小坂 仁

12歳男児.発達遅滞と非定型欠神発作を主訴として3歳1カ時に受診し,3歳9ヵ月時に陽気な性格,特異顔貌,失調歩行などからAngelman症候群が疑われた.FISH解析では異常を認めなかったが,UBE3Aシークエンスで,エクソン8の1塩基欠失(668delA)を認め,確定診断ができた.本症例にみられた変異型は,母親が変異保因者である可能性があり,診断治療のみならず,家系内における再発危険率評価を含む遺伝カウンセリングの適応がある

The genes of the majority neurodegenerative disorders have been identified for the past decade. Diseases of early onset are usually transmitted as autosomal recessive trait and caused by the deficiency of the gene products, becoming good candidates for gene or protein transfers. Late onset diseases are usually transmitted dominantly where the gains of function by the mutant gene accumulate into specific lesion. The pathophysiology following gene mutation need to be clarified for the therapeutic approach. Recent progresses on neurodegenerative mechanism have specified crucial targets for the treatments. Stimulation to intrinsic mechanisms, i.e., chaperon, ubiquitin-proteasome system and stress response in endoplasmic reticulum and/or antagonize the toxic cascade by caspases, mitochondria insufficiency are argued as therapeutic targets, hoping that in this decade we can propose effective therapies for these devastating disorders.

BACKGROUND AND PURPOSE: Pelizaeus-Merzbacher's disease (PMD) is caused by mutations in the proteolipid protein (PLP) gene. Recent studies have shown that an increased PLP dosage, resulting from total duplication of the PLP gene, invariably causes the classic form of PMD, The purpose of this study was to compare the MR findings of PMD attributable to PLP duplication with those of PMD arising from a missense mutation. METHODS: Seven patients with PMD, three with a PLP missense mutation in either exon 2 or 5 (patients 1-3), and four with PLP duplication (patient 4 having larger PLP duplication than patients 5-7) were clinically classified as having either the classic or connatal form of PMD. Cerebral MR images were obtained to analyze the presence of myelination and T1 and T2 shortening in the deep gray matter. Multiple MR studies were performed in six of the seven patients to analyze longitudinal changes. RESULTS: Four patients (patients 1-4) were classified as having connatal PMD, whereas the other three (patients 5-7) were classified as having classic PMD, Myelination in the cerebral corticospinal tract, optic radiation, and corpus callosum was observed in three cases of classic PMD with PLP duplication. In patient 4, myelination extended to the internal capsule, corona radiata, and centrum semiovale over a 3-year period. No myelination was observed in three PMD cases with a PLP point mutation. T2 shortening in the deep gray matter was recognized in all patients with PMD. CONCLUSION: The presence of myelination in the cerebral corticospinal tract with diffuse white matter hypomyelination on MR images could be a marker for PMD with PLP duplication. It is suggested that progression of myelination may be present in connatal PMD with large PLP duplication.

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder characterized by dysmyelination of the central nervous system (CNS) caused by mutations involving the proteolipid protein gene (PLP). In addition to point and frameshift mutations in the coding region, duplications involving the entire PLP have been recognized recently as a major genetic abnormality causing PMD. We devised an interphase fluorescence in situ hybridization (FISH) assay to establish an efficient screening test for PLP duplication. Thirteen patients from II Japanese PMD families were determined to have PLP duplications. This molecular diagnostic FISH test also readily detected female carriers. Molecular analysis revealed that the size of the duplication and location of the breakpoints showed striking variation. Fiber FISH demonstrated that the duplication is tandem in nature.:Haplotype analysis indicated an intrachromosomal origin for the duplication. These results suggest that an unequal sister chromatid exchange in male meiosis is likely to be the major mechanism leading to the formation of the duplication. Patients with the duplication commonly present with a mild PMD phenotype. Two patients with an exceptionally severe clinical phenotype-carried large duplications, suggesting that either the larger duplicated segment incorporates additional dosage-sensitive genes or that the location of the duplication junction may affect the phenotype.