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Machado-Joseph disease: clinical, molecular, and metabolic characterization in Chinese kindreds
1Department of Neurology, National Yang-Ming University School of Medicine and National Defense Medical Center, Taipei, Taiwan, Republic of China.
Abstract:
Machado-Joseph disease, an autosomal dominant multisystem motor degeneration, has been described mainly in people of Portuguese descent. Our report documents the presence of Machado-Joseph disease in the Chinese population, based on the specific molecular marker of a CAG repeat array in the 3' end of the MJD gene. We screened 21 Chinese families with dominant spinocerebellar ataxia. The results showed that Machado-Joseph disease with CAG expansion accounted for 52% of families with autosomal dominant cerebellar ataxia in this series. The clinical characteristics, besides the well-documented cerebellar ataxia, dysarthria, nystagmus, corticospinal dysfunctions, a variable degree of facial muscle fasciculation, and proprioceptive loss, included loss of optokinetic nystagmus and autonomic nervous system dysfunction. The CAG repeat number in the MJD gene ranged from 14 to 39 among normal alleles, and from 63 to 81 among MJD alleles. There was a strong inverse correlation (gamma = -0.77) between number of CAG repeats and age at symptom onset, accounting for 60% of the variance of age at onset. A strong clinical anticipation of age at onset existed in successive generations. Mild instabilities of expanded CAG repeat numbers during meiotic transmission occurred, with no significant difference according to the gender of the transmitting parent. Finally, brain metabolism in Machado-Joseph disease, studied with positron emission tomography, was characterized by significant progressive regional hypometabolism in the occipital cortex, as well as the cerebellar hemispheres, vermis, and brainstem.
Insights
Machado-Joseph disease, a genetic neurological disorder, is now identified in the Chinese population. Molecular analysis confirmed a CAG repeat expansion in the MJD gene, correlating with disease severity and early onset.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Machado-Joseph disease (MJD), an autosomal dominant disorder, primarily affects individuals of Portuguese descent.
- It is characterized by multisystem motor degeneration, impacting the nervous system.
Purpose of the Study:
- To document the presence and characteristics of Machado-Joseph disease in the Chinese population.
- To investigate the molecular basis, clinical manifestations, and genetic factors of MJD in this ethnic group.
Main Methods:
- Screening of 21 Chinese families with autosomal dominant spinocerebellar ataxia.
- Molecular analysis of the MJD gene for CAG repeat expansion.
- Clinical assessment of neurological and autonomic dysfunction.
- Positron emission tomography (PET) for brain metabolism studies.
Main Results:
- Machado-Joseph disease with CAG expansion was identified in 52% of studied families with autosomal dominant cerebellar ataxia.
- Clinical features included cerebellar ataxia, dysarthria, nystagmus, corticospinal dysfunction, and autonomic nervous system dysfunction.
- CAG repeat numbers correlated inversely with age of onset, and anticipation was observed across generations. PET revealed progressive hypometabolism in specific brain regions.
Conclusions:
- Machado-Joseph disease is present in the Chinese population, linked to MJD gene CAG repeat expansion.
- CAG repeat length is a significant determinant of age at onset and disease progression.
- The study highlights the importance of molecular diagnostics and provides insights into MJD's neurobiological underpinnings.