Machado‐joseph disease: Clinical, molecular, and metabolic characterization in chinese kindreds

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.

Cognitive Impairment in Spinocerebellar Degeneration

“…These lesions, newly recognized by polyglutamine immunohistochemistry, may be responsible for the cerebral cortical dysfunctions in SCA3 patients. Consistent with the results of this pathological study, the regional cerebral glucose metabolism or perfusion in SCA3, studied with PET or SPECT, was found to be significantly decreased in the entire cerebral cortex [41], occipital cortex [42], frontal, temporal and parietal lobes [43] aswell as in the cerebellar hemispheres, vermis, and brain stem. Murata et al [44] found similar results using MRI; not only were the widths of the superior cerebellar peduncles reduced and the transverse diameters of the globus pallidus and pons diminished, but the frontal and temporal lobes were also atrophied.…”

The SCA1 (Spinocerebellar ataxia type 1) and MJD (Machado-Joseph disease) CAG repeats in normal individuals: segregation analysis and allele frequencies

“…Normal variation in size of the CAG repeats of SCA1 and MJD genes has been reported in a few surveys (Rubinsztein et al, 1995;Watkins et al, 1995;Limprasert et al, 1996;Richards et al, 1996;Jodice et al, 1997;Limprasert et al, 1997;Takano et al, 1998), as well as in comparative studies carried out in affected and control groups (Dürr et al, 1996;Goldfarb et al, 1996;Maruyama et al, 1996;Matsumura et al, 1996;Hsieh et al,1997;Soong et al, 1997;Zhou et al, 1997;Lokkegaard et al, 1998).…”

Regional patterns of cerebral glucose metabolism in spinocerebellar ataxia type 2, 3 and 6

“…SCA3 [11,28,29] and SCA6 [31] have previously been studied by us with PET using 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG). The aim of this study was to elucidate the regional patterns of cerebral hypometabolism in three genetically defined subtypes of SCA: SCA2, SCA3, and SCA6.…”