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Background: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal-recessive disorder with preferential involvement of the tibialis anterior muscle that starts in young adulthood and spares quadriceps muscles. The disease locus has been mapped to chromosome 9p1-q1, the same region as the hereditary inclusion body myopathy (HIBM) locus. HIBM was originally described as rimmed vacuole myopathy sparing the quadriceps; therefore, the two diseases have been suspected to be allelic. Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase ( GNE ). Objective: To determine whether DMRV and HIBM are allelic. Methods: The GNE gene was sequenced in 34 patients with DMRV. The epimerase activity in lymphocytes from eight DMRV patients was also measured. Results: The authors identified 27 unrelated DMRV patients with homozygous or compound-heterozygous mutations in the GNE gene. DMRV patients had markedly decreased epimerase activity. Conclusions: DMRV is allelic to HIBM. Various mutations are associated with DMRV in Japan. The loss-of-function mutations in the GNE gene appear to cause DMRV/HIBM.

To evaluate the clinical characteristics of Machado-Joseph disease (MJD) with reference to CAG repeat length and disease duration, we analyzed neurologic findings in 108 patients from 84 families. The majority of MJD patients presented with an ataxic gait as the initial symptom. Dysarthria and nystagmus were observed from an early stage. Bulging eyes, muscle atrophy and bradykinesia developed later. Patients with a shorter CAG repeat length or later onset had more frequent involvement of proprioceptive sensory deficit. Incidence of abnormal reflexes, tones, and proprioceptive sensation was not associated with disease duration, but with CAG repeat length. Based on these results, we propose a new clinical classification: type A (juvenile type), with hyperreflexia and dystonia, but without a proprioceptive sensory deficit; type C (adult type), with hyporeflexia and a proprioceptive sensory deficit, but without dystonia; and type B (intermediate type), the remaining patients with a mixed presentation.

Objective To clarify the characteristic magnetic resonance imaging (MRI) findings in patients with Machado-Joseph disease (MJD) diagnosed by genetic analysis. Patients and Methods Using MRI, we examined 31 patients genetically diagnosed as having MJD, 20 patients with sporadic olivopontocerebellar atrophy, and 26 control subjects. Results The MRIs of patients with MJD disclosed remarkably reduced width of the superior cerebellar peduncles, atrophy in the frontal and temporal lobes, diminished transverse diameter of the globus pallidus, and decreased anteroposterior and transverse diameters of the pons, which correlated with the width of the middle cerebellar peduncle. The width of the superior cerebellar peduncles also correlated with the diameter of the dentate or red nucleus in patients with MJD, but not in controls or in patients with sporadic olivopontocerebellar atrophy. On T 2 - and/or proton-weighted axial MR imaging, a high signal intensity in the transverse pontine fibers was observed in 14 (45.2%) of 31 patients with MJD and in all patients with sporadic olivopontocerebellar atrophy, but not in any controls. Conclusion 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.

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.