メキシコのNiemann-Pick病B型患者における病原性化合物ヘテロ接合性突然変異

Pathogenic Compound Heterozygous Mutations in a Mexican Mestizo Patient with Niemann-Pick Disease Type B.

• J Salvador Velarde-Félix
• J F Osuna-Ramos
• M G Sánchez-Leyva
• E R Ríos Burgueño
• L M Monroy Arellano

抄録

Niemann-Pick病（NPD）B型は，酸スフィンゴミエリン酵素（ASM）の欠乏によって引き起こされるリソソソーム貯蔵障害である． 本研究では，中枢神経系の病変を伴わず，肝脾腫，低密度リポ蛋白（HDL）コレステロール，血小板減少症を呈した16歳のメキシコ人メスティゾ女性のNPD B型表現型を追跡調査した． 重度の貧血と汎血球減少症を伴うデング熱のエピソードの後、骨髄検査を行ったところ、発泡性の組織球が認められ、ニーマンピック病が疑われ、生化学的・分子的検査で確認された。 SMPD1遺伝子のミスセンスc.1343 A>G (p.Tyr448Cys、旧Y446C)とc.1426C>T (p.Arg476Trp、旧R474W)の変異が同定された。 これらの突然変異はメキシコの集団では報告されていない。 c.1343 A>G (Y446C)変異は日本人のNPD A型患者で報告されているので、我々はc.1426C>T (R474W)対立遺伝子の減衰効果を示唆している（以前はNPD B型表現型と関連していた）。 以上のことから，メキシコ人のNPD B型患者において，Y446CとR476Wの突然変異が共存していたことを初めて明らかにし，希少な遺伝性代謝性疾患の診断における専門的な検査の重要性を示した．

Niemann-Pick disease (NPD) type B is a lysosomal storage disorder caused by a deficiency of acid sphingomyelinase (ASM). We report the clinical follow-up of a 16-year-old Mexican mestizo woman with a NPD type B phenotype who presented hepatosplenomegaly, persitstenly low high-density lipoprotein (HDL) cholesterol and thrombocytopenia, without central nervous system involvement. After of a dengue fever episode with severe anemia and pancytopenia, leading to a bone marrow study n which foamy histiocytes were noticed and diagnosis of NiemannPick disease was suspected; and confirmed by biochemical and molecular tests. The missense c.1343 A>G (p.Tyr448Cys, formerly Y446C) and c. 1426C>T (p.Arg476Trp, formerly R474W) mutations in the SMPD1 gene were identified. These mutations have never been reported in the Mexican population. Since the c.1343 A>G (Y446C) mutation has been previously reported in a Japanese patient with NPD type A, we suggest an attenuator effect of c.1426C>T (R474W) allele (previously associated with the NPD type B phenotype). In conclusion, this is the first description of the concomitant occurrence of Y446C and R476W mutations in a Mexican patient with NPD type B, showing the importance of increased awareness and availability of specialized diagnostic tests in the diagnosis of rare inherited metabolic diseases.