Machado-Joseph Disease: Clinical, Molecular, and Metabolic Characterization in Chinese Kindreds Bing-wen Soong, MD, PhD,*t Chung-hui Cheng, BS,t Ren-shyan Liu, MD,$ and Din-e Shan, MD, PhDt 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 zyxwvu 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 nystagntus and autonomic nervous system dysfunc- tion. The CAG repeat number in the MJD gene ranged from 14 to 39 among normal alleles, and from 63 to zy 81 among MJD alleles. There was a strong inverse correlation zyxwvu (y zyxwvuts = -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 hypo- metabolism in the occipital cortex, zyxwvut as well as the cerebellar hemispheres, vermis, and brainstem. Soong R-w, Cheng C-h, Liu K-s, Shall D-e. Machado-Joseph disease: clinical, molecular, and riietdbolic CharxteriLdtion in Chinese kmdreds. Ann Neurvl zyxw 1997;41:446-4 52 The autosomal dominant inherited spinocerebellar atax- ias (ADSCAs) are a heterogeneous group of neurode- generative disorders characterized by variable degrees of cerebellar dysfunction [I]. Aniong them, Machado- Joseph disease (MJD, MIM 109 150) is characterized by cerebellar ataxia, pyramidal signs, and progressive external ophthalmoplegia and is associated to variable degrees with bulging eyes, peripheral amyotrophy, and dystonia [l]. MJD was first and most often described in families of Portuguese origin living in the United States [2-51, the Azores [GI, and Portugal [7, 81 and was thought to originate in Portugal [9]. However, MJD has also been documented in families not known to be of Portuguese ancestry [lo]. The MJD locus was first mapped to chromosome 14q32.1 in Japanese families [1 zyxwvutsrq I] and linkage was then confirmed in families of Portuguese pedigrees [ 12-14]. Since then the MJD gene has been isolated and char- acterized [15] and the mutation has been demonstrated to be an expansion of a trinucleotide CAG repeat that lies at the 3’ terminal of the coding region [15]. Up to now MJD has rarely been reported among the From the ‘Deparnnent of Neurology, National Yang-Ming Univer- sity School of Medicine and National Defense Medical Center, Tai- pei, and tNeurological lnstiture and $National 1’El‘ICyclorron Center, Veterans General Hospital-Taipei, Taipei, Taiwan, Kepublic of China. Chinese population [16]. For this study, we first screened 21 families of Chinese origin in Taiwan with ADSCA for the MJD mutation by polymerase chain reaction (PCR). In 11 of the 21 ADSCA kindreds, an expanded CAG repeat region in the MJD gene was identified, suggesting that the MJD mutation is the most conimon cause of ADSCA in this population. Twenty-five affected individuals from these pedigrees were then studied by clinical examination, and 8 of them were also studied with positron emission tomog- raphy (PET). We confirmed that pathological expan- sions of the CAG repeat in the MJD gene underlie the MJD phenotype, and further characterized its behavior on transmission in Chinese pedigrees. In addition to traditional pathological reports, our PEI’ studies iden- tified significant progressive metabolic changes in the occipital cortex of individuals affected with MJD. Subjects and Methods zyxw Su bjectj Blood samples were obtained from 100 unrelated normal Chincsc voiunteera, and 70 family niembers from 21 Chinese Received Mar 25, 1996, and in revised form Jul 8. Accepted for publication Scp 5, 1996. Address correspondcnce to Dr Soong, Neurological Institute, Vet- erdns <;ericra! Hospical-Taipei, ‘I’dipei, ‘l’diwari, 1 121 zyx 7, ROC. 446 Copyright 0 19%‘ by the American Neurologicdl Association