Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes
Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes
复制标题
DOI：
10.1001/archneur.60.10.1445
复制
发表时间：
2003-10-01
影响因子：
--
通讯作者：
DiMauro, S
中科院分区：
文献类型：
--
作者：
Mancuso, M;Filosto, M;DiMauro, S
目的：记录发生在同一婴儿身上的2种明显不协调的临床疾病：先天性肌病伴肌磷酸化酶缺乏症（McArdle病）和线粒体肝病伴肝功能衰竭和线粒体DNA缺失。方法：1例摩洛哥近亲父母所生的女婴先天性严重低张力及肝肿大，并发肝功能衰竭，于5月龄死亡。我们对肌肉和肝脏活检标本进行了组织化学和生物化学研究，并对脱氧鸟苷激酶（dGK）和肌磷酸化酶（PYGM）基因的整个编码区进行了测序。结果：肌肉活检显示肌鞘下糖原积聚，磷酸化酶组织化学反应阴性。肝活检显示小结节状肝硬化和大量线粒体增生。生化分析显示肌肉磷酸化酶缺乏，肝脏细胞色素c氧化酶缺乏。我们在PYGM的第11外显子456密码子上发现了一个新的纯合错义G-to-A突变，在dGK的第6外显子上发现了一个纯合的4碱基对GATT重复（核苷酸763-766），该重复在核苷酸766至768处产生了一个帧移位和一个过早的TGA终止密码子，导致255个氨基酸的蛋白被截断。在100名健康个体中没有这两种突变。结论：我们的数据进一步扩大了麦卡德尔病患者的遗传异质性；证实线粒体DNA缺失综合征、肝脏受累和dGK突变之间的密切关系；并建议在异常严重表型的患者中应考虑遗传“双重麻烦”。
Objectives: To document 2 apparently incongruous clinical disorders occurring in the same infant: congenital myopathy with myophosphorylase deficiency (McArdle disease) and mitochondrial hepatopathy with liver failure and mitochondrial DNA depletion.Methods: An infant girl born to consanguineous Moroccan parents had severe congenital hypotonia and hepatomegaly, developed liver failure, and died at 5 months of age. We studied muscle and liver biopsy specimens histochemically and biochemically, and we sequenced the whole coding regions of the deoxyguanosine kinase (dGK) and myophosphorylase (PYGM) genes.Results: Muscle biopsy specimens showed subsarcolemmal glycogen accumulation and negative histochemical reaction for phosphorylase. Liver biopsy specimens showed micronodular cirrhosis and massive mitochondrial proliferation. Biochemical analysis showed phosphorylase deficiency in muscle and cytochrome c oxidase deficiency in liver. We identified a novel homozygous missense G-to-A mutation at codon 456 in exon 11 of PYGM, as well as a homozygous 4-base pair GATT duplication (nucleotides 763-766) in exon 6 of dGK, which produces a frame shift and a premature TGA stop codon at nucleotides 766 to 768, resulting in a truncated 255-amino acid protein. Both mutations were absent in 100 healthy individuals.Conclusions: Our data further expand the genetic heterogeneity in patients with McArdle disease; confirm the strong relationship between mitochondrial DNA depletion syndrome, liver involvement, and dGK mutations; and suggest that genetic "double trouble" should be considered in patients with unusual severe phenotypes.