Yoshioka Mieko, Higuchi Yoshihisa, Fujii Tatsuya, Aiba Hideo, Toda Tatsushi
Department of Pediatric Neurology, Kobe City Pediatric and General Rehabilitation Center for the Challenged, 2-3-50 Maruyama-cho, Nagata-ku, Kobe 653-0875, Japan.
Brain Dev. 2008 Jan;30(1):59-67. doi: 10.1016/j.braindev.2007.05.012. Epub 2007 Jun 26.
Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder prevalent in Japan, characterized by cobblestone lissencephaly and dystrophic changes in skeletal muscle, resulting in mental retardation, epilepsy and motor impairment. FCMD patients in Japan carry at least one copy of an ancestral founder mutation, a 3 kb insertion in a 3'-untranslated region, that results in a reduction in fukutin mRNA levels. We analyzed 35 patients with FCMD and found 18 patients carried a homozygous founder mutation (homozygotes) and 17 a combined heterozygous between founder mutation and a nonsense or missense mutation (heterozygotes). During an average follow-up of over 10 years, 61% of homozygotes and 82% of heterozygotes developed febrile or afebrile seizures. The ages at onset of febrile and afebrile seizures on average were 5.4 and 4.6 years, respectively, in homozygotes and 3.6 and 3.7 years, respectively, in heterozygotes. Repeated seizures were treated with antiepileptic drugs. While all homozygotes showed good seizure control, four heterozygotes had intractable seizures. Mutations other than the 3 kb insertion were identified in seven of 12 heterozygotes examined. Five patients with a nonsense mutation in exon 3 and one with a missense mutation in exon 5 had a severe phenotype and some showed intractable seizures. On the other hand, one with a nonsense mutation in exon 8 had only one febrile seizure. It was concluded mutational analysis of the FCMD gene could predict seizure prognosis. Heterozygotes usually developed seizures earlier than homozygotes and some heterozygotes showed intractable seizures. Mutational analysis other than of the 3 kb insertion may also help to predict seizure prognosis.
福山型先天性肌营养不良（FCMD）是一种在日本常见的常染色体隐性疾病，其特征为鹅卵石样无脑回畸形和骨骼肌营养不良性改变，导致智力发育迟缓、癫痫和运动功能障碍。日本的FCMD患者至少携带一份祖传奠基者突变的拷贝，即在3'-非翻译区有一个3 kb的插入，这导致福库蛋白（fukutin）mRNA水平降低。我们分析了35例FCMD患者，发现18例患者携带纯合奠基者突变（纯合子），17例患者携带奠基者突变与无义或错义突变的复合杂合突变（杂合子）。在平均超过10年的随访期间，61%的纯合子和82%的杂合子出现了发热性或无热惊厥。纯合子发热性和无热惊厥的平均发病年龄分别为5.4岁和4.6岁，杂合子分别为3.6岁和3.7岁。反复惊厥用抗癫痫药物治疗。虽然所有纯合子的惊厥都得到了良好控制，但4例杂合子有难治性惊厥。在12例检测的杂合子中，有7例鉴定出3 kb插入以外的突变。5例第3外显子有一个无义突变的患者和1例第5外显子有一个错义突变的患者有严重的表型，一些患者表现为难治性惊厥。另一方面，1例第8外显子有一个无义突变的患者仅出现一次发热性惊厥。得出的结论是，FCMD基因的突变分析可以预测惊厥的预后。杂合子通常比纯合子更早出现惊厥，一些杂合子表现为难治性惊厥。3 kb插入以外的突变分析也可能有助于预测惊厥的预后。
