Machado-Joseph disease: essay of definition

149

Disease duration can explain part of the heterogeneity of ataxia, dysarthria, dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia, in MJD. Type 1 MJD was positively associated with nuclear ophthalmoplegia; type 3 MJD was positively associated with supranuclear ophthalmoplegia. Higher mean CAG lengths were found to correlate with the pyramidal syndrome and dystonia. Nystagmus, eyelid retraction, rigidity and/or bradykinesia, and optic atrophy were hardly attributable to any known reason or variable.

Section: Commentsupporting

confidence: 81%

Section: Commentmentioning

confidence: 99%

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Neurologic Findings in Machado-Joseph Disease

Jardim

Pereira²,

Silveira³

et al. 2001

149

“…A later form of the disease, corresponding to type 3 described by Coutinho and Andrade, 15 demonstrates a slow evolution of symptoms, allowing the affected individuals to reach a considerable age. 16 Therefore, in patients with type 3 MJD, the registered cause of death is likely not to be MJD. One additional factor could be responsible for the nonreporting of MJD as the cause of death in some cases: if the individuals die of an unrelated illness (eg, cancer) at the beginning of the natural course of the disease, it is probable that there will be no reference to MJD when the cause of death is listed.…”

Section: Commentmentioning

confidence: 99%

Causes of Death in Machado-Joseph Disease

Lima

Coutinho²,

Abade³

et al. 1998

Self Cite

“…5,6 Patients with MJD have a clinically heterogeneous presentation with a mean age at onset of approximately 40 years, but extremes range from as young as 4 years 7 to as old as 70 years. 8 Variation in the age at onset is only partially explained (approximately 50%-75%) 9,10 by the size of the (CAG) n tract in the expanded ATXN3 alleles. Familial factors may explain additional variance in age at onset, 11,12 indicating that modifier genes may play a role.…”

mentioning

confidence: 99%

The <emph type="ital">APOE</emph> ε2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease

Bettencourt

Raposo²,

Kazachkova³

et al. 2011

Background. Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset, caused by a (CAG) n expansion at the ATXN3 gene (14q32.1). Variation in age-at-onset is partially explained by the size of the (CAG) n tract in expanded alleles. The remaining variation should be the product of other factors, namely modifier genes. The genotype at the APOE locus has been described as a possible modifier in different neurological disorders, namely Parkinson (PD) and Huntington disease (HD). In the CNS, apolipoprotein E constitutes an important mediator of cholesterol transport/metabolism, which is essential for synaptic integrity and neuronal function.Objective. To investigate a modulating effect of the APOE polymorphism on ageat-onset of MJD. Design and Subjects.The APOE polymorphism was typed in a series of 192 MJD patients. Results.Cases with the ε2/ε3 genotype presented an earlier onset, when compared with those with ε3/ε3 or ε3/ε4. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age-at-onset. When combining, in a general linear model, several other predictors, namely the presence/absence of the APOE ε2 allele, with the size of the (CAG) n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the ε2 allele was associated with an onset below 39 years (OR=5.00; 95% CI: 1.18-21.14). Conclusions.These findings indicate that the polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype.