多种羧化酶缺乏症15例临床分析及长期随访

Clinical analysis and long-term follow-up of multiple carboxylase deficiency in 15 children

目的 探讨多种羧化酶缺乏症（MCD）2种类型的临床特点、诊断与治疗方法.方法 应用气相色谱质谱（GC/MS）联用尿液有机酸分析、外周血生物素酶（BT）活性测定、BT及全羧化酶合成酶（HLCS）基因突变分析进行诊断与分型,对15例MCD患儿的临床资料进行总结分析并随诊.结果 1.MCD 15例患儿尿GC/MS分析见乳酸、3-羟基丁酸、3-羟基异戊酸,3-甲基巴豆酰甘氨酸、甲基枸橼酸及3-羟基丙酸.其中14例确诊为HLCS缺乏症,1例为BT缺乏症.2.HLCS缺乏症起病早,大多数出生后5个月内发病,14例均以反复皮疹为首发症状,伴反复气促9例,精神运动发育迟缓8例,反复呕吐5例,喂养困难3例,运动倒退、抽搐各1例.血气分析示持续性代谢性酸中毒,大部分患儿有酮尿、高乳酸血症、高尿酸血症、高氨血症、低血糖.除1例死亡外,13例给予生物素治疗,48 h内代谢紊乱纠正,随诊至今3～11（6.47 ＆#177;2.70）年,未再发,体格、智力发育正常.3.BT缺乏症1例患儿于1岁4个月起病,表现为神志改变、肢体颤抖,呼吸不规则,头颅磁共振检查提示胼胝体脱髓鞘样损害,起病第2天开始生物素治疗,随访1年,右侧肢体肌力仍未能完全恢复.结论 反复皮疹、气促、代谢紊乱是HLCS缺乏症的主要临床特征;BT缺乏症以神经系统损害更明显,常以神经系统急性脱髓鞘改变起病.GC/MS尿有机酸分析是早期诊断的重要依据.2种类型MCD早期开始生物素治疗疗效显著,长期随诊,预后良好,部分BT缺乏症治疗不及时可遗留神经系统后遗症.

Objective Multiple carboxylase deficiency（MCD） is an autosomal recessively inherited defect of organic acid metabolism.The underlying mechanism is biotinidase（BT） or holocarboxylase synthetase（HLCS） deficiency.The authors reported 15 cases of MCD（clinical characteristics,diagnosis and treatment） and outcomes of long-term follow-up.Methods The clinical data of 15 patients with MCD admitted to Guangzhou Women and Children＆#39;s Medical Center between Aug.2001 and Feb.2013 were analyzed.The diagnosis was confirmed by urinary organic acid analysis with gas chromatography/mass spectrometry （GC/MS）,blood enzymatic determination and gene analysis.The patients consisted of 12 male and 3 female.The onset age ranged from newborn infants to 16 months.Results 1.Remarkable elevations of urinary lactate,3-oxy-butyric acid,3-OH-isovalerate,methylcitrate,3-methylcrontonylglycine,3-OH-propionate were detected in all of 15 cases.Fourteen cases with HLCS deficiency and 1 case with BT deficiency were confirmed by gene analysis.2.Most of patients with HLCS deficiency presented in the neonatal period or early infancy.The main clinical manifestations were skin rash （14 cases）,tachypnea （9 cases）,developmental retardation （8 cases）,vomiting（5 cases）,poor feeding （3 cases）,developmental regradation （1 case）,convulsion （1 case）.Laboratory evaluation showed persistent metabolic acidosis and varied degree of ketosis,lactic acidosis,hyperuricacidemia,ammoniemia and hypoglycemia.Biotin was given to 13 patients in 10 mg/d and their metabolic disorders were corrected within 48 h,except one who gave up treatment and died.Treatment with Biotin in 5 mg/d provided clinical stability and normal neurodevelopmental outcome on follow-up for 3-11 （6.47 ＆#177; 2.70） years.3.One patient with BT deficiency presented with severe neurological symptoms（impaired consciousness,limbs trembling,tachypnea with irregular respiratory rhythm） at 16 months old.Demyelination of corpus callosum was evident on magnetic resonance imaging.Biotin treatment was given to him on the second of onset,and 1-year follow-up indicated significant improvement of his clinical symptoms,but the right limb weakness did not completely recover.Conclusions The main clinical features of HLCS deficiency include frequent skin rash,tachypnea,and metabolic disorders.BT deficiency may produce variable neurologic manifestations including demyelination of corpus callosum.Urinary organic acid analysis with GC/MS is critical to the early diagnosis of MCD.Prompt biotin treatment is recommended to correct metabolic derangements and continued therapy is essential to the improvement of long-term prognosis.Delayed commencement of therapy in BT deficiency can result in irreversible neurological damage.