维生素B12 缺乏致婴儿继发性甲基丙二酸血症临床诊治体会

目的:探讨维生素B12 缺乏导致的继发性甲基丙二酸血症(S-MMA) 临床表现、生化特点、治疗及预后。方法:回顾性分 析2016 年6 月至2022 年6 月就诊于河南省儿童医院的11 例确诊为维生素B12 缺乏导致继发性S-MMA(S-MMA 组)患儿的临 床表现、实验室检查、治疗效果、母亲孕期情况及生化特点。依据年龄、性别按照1 ∶ 3 匹配同期确诊为cblC 型MMA( C-MMA 组),维生素B12 缺乏非MMA 组为维生素B12 缺乏组10 例,应用SPSS 20. 0 软件比较三组患儿临床资料。结果:三组患儿临床 表现主要为贫血、呕吐、发育落后,S-MMA 组及C-MMA 组患儿头颅磁共振主要表现为髓鞘化落后。S-MMA 组患儿治疗前后血 清维生素B12 水平上升,红细胞平均体积(MCV)、同型半胱氨酸、丙酰肉碱( C3)、丙酰肉碱/ 乙酰肉碱( C3/ C2)、尿甲基丙二酸 水平下降,差异有统计学意义(P<0. 05)。S-MMA 患儿预后良好,极个别(9%)因诊断治疗较晚遗留轻度智力低下和运动落后。 S-MMA 组与C-MMA 组治疗前血清维生素B12 水平、MCV、总同型半胱氨酸、C3、C3/ C2 水平以及尿甲基丙二酸水平比较差异均 有统计学意义(P<0. 05)。结论:孕期维生素B12 缺乏可导致婴儿S-MMA,特殊生化指标有助于早期识别S-MMA。     

A novel deleterious ETFA promoter variant causative of multiple acyl-CoA dehydrogenase deficiency

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism. We describe a patient identified through newborn screening in which the diagnosis of MADD was confirmed based on metabolic profiling, but clinical molecular sequencing of ETFA, ETFB, and ETFDH was normal. In order to identify the genetic etiology of MADD, we performed whole genome sequencing and identified a novel homozygous promoter variant in ETFA (c.-85G > A). Subsequent studies showed decreased ETFA protein expression in lymphoblasts. A promoter luciferase assay confirmed decreased activity of the mutant promoter. In both assays, the variant displayed considerable residual activity, therefore we speculate that our patient may have a late onset form of MADD (Type III). Our findings may be helpful in establishing a molecular diagnosis in other MADD patients with a characteristic biochemical profile but apparently normal molecular studies.     

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

Objective

Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria.

Methods

We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data.

Results

Thirty-seven patients, 1–31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy.

Significance

Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.