Friedreich's ataxia. Revision of the phenotype according to molecular genetics
| Autor: | G. Frank, C Epplen, Horst Przuntek, Ludger Schöls, G. Amoiridis, Jörg T. Epplen |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Ataxia Adolescent Biology Nuclear Family Genomic Imprinting Trinucleotide Repeats Reference Values Locus heterogeneity Iron-Binding Proteins Molecular genetics medicine Humans Age of Onset Allele Molecular Biology Alleles Genetics Cerebellar ataxia Genetic heterogeneity Genetic Carrier Screening Chromosome Mapping nutritional and metabolic diseases medicine.disease Pedigree nervous system diseases Meiosis Phosphotransferases (Alcohol Group Acceptor) Phenotype Friedreich Ataxia Female Neurology (clinical) medicine.symptom Age of onset Chromosomes Human Pair 9 Trinucleotide repeat expansion |
| Zdroj: | Brain. 120:2131-2140 |
| ISSN: | 1460-2156 |
| Popis: | Friedreich's ataxia is an autosomal recessively inherited neurodegenerative disorder caused by expansions of an unstable GAA trinucleotide repeat in the STM7/X25 gene on chromosome 9q. We studied the (GAA)n polymorphism in 178 healthy controls and 102 patients with idiopathic ataxia. The repeat size ranged from 7 to 29 (GAA)n motifs on normal chromosomes and from 66 to 1360 trinucleotide repetitions in Friedreich's ataxia patients. Meiotic instability of expanded alleles was observed without significant differences in maternal and paternal transmissions. Thirty-six of 102 patients were typed homozygous for expanded (GAA)n alleles. Twenty-seven of these presented with the typical Friedreich's ataxia symptoms and nine patients with an atypical Friedreich's ataxia phenotype. Before molecular genetic diagnosis had been performed seven of these patients had been classified as early onset cerebellar ataxia and two as idiopathic sporadic cerebellar ataxia of late onset. In contrast, in one family with typical Friedreich's ataxia phenotype we did not find an expanded allele; this suggests that there can be either point mutations in the X25 gene on both chromosomes or locus heterogeneity in Friedreich's ataxia. The phenotypic spectrum of Friedreich's ataxia is much broader than considered before. Early onset, areflexia, extensor plantar responses and reduced vibration sense should no longer be considered essential diagnostic criteria of Friedreich's ataxia. In comparison with the non-Friedreich's ataxia group hypertrophic cardiomyopathy seems to be the only symptom specific for Friedreich's ataxia. However, it is not obligatory. The phenotype is significantly influenced by the number of GAA repeats with close genotype-phenotype relationships when the smaller of the two alleles is considered. Repeat length correlated inversely with age at onset, onset of dysarthria and progression rate. In conclusion, molecular genetic analysis appears mandatory for the diagnosis and genetic counselling of Friedreich's ataxia. The molecular genetic test should be applied not only to patients with typical Friedreich's ataxia phenotype but also in all cases of idiopathic autosomal recessive or sporadic ataxia. |
| Databáze: | OpenAIRE |
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