以Leigh样综合征为表现的钼辅因子缺乏症B型一例并文献复习

目的探讨Leigh样综合征起病钼辅因子缺乏症B型的表型及基因型特点。方法对2018年12月在河北省儿童医院及北京儿童医院神经内科确诊的1例钼辅因子缺乏症B型患儿的临床资料、实验室检查、影像学检查及基因结果等资料进行收集并回顾性分析。以“MOCS2”“钼辅因子缺乏症”“Leigh-like syndrome,MOCS2”“molybdenum cofactor deficiency,Leigh-like syndrome”分别在万方数据知识服务平台、中国期刊全文数据库(CNKI)、PubMed建库至2020年9月进行文献检索并文献复习。总结MOCS2基因相关钼辅因子缺乏症表型及基因型特点。结果患儿男,7月龄14日龄,因“咳嗽6 d,姿势异常4 d,发热2 d”于2018年12月收入河北省儿童医院神经内科。患儿姿势异常表现为“角弓反张”样,伴吞咽困难,无惊厥发作,发病前发育基本同正常同龄儿。否认围生期缺氧窒息史,父母非近亲婚配。辅助检查示血乳酸轻度增高;血尿酸明显降低;尿代谢筛查示尿黄嘌呤和次黄嘌呤水平增高;头颅磁共振成像提示双侧苍白球、大脑脚对称斑片样T2加权相、液体衰减反转恢复序列高信号。诊断为Leigh样综合征,予鸡尾酒疗法及对症治疗好转不明显。完善全外显子组测序示受检者携带MOCS2基因c.19G>T(p.Val7Phe)纯合变异,父母携带c.19G>T杂合变异,该位点为文献已报道的致病位点,可导致钼辅因子缺乏症B型。文献检索加上本例共收集41例MOCS2基因相关钼辅因子缺乏症患者,30例信息完整,其中23例(77%)新生儿期起病,表现为难治性癫痫,发育落后等,血尿酸明显降低,尿黄嘌呤、次黄嘌呤升高,头颅影像学提示脑萎缩,囊状脑软化等,神经系统受累程度重。7例发病年龄在5月龄至23岁,4例发病前发育正常,均在诱因下出现急性神经系统症状或原有症状加重,均有基底节受累。30例中3例临床表型相对较轻,可简单交流及独走或扶走。结论钼辅因子缺乏症B型罕见,多数表型严重预后不良,但也有部分患儿临床表型相对较轻。MOCS2基因变异所致钼辅因子缺乏症B型可表现为Leigh样综合征的代谢性脑病,早期发育可正常,感染后进行性加重;血尿酸降低,尿黄嘌呤和次黄嘌呤增高为其生化特征,发现MOCS2基因变异可确诊。

Molybdenum cofactor deficiency type B manifested as Leigh-like syndrome:a case report and literature review

Objective To explore the phenotypes and genotypes of molybdenum cofactor deficiency type B(MoCD-B)manifested as Leigh-like syndrome.Methods The clinical data,laboratory tests,neuroimaging and gene results of one patient diagnosed as MoCD-B at Beijing Children′s Hospital and Hebei Children′s Hospital in December 2018 were collected.Related literature was searched and reviewed at Wanfang Data Knowledge Service Platform,China National Knowledge Infrastructure and PubMed(up to September 2020)by using terms"MOCS2""molybdenum cofactor deficiency""Leigh-like syndrome,MOCS2""molybdenum cofactor deficiency,Leigh-like syndrome".The phenotypes and genotypes of MoCD-B were summarized.Results A 7 months and 14 days old boy with the chief complaint of"cough for 6 days,abnormal posture for 4 days and fever for 2 days"was admitted to Hebei Children′Hospital on December 2018.His abnormal posture presented as opisthotonos accompanied with dysphagia,without seizures.His previous psychomotor development was described as normal.He was born at term after an uneventful pregnancy to non-consanguineous parents.Blood test showed a slightly increased lactic acid and a significantly decreased uric acid.Urine metabolism test showed an obviously increased xanthine and hypoxanthine.Brain magnetic resonance imaging showed hyperintense signal on T2 weighted image and fluid attenuated inversion recovery in bilateral globus pallidus and pedunculus cerebri.The patient was diagnosed with Leigh-like syndrome.No obvious improvement was achieved after cocktail therapy and symptomatic treatment.The whole exome sequencing showed that the patient carried a homozygous variant of MOCS2 gene,c.19G>T(p.Val7Phe),which was a previously reported pathogenic site in the literature and could cause MoCD-B.His parents carried a heterozygous variant respectively.A total of 41 MoCD-B cases with MOCS2 gene variants were collected through literature review and our study,among which 30 cases had full medical records.The onset ages of 23(77%)cases were in neonate,manifesting with severe encephalopathy,including neonatal-onset intractable seizures,developmental delay,laboratory abnormalities included very low levels of serum and urinary uric acid,increased urinary levels of xanthine and hypoxanthine.Cranial imaging showed cerebral atrophy,cystic encephalomalacia,etc.The onset ages of 7 patients varied from 5 months to 23 years.Four cases had normal psychomotor development before disease onset.Neurological disorders appeared acutely or exacerbated after external triggers and all of them had basal ganglia involvement.Among the 30 cases,3 cases had a relatively milder phenotype with the ability of brief communication and walking without or with support.Conclusions Molybdenum cofactor deficiency is a rare disease.Most cases had severe phenotypes and poor outcomes,but some cases may have mild phenotype.MoCD-B caused by MOCS2 gene variants may manifest as Leigh-like syndrome with a normal psychomotor development before the trigger of infection strike.Hypouricemia,xanthinuria and hypoxanthinuria can be indicators of the disease.The presence of MOCS2 gene variants would confirm a final diagnosis.