Complete resolution of epileptic spasms with vigabatrin in a patient with 3‐methylglutaconic aciduria caused by TIMM50 gene mutation
Complete resolution of epileptic spasms with vigabatrin in a patient with 3‐methylglutaconic aciduria caused by TIMM50 gene mutation
复制标题
氨己烯酸彻底缓解 TIMM50 基因突变引起的 3-甲基戊烯酸尿症患者的癫痫痉挛
DOI：
10.1111/cge.13763
复制
发表时间：
2020
影响因子：
3.5
通讯作者：
S. Bashir
中科院分区：
文献类型：
--
作者：
A. Mir;Safeya Hadab;M. Sammak;Rami Alhazmi;Yousef Housawi;S. Bashir
癫痫痉挛是一种常见的癫痫发作类型，常伴有严重的智力障碍和脑电图上的心律失常。ES可与多种疾病相关，其病因学可指导治疗和预后。最近，TIMM 50基因突变的严重ID和ES患者伴有3-甲基戊烯二酸尿症（3-MGA）和可变线粒体复合物V缺陷。我们描述了一个非常罕见的情况下，3-MGA引起的TIMM 50基因突变与ES谁已完全解决ES和高心律失常与氨己烯酸（VGB）。这是一个20个月大的沙特女孩，父母是近亲。她在2个月大时出现ES。她足月出生，出生体重为1450 g。她有一个小的动脉导管未闭和轻微的左心室肥大。她有全面发育迟缓。她是她父母的第一个也是唯一的孩子。在4个月龄时检查时，所有生长参数均低于第5百分位数。她有长睫毛、前额隆起、高弓腭、斜视、宽间距乳头和短脖子的畸形。她对周围的环境不感兴趣，也无法注视或跟随。全身肌张力减退伴头滞后。上肢反射正常，但下肢未引起反射。脑电图显示高血压模式。捕获了5个多ES簇。患者手臂和面部有舞蹈样手足徐动症样运动，但没有任何异常脑电图相关。她立即开始接受VGB，滴定至150 mg/kg/天，并表现出明显的反应，表现为ES停止和EEG正常化。VGB在16个月大时断奶，她继续保持无流产。她变得专注，对周围感兴趣，咕咕叫，说妈妈，跟随和注视，抱着头，坐着支持，玩和抓物体，翻身，回应父母。代谢检查显示血浆乳酸轻度升高3 mmol/L（正常0.4-2 mmol/L）。尿有机酸显示3-甲基戊烯二酸和3-甲基戊二酸显著增加。在开始VGB后约4周进行的脑部磁共振成像（MRI）显示苍白球、中脑和背侧脑桥双侧对称性T2高信号伴相应的弥散受限。这些结果被认为是VGB相关的一过性变化。磁共振波谱无异常。2岁时重复脑部MRI显示上述异常几乎完全消退。髓鞘形成的预期进展与患者的年龄相符。在CGC Genetics进行的全外显子组测序检测到TIMM 50基因中表观纯合性的致病性c.755C> Tp.（Thr 252 Met）变体（chr. 19）。没有发现其他符合美国医学遗传学学会次要结果报告标准的变异。3-MGA是一种罕见的常染色体隐性线粒体疾病，由亮氨酸代谢途径缺陷引起。原发性3-MGA是由涉及3-甲基戊烯二酰辅酶A水合酶基因的突变引起的。3-甲基戊烯二酸单酰辅酶A水合酶活性缺陷导致3-甲基戊烯二酸蓄积。3-MGA的临床谱可从重度暴发性新生儿至迟发性表现。3-MGA患者的测序分析显示存在引起不同代谢疾病的不同突变，包括SUCLA 2（琥珀酰CO-A裂解酶基因）、POLG 1（引起进行性mtDNA耗竭）、RYR 1（引起全身性肌病形式）和TMEM 70（线粒体脑-心-肌病）。线粒体内膜转位酶50（TIMM 50）基因位于染色体19q13.2。Shahrour等人报告了来自两个不相关家族的4名患者，这些患者患有重度ID、癫痫、乳酸盐轻度升高、3-MGA和可变线粒体复合物V缺乏症，并在TIMM 50基因中鉴定出两个纯合错义突变Arg 217 Trp和一个与我们的患者Thr 252 Met相似的突变。他们引用了一篇摘要，其中报道了TIMM 50基因中的纯合突变Gly 372 Ser，在三个患有癫痫，发育迟缓，伴有3-MGA的兄弟姐妹中。Shahrour等人报告的患者的临床特征和研究与我们的病例沿着在表1中进行了比较。他们报告的两例病例（A-II-1和A-II-3）与我们的病例一样出现ES和高度心律失常，1例使用VGB的患者与我们的患者一样，EEG正常，无癫痫。本报告描述了TIMM 50基因突变、ES和3-MGA之间的罕见关联。它强调了早期治疗ES的重要性，这可以导致有利的结果。
To the Editor, Epileptic spasms (ES) is a seizure type which is usually associated with severe intellectual disability (ID) and hypsarrhythmia on electroencephalogram (EEG). ES can be associated with a variety of disorders, and the etiology may guide in the management and prognosis. Recently, mutations in TIMM50 gene were described in patients with severe ID and ES accompanied by 3-methylglutaconic aciduria (3-MGA) and variable mitochondrial complex V deficiency. We describe a very rare case of 3-MGA caused by a mutation in TIMM50 gene presenting with ES who had complete resolution of ES and hypsarrhythmia with vigabatrin (VGB). This is a 20 month old Saudi girl born to consanguineous parents. She presented with ES at the age of 2 months. She was born at term with a birth weight of 1450 g. She has a small patent ductus arteriosus and mild left ventricular hypertrophy. She has global developmental delay. She is the first and only child of her parents. On examination at the age of 4 months, all the growth parameters were below the fifth percentile. She was dysmorphic with long eyelashes, frontal bossing, high arched palate, strabismus, wide-spaced nipples, and short neck. She was not interested in surrounding and was not able to fixate or follow. There was generalized hypotonia with head lag. Reflexes were normal in upper extremities but were not elicited in the lower extremities. EEG showed a hypsarrhythmic pattern. Five clusters of multiple ES were captured. The patient had choreoathetoid movements of arms and face which did not have any abnormal EEG correlate. She was immediately started on VGB titrated up to 150 mg/kg/day and showed a remarkable response in the form of cessation of the ES and normalization of the EEG. VGB was weaned at the age of 16 months and she continued to be seizure-free. She became attentive, interested in surrounding, cooing, saying mama, following and fixating, holding the head, sitting with support, playing and grasping objects, roll over, and responding to parents. Metabolic workup showed mildly elevated plasma lactate 3 mmol/L (normal 0.4-2 mmol/L). Urine organic acids showed a marked increase in 3-methyglutaconic acid and 3-methylglutaric acid. The brain magnetic resonance imaging (MRI) which was done approximately 4 weeks after starting the VGB showed bilateral symmetric T2 hyperintensity of the globus pallidi, midbrain and dorsal pons with corresponding diffusion restriction. These findings were considered to be VGB-associated transient changes. Magnetic resonance spectroscopy was unremarkable. A repeat brain MRI at the age of 2 years showed near-complete resolution of the aforementioned abnormalities. There was an expected progression of myelination compatible with the patient's age. Whole exome sequencing performed at the CGC Genetics detected a pathogenic c.755C>T p. (Thr252Met) variant in apparent homozygosity in the TIMM50 gene (chr.19). No other variants that fulfill the American College of Medical Genetics reporting criteria of secondary findings were found. 3-MGA is a rare autosomal recessive mitochondrial disorder that results from a defect in the leucine metabolic pathway. Primary 3-MGA is caused by mutations involving the gene of 3-methylglutaconyl CoA hydratase. Defective 3-methylglutaconyl CoA hydratase enzyme activity results in the accumulation of 3-methylglutaconic acid. The clinical spectrum of 3-MGA could range from a severe fulminant neonatal to lateonset presentation. Sequencing analysis in patients with 3-MGA revealed the presence of different mutations causing different metabolic disorders including SUCLA2 (succinyl CO-A lyase gene), POLG1 (causing progressive mtDNA depletion), RYR1 (causing generalized myopathic form), and TMEM70 (Mitochondrial encephalo-cardio-myopathy). Translocase of inner mitochondrial membrane 50 (TIMM50) gene is located on chromosome 19q13.2. Shahrour et al reported four patients from two unrelated families with severe ID, epilepsy, slightly elevated lactate, 3-MGA, and variable mitochondrial complex V deficiency and identified two homozygous missense mutations, Arg217Trp, and a similar mutation as in our patient Thr252Met in the TIMM50 gene. They cited an abstract which reported a homozygous mutation, Gly372Ser, in the TIMM50 gene in three siblings who had epilepsy, developmental delay, accompanied by 3-MGA. Clinical features and investigations of patients reported by Shahrour et al are compared in Table 1 along with our case. The two cases (A-II-1 and A-II-3) they reported presented with ES and hypsarrhythmia like our case and one patient in whom VGB was used became seizure-free with normal EEG like our patient. This report describes a rare association between TIMM50 gene mutation, ES and 3-MGA. It highlights the importance of early treatment of ES, which can lead to a favorable outcome.