X-linked dystonia-parkinsonism (XDP) is a movement disorder endemic to the Philippines. The disease locus, DYT3, has been mapped to Xq13.1. In a search for the causative gene, we performed genomic sequencing analysis, followed by expression analysis of XDP brain tissues. We found a disease-specific SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion in an intron of the TATA-binding protein-associated factor 1 gene (TAF1), which encodes the largest component of the TFIID complex, and significantly decreased expression levels of TAF1 and the dopamine receptor D2 gene (DRD2) in the caudate nucleus. We also identified an abnormal pattern of DNA methylation in the retrotransposon in the genome from the patient's caudate, which could account for decreased expression of TAF1. Our findings suggest that the reduced neuron-specific expression of the TAF1 gene is associated with XDP.

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Proinflammatory cytokines, including interleukin (IL)‐1β, are known to modulate effects of neurotoxic neurotransmitters discharged during excitation or inflammation in the central nervous system (CNS). They also regulate development of glial scars at sites of CNS injury. To elucidate a genetic predisposition of temporal lobe epilepsy with hippocampal sclerosis (TLE‐HS+), we studied polymorphisms in the IL‐1β, IL‐1α, and IL‐1 receptor antagonist (IL‐1RA) genes in 50 patients with TLE‐HS+ and in 112 controls. Fifty‐three patients who had TLE without HS were also examined (TLE‐HS−) as disease controls. The distribution of the biallelic polymorphism in the promoter region at position −511 of the IL‐1β gene (IL‐1B−511) was significantly different both between TLE‐HS+ patients and controls and between TLE‐HS+ and TLE‐HS− patients. The differences were due to overrepresentation of the homozygotes for IL‐1B−511∗︁2, which is suggested to be a high producer of IL‐1β, in TLE‐HS+ patients compared with both controls and TLE‐HS− patients. In contrast, there was no difference between TLE‐HS− patients and controls. Our data suggest that, in the homozygotes for IL‐1B−511∗︁2, minor events in development such as febrile convulsions could set up a cascade leading to HS. Ann Neurol 2000;47:571–574

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Machado--Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the MJD1 gene was identified as the cause of the disease. We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas normal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association with the clinical anticipation of the disease, a parent--child analysis showed the unidirectional expansion of CAG repeats and no case of diminution in the affected family. The differences in CAG repeat length between parent and child and between siblings are greater in paternal transmission than in maternal transmission. Detailed analysis revealed that a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission. On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.

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Affected afferent and efferent cerebellar tracts and atrophy of the frontal and temporal lobes and globus pallidus are characteristics of MRI of patients with MJD.

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