婴儿脑肌病型线粒体DNA耗竭综合征1例报告

A case of SUCLG 1-related infantile encephalomyopathy mitochondrial DNA depletion syndrome

目的分析罕见的常染色体隐性遗传病——线粒体DNA耗竭综合征的临床及基因突变特点。方法回顾分析1例线粒体DNA耗竭综合征患儿的临床及基因检测资料。结果患儿,男,生后4个月出现肢体无力,9个月就诊时呈营养不良貌,发育落后,四肢肌力、肌张力低下,伴脊柱侧弯、后凸。血清乳酸、丙酮酸增高,肝功能、心肌酶谱异常;血液多种氨基酸降低,丁二酰肉碱增高;尿甲基丙二酸及其代谢产物浓度轻度增高,提示甲基丙二酸尿症。头颅MRI显示双侧豆状核及尾状核萎缩,伴长T2信号及脑萎缩样改变。脑干听觉诱发电位示重度感音神经性耳聋。严重发育落后。基因测序示MUT、MMAA、MMAB等甲基丙二酸尿症相关基因未见可疑致病突变;SUCLG1基因存在c.961C>G(p.A321P)与c.713 T>C(p.D 238 G)两个杂合突变,分别来自表型正常的父母,其中c.961 C>G为已知致病突变,c.713 T>C为未报道新突变。外周血白细胞线粒体DNA拷贝数降低,为244/cell,为正常对照的68.4%。确诊线粒体DNA耗竭综合征。结论不明原因发育落后、肌张力低下、听力障碍伴高乳酸血症、轻度甲基丙二酸血症患儿应考虑线粒体DNA耗竭综合征可能,基因分析可明确诊断。

Objective Mitochondrial DNA depletion syndrome is a rare autosomal recessive disorder characterized by complex genetic and clinical manifestations. This study aimed to investigate the clinical and laboratory features of a boy with mitochondrial encephalomyopathy caused by SUCLG1 mutation. Methods The clinical data and genetic test of a patient with mitochondrial DNA depletion syndrome were retrospectively analyzed. Result The proband presented with limb weakness at the 4th month after birth, and presented dystrophic appearance, muscular hypotonia, psychomotor retardation, failure to thrive, hearing impairment, scoliosis, thoracocyllosis and facial features at 9 months old. Laboratory tests showed blood lactic acid and pyruvate increased, liver damage and abnormal myocardial enzymes. Plasma carnitine ester profiling showed that amino acids decreased and C4-dicarboxylic-carnitine increased. Urinary organic acid analysis showed increased concentration of methylmalonic acid and its metabolites indicating methyl malonic aciduria. MRI showed bilateral T2 hyperintensities in bilateral caudate nuelei and lenticular and brain atrophy-like changes. Brainstem auditory evoked potential showed severe hearing loss. His development quotient was 35. Genetic sequencing of MUT, MMAA, MMAB and other classic mitochondrial disease related genes of the proband revealed no mutation. Two heterozygous mutations, c.961C〉G and c.713T〉C, inherited from the phenotype of normal parents were detected in his SUCLG1 gene. The copy number of mitochondrial DNA was 244/cell in peripheral blood leukocytes, equivalent to 68.4% of that in normal control. Conclusion In this study, an infant with muscular hypotonia, psychomotor retardation, deafness and slightly increased urine methyl malonic acid was diagnosed by genetic test. For patients with unexplained hypotonia, mental retardation, abnormal movements, heating disorder together with increased blood pyruvic acid and lactic acid, mild methylmalonic acidemia and abnormal acylcarnitine, mitochondrial DNA depletion syndrome should be considered. Gene analysis is important for diagnosis and prenatal diagnosis of the next pregnancy.