Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients

Abstract

The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.

Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals

“…In the patient group in the present study, SCA3 locus had more expanded alleles than other loci. This corroborates the hypothesis that the Portuguese and African populations brought a pool of founding genes to Brazil with a common mutation in the SCA3 gene identified as the cause of MJD (SCA3) 37,[41][42][43] . However, other studies of the Portuguese population did not show any correlation between the frequency of the large normal alleles and the frequency of the disease [20][21][22][23] .…”

Spinocerebellar ataxias

“…SCA type 3 is the most common form of the disease worldwide; types 1, 2, 6, 7 and 8 have greatly varying prevalences depending on the ethnic background of the population 1,2,[14][15][16][17][18][19] .…”

“…The SCA types defined as SCA 4,5,11,13,14,15,18,19,20,21,22,23,25,26,27,28,29 and 30 represent very rare forms and have been diagnosed in a small number of cases in different parts of the world, some of which were only reported in isolated families.…”

Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1

“…We 32 and others 24 have determined the frequency of the three different SCAs for which direct molecular diagnosis is available: SCAI, MJD and DRPLA. Families of different geographic and ethnic origins have been reported with the SCAI mutation; however, SCAI seems to occur more frequently in certain ethnic groups such as Italians and Eastern (EuropeansRanum et al 24 , Silveira et al 32 , and Lopes-Cendes unpublished results]. In Southern Italy a cluster of SCAI families has been described sharing the same haplotype for markers closely linked to the SCAI locus, which suggests a common origin of these families 12 .…”