Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria
Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria
复制标题
DOI：
10.1186/1750-1172-8-98
复制
发表时间：
2013-07-09
影响因子：
3.7
通讯作者：
Geraghty, Michael T.
中科院分区：
文献类型：
--
作者：
Marcadier, Julien L.;Smith, Amanda M.;Geraghty, Michael T.
背景资料：甲基丙二酸半醛脱氢酶（MSDH）缺乏症是一种罕见的常染色体隐性遗传疾病，伴有多种代谢物异常，包括3-羟基异丁酸、3-羟基丙酸、3-氨基异丁酸和甲基丙二酸以及β-丙氨酸的蓄积。现有的报告描述了一个高度可变的临床和生化表型，这可能使诊断成为一个挑战。迄今为止，只有三个报告的病例已在分子水平上得到证实，通过鉴定ALDH 6A 1（编码MMSDH的基因）的纯合突变。由于酶底物极其不稳定，迄今为止还不可能通过酶测定进行确认。方法和结果：我们报告了一名儿童，患有严重发育迟缓、脑MRI显示髓鞘形成异常以及乳酸、甲基丙二酸、3-羟基异丁酸和3-氨基异丁酸短暂/可变升高。通过外显子组测序鉴定复合杂合突变，并通过ALDH 6A 1的外显子6（c.514 T > C; p.Tyr172 His）和外显子12（c.1603 C> T; p.Arg535 Cys）内的桑格测序确认。由此产生的氨基酸变化，都发生在哺乳动物中保守的残基中，预计在蛋白质水平上是有害的。随后的MMSDH酶检测表明，患者成纤维细胞的活性降低，测量低于mean.Conclusions 2.5标准差：我们目前报道的第四例MMSDH缺乏症的确认在分子水平上，并扩大什么已经是一个非常可变的临床和生化表型。此外，这是第一份证明MMSDH酶活性相应降低的报告。这份报告说明了新出现的利用全外显子组测序和变异数据过滤使用临床数据作为早期工具，在诊断罕见和可变的条件。
Background: Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as beta-alanine. Existing reports describe a highly variable clinical and biochemical phenotype, which can make diagnosis a challenge. To date, only three reported cases have been confirmed at the molecular level, through identification of homozygous mutations in ALDH6A1, the gene encoding MMSDH. Confirmation by enzyme assay has until now not been possible, due to the extreme instability of the enzyme substrate.Methods and results: We report a child with severe developmental delays, abnormal myelination on brain MRI, and transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p. Arg535Cys) of ALDH6A1. The resulting amino acid changes, both occurring in residues conserved among mammals, are predicted to be damaging at the protein level. Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean.Conclusions: We present the fourth reported case of MMSDH deficiency with confirmation at the molecular level, and expand on what is already an extremely variable clinical and biochemical phenotype. Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity. This report illustrates the emerging utilization of whole exome sequencing and variant data filtering using clinical data as an early tool in the diagnosis of rare and variable conditions.