Clinical and genetic analysis of a Machado-Joseph Italian family

Machado-Joseph disease (MJD) is an autosomal dominant type of neurodegenerative disease characterized by cerebellar ataxia and pyramidal signs associated with variable findings, including a dystonic-rigid syndrome, a Parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. The disease-causing mutation consists of an expansion of a trinucleotide C AG repeat at the 3' terminal of the ataxin 3 coding region, resulting in a polyglutamine domain with unknown function. Pathogenic CAG expansions at the same locus have also been proven to cause spinocerebellar ataxia, type 3. MJD was initially described in Portugal and then in families of Portuguese origin living in the Azores and in the United States, but a worldwide distribution of the disease has now been recognized, being reported in India, Japan, China, and Germany as well. However, the prevalence of SCA3/MJD among the dominantly inherited ataxias is variable, ranging from 10 to 28% of the cases in the USA and France, respectively, 50% among Japanese and German families and up to 84% in Portuguese kindreds. Conversely, population and genetic studies failed to detect any SCA3 gene mutations in the Italian population, suggesting that some geographic variation appears to exist in the occurrence of the disease. Here we report the clinical and genetic analysis of of an Italian family with a history of dominantly inherited ataxia bearing a pathogenic CAG expansion at the SCA3/MJD locus. The family, originating from central Italy, was reported in 1973 as an example of "autosomal dominant spinocerebellar ataxia associated with megalocornea, cataract and morphological abnormalities of red blood cells." The clinical phenotype of the index case was characterized by onset at 25 years of age with unsteadiness of gait, dysarthria, and lower limb stiffness. Neurological examination performed at age 35, when the patient was admitted to the hospital, evidenced gait and truncal ataxia, nystagmus, dysphagia, slurred speech, dyplopia, hyperreflexia of lower limbs and a right Babinski sign. In addition, bilateral muscular atrophy of the forearms, hands and quadriceps was present. A positive family history was ascertained, based on past medical records. Analysis of the SCA3 locus revealed a pathogenic expansion of 67-70 CAG triplet repeats in both offspring of the index case, currently mildly affected by pure cerebellar ataxia with bulging eyes. No Portuguese ancestors were detected in this kindred. This is the first description of an MJD family of Italian origin with a clinical phenotype resembling type 2 and presenting with an age at onset of 20-45 years with cerebellar and pyramidal deficits and a slow progression of disease. Analysis of a MJD/SCA3 locus for possible pathogenic expansions should be recommended in all ataxia cases.