Schöls L, Amoiridis G, Epplen J T, Langkafel M, Przuntek H, Riess O
Department of Neurology, St Josef Hospital, Ruhr-University, Bochum, Germany.
J Neurol Neurosurg Psychiatry. 1996 Nov;61(5):466-70. doi: 10.1136/jnnp.61.5.466.
Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia with extensive phenotypic variability originally described in families of Portuguese ancestry. Recently, the mutation causing the disease has been identified as an expanded CAG trinucleotide repeat. In this study relations between genotype and phenotype were investigated.
A series of 180 German patients with degenerative forms of ataxia were clinically and genetically examined. Patients bearing the MJD mutation were assigned to three phenotypes: phenotype 1 characterised by early onset and dystonia or pronounced rigidity associated with ataxia and spasticity. Main symptoms in phenotype 2 were ataxia and spasticity. In phenotype 3 onset was relatively late and peripheral neuropathy accompanied ataxia. Clinical and molecular data were correlated.
An expanded CAG array was found in 42 patients from 22 families. Repeat length of CAG varied between 67 and 80 CAG motifs and showed an inverse correlation with the age of onset. For the development of phenotype 1 early onset (< 20 years) seemed more decisive than extensive repeat length. Phenotype 2 was present in all patients with more than 73 CAG motifs and onset between 20 and 40. Phenotype 3 developed in most patients with less than 73 CAG motifs and onset was regularly beyond the age of 40. Intrafamilial variability of both repeat length and phenotype was large reflecting meiotic instability of the expanded CAG repeat.
The MJD mutation is the most frequent cause of dominantly inherited ataxia in Germany. Variations in repeat lengths substantially influence age of onset as well as phenotype but cannot explain why MJD characteristics of Portuguese families such as "bulging eyes", dystonia, and rigidity are essentially missing in German families. Despite the genotypic and phenotypic relations found in this study a reliable individual prognosis of the course of the disease is not possible at a presymptomatic stage.
马查多-约瑟夫病（MJD）是一种常染色体显性遗传性小脑共济失调，具有广泛的表型变异性，最初在葡萄牙裔家族中被描述。最近，导致该病的突变已被确定为CAG三核苷酸重复序列扩增。本研究对基因型与表型之间的关系进行了调查。
对180例患有退行性共济失调的德国患者进行了临床和基因检查。携带MJD突变的患者被分为三种表型：表型1的特征为发病早，伴有肌张力障碍或明显的僵硬，同时伴有共济失调和痉挛。表型2的主要症状是共济失调和痉挛。表型3发病相对较晚，伴有周围神经病变和共济失调。对临床和分子数据进行了相关性分析。
在来自22个家族的42例患者中发现了CAG序列扩增。CAG重复长度在67至80个CAG基序之间变化，并且与发病年龄呈负相关。对于表型1的发展，早发（<20岁）似乎比重复序列长度更具决定性。所有CAG基序超过73个且发病年龄在20至40岁之间的患者均表现为表型2。大多数CAG基序少于73个且发病年龄通常超过40岁的患者表现为表型3。重复序列长度和表型的家族内变异性都很大，反映了扩增的CAG重复序列的减数分裂不稳定性。
MJD突变是德国显性遗传性共济失调最常见的病因。重复序列长度的变化对发病年龄和表型有重大影响，但无法解释为什么德国家族中基本上没有葡萄牙家族中MJD的特征，如“突眼”、肌张力障碍和僵硬。尽管在本研究中发现了基因型与表型之间的关系，但在症状前阶段仍无法对疾病进程进行可靠的个体预后判断。
