OBJECTIVE: To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. DESIGN: We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. RESULTS: In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. CONCLUSIONS: We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.
- MeSH
- amidy MeSH
- aminobutyráty MeSH
- butyráty MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny * genetika MeSH
- mladiství MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- polyneuropatie * genetika komplikace patologie MeSH
- senioři MeSH
- spastická paraplegie dědičná genetika komplikace patologie MeSH
- věk při počátku nemoci MeSH
- vezikulární transportní proteiny * genetika MeSH
- zdraví rodiny MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- chybná diagnóza prevence a kontrola MeSH
- dítě MeSH
- kalpain genetika MeSH
- nemoci svalů genetika MeSH
- Check Tag
- dítě MeSH
- Publikační typ
- kongresy MeSH
- MeSH
- genetické techniky MeSH
- prenatální diagnóza MeSH
- svalová atrofie diagnóza genetika MeSH
- Geografické názvy
- Bulharsko MeSH
- MeSH
- genetické nemoci vrozené prevence a kontrola MeSH
- Geografické názvy
- Bulharsko MeSH
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism. It is one of the most frequent genetic metabolic disorders among Caucasian children. The G985 allele represented 90% of all the variant alleles of the MCAD gene in an extensive series of retrospective studies. To study the distribution of the G985 allele, newborn blood samples from the following countries were tested; 3000 from Germany (1/116). 1000 each from Belgium (1/77). Poland (1/98), Czech Republic (1/240). Hungary (1/168), Bulgaria (1/91), Spain (1/141). Turkey (1/216), and 500 from Japan (none). The frequency is shown in parentheses. The haplotype of G985 alleles in 1 homozygote and 57 heterozygote samples were then analyzed using two intragenic MCAD gene polymorphisms (Iaq1 and GT-repeat). The result indicated that only 1 of the 10 known haplotypes was associated with the G985 mutation, suggesting that G985 was derived originally from a single ancestral source. We made a compilation of the G985 frequencies in these countries and those in nine other European countries studied previously. The G985 distribution was high in the area stretching from Russia to Bulgaria in the east and in all northern countries in western and middle Europe, but low in the southern part of western and middle Europe. The incidence among ethnic Basques appeared to be low. This distribution pattern and the fact that all G985 alleles belong to a single haplotype suggest that G985 mutation occurred later than the delta F508 mutation of the CFTR, possibly in the neolithic or in a later period, and was brought into Europe by IndoEuropean-speaking people. The panEuropean distribution of the G985 allele, including Slavic countries from which patients with MCAD deficiency have rarely been detected, indicates the importance of raising the level of awareness of this disease.
- MeSH
- acyl-CoA-dehydrogenasy * genetika MeSH
- alely MeSH
- biologická evoluce * MeSH
- frekvence genu MeSH
- genetická variace * MeSH
- genetické testování * metody MeSH
- haplotypy * MeSH
- lidé MeSH
- mapování chromozomů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Geografické názvy
- Evropa MeSH
- Japonsko MeSH
- Turecko MeSH
- východní Evropa MeSH
- MeSH
- biochemická analýza krve MeSH
- dítě MeSH
- fenylketonurie diagnóza epidemiologie MeSH
- galaktosemie diagnóza epidemiologie MeSH
- hypotyreóza MeSH
- lidé MeSH
- nemoci novorozenců diagnóza MeSH
- novorozenec MeSH
- plošný screening MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- Geografické názvy
- Bulharsko MeSH
- MeSH
- diagnostické techniky a postupy MeSH
- diagnóza MeSH
- dítě MeSH
- lidé MeSH
- moč analýza MeSH
- plošný screening MeSH
- prenatální diagnóza metody MeSH
- testy genotoxicity MeSH
- vrozené poruchy metabolismu diagnóza epidemiologie prevence a kontrola MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Geografické názvy
- Bulharsko MeSH
