Improvement in the molecular diagnosis of Machado-Joseph disease.

BACKGROUND Direct detection of the gene mutation allows for the confirmation of the clinical diagnosis of Machado-Joseph disease (MJD), the most frequent cause of autosomal dominant spinocerebellar ataxia worldwide. OBJECTIVE To address the main difficulties in our national MJD predictive testing program. The first was the emergence of intermediate alleles, for which it is not yet possible to determine whether they will cause disease. The second was the issue of homoallelism, ie, homozygosity for 2 normal alleles with exactly the same (CAG)(n) length, which occurs in about 10% of all test results. METHODS A large pedigree with 1 affected patient carrying a 71 and a 51 CAG repeat and 2 asymptomatic relatives carrying the 51 CAG repeat and normal-size alleles underwent clinical and molecular studies. Intragenic haplotypes for these alleles were determined. A representative sample of the healthy population in the region was obtained to assess the distribution of the normal (CAG)(n) length. We established the genotype for 4 intragenic polymorphisms in the gene for MJD (MJD1) in 21 homoallelic individuals, to distinguish their 2 normal chromosomes. In addition, we developed a new Southern blot method to completely exclude cases of nonamplification of expanded alleles in the homoallelic individuals. RESULTS The study of the family in which the 51 CAG repeat was found suggests that the allele is apparently not associated with disease. These intermediate alleles were not present in a large sample of the healthy population from the same region. Intragenic polymorphisms allowed distinction of the 2 different normal alleles in all cases of homoallelism. The absence of an expanded allele was also confirmed by Southern blot. CONCLUSIONS We propose an improved protocol for molecular testing for MJD. These strategies, developed to overcome the practical difficulties mostly in the presymptomatic and prenatal diagnosis of MJD, should prove useful for other polyglutamine-related disorders.

[1]  Í. Lopes-Cendes,et al.  Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study. , 2001, American journal of human genetics.

[2]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[3]  H. Kawakami,et al.  Variation in the number of CAG repeats in the Machado–Joseph disease gene (MJD1) in the Japanese population , 1999, Journal of the Neurological Sciences.

[4]  M. Gratacós,et al.  Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases , 1999, Human Genetics.

[5]  Í. Lopes-Cendes,et al.  Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract , 1999, European Journal of Human Genetics.

[6]  G. Rouleau,et al.  Prenatal diagnosis of Machado–Joseph disease by direct mutation analysis , 1998, Prenatal diagnosis.

[7]  G. Rouleau,et al.  Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. , 1998, American journal of medical genetics.

[8]  G. Sobue,et al.  Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6 , 1998, Clinical genetics.

[9]  P. Coutinho,et al.  Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. , 1997, Journal of clinical epidemiology.

[10]  M. Vermeulen,et al.  Machado-Joseph disease presenting as severe asymmetric proximal neuropathy , 1997, Journal of neurology, neurosurgery, and psychiatry.

[11]  I. Kanazawa,et al.  Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1. , 1997, American journal of human genetics.

[12]  M. Nishizawa,et al.  Machado-Joseph disease: Cerebellar ataxia and autonomic dysfunction in a patient with the shortest known expanded allele (56 CAG repeat units) of the MJD1 gene , 1997, Neurology.

[13]  Hung-Ming Wu,et al.  Studies of the CAG repeat in the Machado-Joseph disease gene in Taiwan , 1997, Human Genetics.

[14]  Ren-Shyan Liu,et al.  Machado‐joseph disease: Clinical, molecular, and metabolic characterization in chinese kindreds , 1997, Annals of neurology.

[15]  J. Weissenbach,et al.  Machado-Joseph disease in four Chinese pedigrees , 1997, Neurology.

[16]  L. Schöls,et al.  Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[17]  Í. Lopes-Cendes,et al.  Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease. , 1996, Archives of neurology.

[18]  Í. Lopes-Cendes,et al.  Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins , 1996, Human Genetics.

[19]  L. Cupples,et al.  A familial factor independent of CAG repeat length influences age at onset of Machado-Joseph disease. , 1996, American journal of human genetics.

[20]  Na Ma.  Huntington disease--another chapter rewritten. , 1996 .

[21]  H. Maruyama,et al.  A family with Machado-Joseph disease, previously diagnosed as dentatorubral-pallidoluysian atrophy , 1996, Neurology.

[22]  Í. Lopes-Cendes,et al.  Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients , 1996, Neurology.

[23]  Y. Agid,et al.  Characterisation of the unstable expanded CAG repeat in the MJD1 gene in four Brazilian families of Portuguese descent with Machado-Joseph disease , 1995, Journal of medical genetics.

[24]  P. S. St George-Hyslop,et al.  Dopa‐responsive parkinsonism phenotype of Machado‐Joseph disease: Confirmation of 14q CAG expansion , 1995, Annals of neurology.

[25]  H. Cann,et al.  Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus. , 1995, American journal of human genetics.

[26]  L. Farrer,et al.  Gender equality in Machado–Joseph disease , 1995, Nature Genetics.

[27]  F. Leweke,et al.  Spinocerebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD) , 1995, Journal of the Neurological Sciences.

[28]  T D Bird,et al.  Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. , 1995, American journal of human genetics.

[29]  Í. Lopes-Cendes,et al.  Correlation between CAG repeat length and clinical features in Machado-Joseph disease. , 1995, American journal of human genetics.

[30]  H. Zoghbi,et al.  Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado‐Joseph disease , 1995, Annals of neurology.

[31]  L. Schöls,et al.  Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. , 1995, Human molecular genetics.

[32]  G. Sobue,et al.  Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. , 1995, Human molecular genetics.

[33]  G. Sobue,et al.  Unique features of the CAG repeats in Machado–Joseph disease , 1995, Nature Genetics.

[34]  S. Tsuji,et al.  A clinical and pathologic study of a large Japanese family with Machado‐ Joseph disease tightly linked to the DNA markers on chromosome 14q , 1994, Neurology.

[35]  N. Gadoth,et al.  Machado‐Joseph (Azorean) disease in a Yemenite Jewish family in Israel , 1994, Neurology.

[36]  H. Lehrach,et al.  False-negative result for Huntington's disease mutation , 1994, The Lancet.

[37]  A. Reiss,et al.  Neurobehavioral effects of the fragile X premutation in adult women: a controlled study. , 1993, American journal of human genetics.

[38]  Y. Takiyama,et al.  A large Japanese family with Machado‐Joseph disease: clinical and genetic studies , 1989, Acta neurologica Scandinavica.

[39]  R. Rosenberg,et al.  Autosomal dominant motor system disease of the Portuguese , 1981, Neurology.

[40]  P. Coutinho,et al.  Clinical criteria for diagnosis of Machado‐Joseph disease , 1980, Neurology.

[41]  C. Andrade,et al.  Autosomal dominant system degeneration in Portuguese families of the Azores Islands , 1978, Neurology.

[42]  M. Nance.  Huntington disease--another chapter rewritten. , 1996, American journal of human genetics.

[43]  渡辺 光法.  Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease , 1996 .

[44]  Shigenobu Nakamura,et al.  CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 , 1994, Nature Genetics.

[45]  P. Coutinho,et al.  Epidemiology and clinical aspects of Machado-Joseph disease. , 1993, Advances in neurology.