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Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)n
L B Jardim1, M L Pereira, I Silveira
1MD, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto Alegre, Brazil. laurajardim@terra.com.br
Context:
Machado-Joseph disease (MJD), an autosomal dominant spinocerebellar degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a heterogeneous disorder for clinical manifestations. The reasons for the wide range of neurologic findings in this disease are poorly understood.
Objective:
To explain part of this heterogeneity through the association of the neurologic findings with sex, disease duration, age of onset, clinical type, and size of CAG repeat expansion.
Design:
A case-control study.
Setting:
Ambulatory care.
Patients:
A consecutive sample of 62 patients with MJD.
Main Outcome Measure:
Neurologic signs.
Results:
A direct relationship was found between the disease duration and severity of gait and limb ataxia, dysarthria, dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia (P<.02). The most severe forms of nuclear ophthalmoplegia were associated with type 1 MJD, whereas those of supranuclear ophthalmoplegia were associated with type 3 MJD (P<.001). It was also found that higher mean (CAG)(n) lengths were associated with worse degrees of the pyramidal syndrome and dystonia (P<.001). The presence and severity of nystagmus, eyelid retraction, rigidity and/or bradykinesia, and optic atrophy were not clearly associated with any of the predictive variables under study.
Conclusions:
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.
Insights
Machado-Joseph disease (MJD) heterogeneity is partly explained by disease duration, which impacts ataxia and other symptoms. Specific MJD types correlate with distinct ophthalmoplegia forms, and CAG repeat length influences pyramidal syndrome and dystonia severity.
Area of Science:
- Neurology
- Genetics
- Clinical Medicine
Background:
- Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration.
- It is caused by an expanded CAG repeat on chromosome 14q32.1.
- MJD exhibits significant clinical heterogeneity, with poorly understood reasons for varied neurologic findings.
Purpose of the Study:
- To investigate the association between neurologic manifestations in MJD and factors like sex, disease duration, age of onset, clinical type, and CAG repeat expansion size.
- To elucidate the sources of clinical heterogeneity in MJD.
Main Methods:
- A case-control study design was employed.
- Data were collected from a consecutive sample of 62 ambulatory MJD patients.
- Neurologic signs served as the main outcome measure.
Main Results:
- Disease duration directly correlated with the severity of gait/limb ataxia, dysarthria, dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia (P<.02).
- Severe nuclear ophthalmoplegia was linked to MJD type 1, while supranuclear ophthalmoplegia was associated with MJD type 3 (P<.001).
- Increased mean CAG repeat lengths correlated with more severe pyramidal syndrome and dystonia (P<.001).
Conclusions:
- Disease duration contributes to the heterogeneity of ataxia, dysarthria, dysphagia, fasciculations, pyramidal syndrome, and ophthalmoplegia in MJD.
- MJD type 1 is associated with nuclear ophthalmoplegia, and type 3 with supranuclear ophthalmoplegia.
- Higher CAG repeat lengths correlate with pyramidal syndrome and dystonia, while other symptoms like nystagmus remain unexplained by studied variables.