小儿脂质沉积性肌病的临床、病理及分子遗传学分析

Clinical, pathological and molecular genetic analysis of pediatric lipid storage myopathy

目的 通过分析病理确诊的15例脂质沉积性肌病患儿的临床、病理及分子遗传学资料,探讨儿童脂质沉积性肌病的病因及诊治方案.方法 回顾性分析患儿的临床资料、肌肉活检病理资料、尿代谢筛查、血氨基酸和肉碱谱分析、SLC22A5、PNPLA2基因检测.随访患儿5个月～5年4个月.结果 15例患儿（男10例,女5例）中隐匿起病13例,亚急性起病2例;13例以四肢无力和运动耐力下降就诊,2例患儿因肌酸激酶升高就诊（尚无临床症状）;患儿肌肉活检病理均显示肌纤维内脂滴显著增多.血、尿代谢筛查诊断戊二酸尿症Ⅱ型5例,10例无特异性改变;对此10例患儿行SLC22A5、PNPLA2基因检测,均未发现致病突变.补充维生素B2、辅酶Q1o和左旋肉碱治疗后,5例戊二酸尿症Ⅱ型患儿运动恢复正常;8例原因不明脂质沉积性肌病患儿中7例症状减轻,1例死亡.2例拒绝药物治疗的患儿仍有运动耐力下降.结论 脂质沉积性肌病病因复杂,多种辅助检查方法（血肉碱谱分析、尿有机酸筛查和基因检测）联合应用也仅能明确部分患者的病因,戊二酸尿症Ⅱ型可能是儿童脂质沉积性肌病最常见的病因.脂质沉积性肌病的治疗效果取决于病因,但对于病因不明确的患者,补充肉碱和改善能量代谢治疗亦可改善大部分患者的临床症状.

Objective To analyze the clinical,pathological and molecular genetic data from 15 children with pathologically demonstrated lipid storage myopathy（LSM）,and to explore the spectrum of causes,establish approaches on diagnosis and treatment of LSM in children.Methods Clinical data were retrospectively analyzed,including medical history,muscle pathology,urine amino acids and organic acids analysis,blood amino acids and acylcarnitine spectrum analysis.SLC22A5 and PNPLA2 gene mutations were detected.The follow-ups lasted from 5 months to 5 years and 4 months.Results Out of 15 cases,the onset of the disease was occult in 13 patients,subacute in 2 patients.Muscle weakness and exercise intolerance were presented in 13 patients,while 2 patients were asymptomatic with elevated serum creatine kinase levels.Muscle pathology in all patients showed accumulation of lipid drops in skeletal muscle fibers.Glutaric aciduria type Ⅱ was diagnosed in 5 cases by urinary and blood metabolic screening while no specific changes were found in 10 cases.SLC22A5 and PNPLA2 genes mutational analysis by PCR and sequencing were performed in these 10 cases,and no causative mutations were found.Thirteen patients were treated with vitamin B2,carnitine and coenzyme Q10,5 patients with glutaric aciduria type Ⅱ regained nornmal exercise capacity;7 cases out of 8 cases with unknown causes had improvement of muscle strength and exercise tolerance,1 case died.Two patients who refused drug treatment still present with exercise intolerance.Conclusions The causes of lipid storage myopathy were variant.Combined laboratory tests including blood acylcarnitine spectrum analysis,urine organic acids analysis,and genetic testing,may confirm the causes of some patients.Glutaric aciduria type Ⅱ may be the most common cause of LSM in Chinese children.Although the responses to treatment depend mainly on the causes,L-carnitine,Vitamin B2 and CoQ10 may improve the clinical symptoms in most patients.