Prasad Asuri N, Rupar Charles A, Prasad Chitra
Department of Pediatrics, University of Western Ontario, London, Canada.
Brain Dev. 2011 Oct;33(9):758-69. doi: 10.1016/j.braindev.2011.05.014. Epub 2011 Jul 22.
A recessively inherited defect leading to deficiency of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) underlies one form of hyperhomocysteinemia. We describe the association of severe MTHFR deficiency and neurological manifestations with particular attention to neurodevelopment and evolution of epileptic seizures.
Case study and review of literature.
A 9 year old female infant born to Caucasian non-consanguineous parents presented with infantile spasms and developmental regression in the first year. The biochemical profile of low plasma methionine (below detectable limits), and slightly elevated homocystine (3 μmol/L (0-trace) and homocystinuria (234 μmol/gm creatinine) (0-trace amounts) was suggestive of a disturbance in homocysteine metabolism. Plasma homocysteine measurements (30.7 μmol/L, normal <13.5 μmol/L) confirmed hyperhomocysteinemia. Enzyme assay in skin fibroblasts confirmed severe MTHFR deficiency (patient 0.92, control 13.3±4.6nmol/mg/h). Molecular genetic studies identified compound heterozygosity for 2 variant polymorphisms (c.677C>T, and c.1298A>C) and a splicing mutation (c.1348+1G>A). This is a novel mutation that removes a splice site at the end of exon 7 resulting in a premature stop codon that truncates the protein, losing exons 8-11. CSF neurotransmitter analysis showed an extremely low level of 5-methyl tetrahydrofolate of <5 (40-128 nmol/L). The course of epilepsy has been characterized by progression to severe epileptic encephalopathy. Periventricular white matter change consistent with demyelination is seen on MR imaging. Treatment protocols include; oral betaine, supplementation with methionine, folic acid, and 5-methyltetrahydrofolate with questionable benefit. Epileptic seizures remain pharmacoresistant to antiepileptic medications singly and in combinations. Frequent bouts of status epilepticus have led to multiple hospitalizations, and neurosurgical interventions (corpus callosotomy, vagal nerve stimulation). At age 9 years, the patient remains severely impaired by vertebral compressive and limb fractures secondary to severe osteoporosis.
Severe MTHFR deficiency is an important diagnostic consideration in infantile epileptic encephalopathies. Early diagnosis and specific treatment interventions are possible. Further research is needed into effective treatment of epilepsy and prevention of complications in this disorder. Genotype and phenotype correlations will be explored in the light of available biochemical and molecular genetic data.
一种隐性遗传缺陷导致5,10-亚甲基四氢叶酸还原酶（MTHFR）缺乏，是高同型半胱氨酸血症的一种形式的基础。我们描述了严重MTHFR缺乏与神经学表现的关联，特别关注神经发育和癫痫发作的演变。
病例研究及文献综述。
一名9岁女性婴儿，其父母为白种人且非近亲结婚，在出生后第一年出现婴儿痉挛和发育倒退。血浆蛋氨酸水平低（低于可检测限度）、同型半胱氨酸轻度升高（3μmol/L（0 - 微量））和同型胱氨酸尿症（234μmol/g肌酐）（0 - 微量）的生化特征提示同型半胱氨酸代谢紊乱。血浆同型半胱氨酸测量值（30.7μmol/L，正常<13.5μmol/L）证实存在高同型半胱氨酸血症。皮肤成纤维细胞的酶分析证实存在严重的MTHFR缺乏（患者为0.92，对照组为13.3±4.6nmol/mg/h）。分子遗传学研究确定了2种变异多态性（c.677C>T和c.1298A>C）和1种剪接突变（c.1348 + 1G>A）的复合杂合性。这是一种新的突变，它去除了外显子7末端的一个剪接位点，导致产生一个过早的终止密码子，使蛋白质截短，丢失外显子8 - 11。脑脊液神经递质分析显示5 - 甲基四氢叶酸水平极低，<5（40 - 128nmol/L）。癫痫病程的特点是进展为严重的癫痫性脑病。磁共振成像显示脑室周围白质改变，符合脱髓鞘表现。治疗方案包括：口服甜菜碱、补充蛋氨酸、叶酸和5 - 甲基四氢叶酸，但疗效存疑。癫痫发作对抗癫痫药物单药及联合治疗均耐药。频繁的癫痫持续状态发作导致多次住院及神经外科干预（胼胝体切开术、迷走神经刺激术）。9岁时，患者因严重骨质疏松继发椎体压缩性骨折和肢体骨折而严重受损。
严重MTHFR缺乏是婴儿癫痫性脑病的一个重要诊断考虑因素。早期诊断和特定的治疗干预是可行的。需要进一步研究该疾病中癫痫的有效治疗和并发症的预防。将根据现有的生化和分子遗传学数据探索基因型和表型的相关性。
