ataxias. [14][15][16] In particular, the protein product of spinocerebellar ataxia 1 (SCA1), ataxin-1 (ATXN-1), forms aggregates in the nucleus and binds to coiled bodies, exerting a toxic effect on RNA metabolism, thus leading to neuron degeneration including motor neurons.
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