Transient neonatal renal failure and massive polyuria in MEGDEL syndrome

Carole Harbulot; Stéphanie Paquay; Imen Dorboz; Samia Pichard; Agnès Bourillon; Jean-Fran?ois Benoist; Claude Jardel; Hélène Ogier de Baulny; Odile Boespflug-Tanguy; Manuel Schiff

摘要

Abstract BackgroundMEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome) syndrome is a mitochondrial disorder associated with recessive mutations in SERAC1 .ObjectivesTo report transient neonatal renal findings in MEGDEL syndrome.ResultsThis 7?year-old girl was the first child of consanguineous Turkish parents. She exhibited an acute neonatal deterioration with severe lactic acidosis and liver failure. Initial evaluation revealed massive polyuria and renal failure with 3-methylglutaconic aciduria. Symptoms and biological findings progressively improved with symptomatic treatment but lactic acidosis and high lactate to pyruvate ratio along with 3-methylglutaconic aciduria persisted. At 8?months of age, a subacute neurological degradation occurred with severe hypotonia, dystonia with extrapyramidal movements and failure to thrive. Brain MRI revealed basal ganglia lesions suggestive of Leigh syndrome. At 3?years of age, sensorineural deafness was documented. MEGDEL syndrome was further confirmed by the identification of an already reported homozygous mutation in SERAC1 .ConclusionTransient neonatal polyuria and renal failure have not been reported to date in SERAC1 defective patients. Such neonatal kidney findings expand the clinical spectrum of MEGDEL syndrome. Keywords Mitochondrial disease ; MEGDEL ; SERAC1 ; Kidney prs.rt("abs_end"); 1. Introduction MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MIM 614739 ) syndrome is a recessively inherited disorder recently associated with recessive mutations in SERAC1 [1] . SERAC1 (serine active site containing 1) is a protein involved in phosphatidylglycerol remodeling located in the mitochondrial-associated membrane at the contact site between endoplasmic reticulum and mitochondria. The identification of SERAC1 mutations in MEGDEL syndrome helped defining a new category of nuclear-encoded mitochondrial-related diseases, namely genetic defects of phospholipid biosynthesis, remodeling and metabolism [2] , [3] , [4] , [5] and [6] . These diseases present a large spectrum of clinical consequences. Such new category of mitochondrial-related inborn errors of phospholipid metabolism became clearly identifiable with the recent application of next generation sequencing methodologies. These diseases include TAZ mutations (Barth syndrome), DNAJC19 (DCMA syndrome), SERAC1 mutations (MEGDEL syndrome), AGK mutations (Sengers syndrome), DDHD1 and DDHD2 mutations (hereditary spastic paraplegia). In TAZ , SERAC1 , DNAJC19 and AGK mutations, 3-methylglutaconic aciduria (3-MGA) is observed [3] . We report herein transient kidney features in a neonate later diagnosed with MEGDEL syndrome. 1.1. Case description This first girl from consanguineous healthy Turkish parents was born at 39?weeks of gestation by caesarean section because of fetal bradycardia. Birth weight, height and head circumference were 2.200?kg, 45?cm, and 31?cm respectively, ( At 20?h of life, she was admitted to the intensive care unit for respiratory failure and tachycardia along with truncal hypotonia and tremor. Labs showed metabolic acidosis with increased anion gap due to hyperlactatemia (19.8?mM, normal value From the age of 8?months, she exhibited failure to thrive along with head circumference growth arrest. Psychomotor milestones were delayed and truncal hypotonia with left eye strabismus were noted. At 15?months of age, her weight, height and head circumference were 7.250?kg ( From 3?years of age, severe dystonia, spastic tetraparesis and hearing loss were noted. Audiometry revealed bilateral sensorineural deafness, which was severe on the right side and profound on the left side. Speech development was absent and motor development milestones severely delayed but rigorous assessment of neurodevelopment could not be performed. The patient is currently 7?years and 9?months old and exhibits a severe and slowly progressive dystonic encephalopathy with correct growth parameters (weight: ??0.5?SD, height: 0?SD) due to improvement of the caloric intake. Renal function (as assessed by serum creatinine) is normal and there is no polyuria. Mitochondrial respiratory chain activities were normal in skin fibroblasts and skeletal muscle (not shown). MEGDEL syndrome was suspected. Whole exome sequencing had been performed just before the identification of the molecular basis of MEGDEL syndrome ( i.e. description of SERAC1 mutations [1] ) and found an already reported homozygous mutation in SERAC1 [1] . This mutation (c.1822_1828?+?10del17ins9) was confirmed by Sanger sequencing with appropriate parental segregation. 2. Discussion Clinical and neuroradiological [7] presentation of approximately 40 reported MEGDEL patients is relatively homogeneous. However, some additional, initially undescribed features were reported such as neonatal hepatopathy [8] , optic nerve atrophy, microcephaly, and myoclonic epilepsy [9] . None of these additional fi

机译：摘要背景MEGDEL（3-甲基戊二酸尿症合并耳聋，脑病和Leigh-like综合征）是一种线粒体疾病，与SERAC1的隐性突变有关。目的报道MEGDEL综合征的新生儿短暂性肾脏病结果。结果该7岁的女孩是第一个土耳其近亲的孩子。她表现出急性新生儿恶化，伴有严重的乳酸性酸中毒和肝功能衰竭。初步评估显示大量多尿和3-甲基戊二酸尿症的肾衰竭。通过对症治疗，症状和生物学发现逐渐改善，但乳酸性酸中毒和乳酸与丙酮酸的高比率以及3-甲基戊二酸尿症持续存在。在8个月大时，出现了亚急性神经功能退化，伴有严重的肌张力低下，肌张力障碍，锥体外系运动和无法存活。脑部MRI显示提示Leigh综合征的基底神经节病变。在3岁时，有感音神经性耳聋的记录。通过鉴定SERAC1中已经报道的纯合突变进一步证实了MEGDEL综合征。结论SERAC1缺陷患者迄今尚未报道暂时性新生儿多尿和肾衰竭。这种新生儿肾脏发现扩大了MEGDEL综合征的临床范围。线粒体疾病; MEGDEL; SERAC1;肾脏prs.rt（“ abs_end”）; 1.简介MEGDEL（伴有耳聋，脑病和Leigh样综合征的3-甲基谷氨酸酸尿症，MIM 614739）综合征是一种隐性遗传疾病，最近与SERAC1的隐性突变有关[1]。 SERAC1（丝氨酸活性位点含1）是一种参与磷脂酰甘油重塑的蛋白质，位于内质网与线粒体接触部位的线粒体相关膜中。识别MEGDEL综合征中的SERAC1突变有助于定义一类新的核编码线粒体相关疾病，即磷脂生物合成，重塑和代谢的遗传缺陷[2]，[3]，[4]，[5]和[6] ]。这些疾病表现出广泛的临床后果。随着新一代测序方法的最新应用，这种新类别的与线粒体相关的先天性磷脂代谢错误变得显而易见。这些疾病包括TAZ突变（Barth综合征），DNAJC19（DCMA综合征），SERAC1突变（MEGDEL综合征），AGK突变（Sengers综合征），DDHD1和DDHD2突变（遗传性痉挛性截瘫）。在TAZ，SERAC1，DNAJC19和AGK突变中，观察到3-甲基戊二酸尿症（3-MGA）[3]。我们在此报告后来被诊断为MEGDEL综合征的新生儿的短暂肾功能。 1.1。病例描述这名来自土耳其健康近亲父母的第一个女孩因胎儿心动过缓而在剖宫产时妊娠39周出生。出生体重，身高和头围分别为2.200？kg，45？cm和31？cm（在生命的20小时时，她因呼吸衰竭和心动过速以及截断性肌张力减退和震颤被送入重症监护病房。实验显示，高乳酸血症（19.8？mM，正常值）可导致代谢性酸中毒，且阴离子间隙增加，从8个月大起，她就表现出无法failure壮成长并伴有头围生长停滞的现象。在15个月大时，她的体重，身高和头围为7.250千克（从3岁起，出现严重的肌张力障碍，痉挛性四轻瘫痪和听力下降。听力测验显示双侧感觉神经性耳聋，严重者为双耳）。右侧，左侧则很深，没有语言发展，运动发展的里程碑严重延迟，但无法对神经发育进行严格的评估，患者目前为7岁在9个月大和9个月大时，由于热量摄取的改善，表现出严重且缓慢进展的肌张力障碍性脑病，并具有正确的生长参数（体重：0.5？SD，身高：0？SD）。肾功能（通过血清肌酐评估）正常，无多尿。皮肤成纤维细胞和骨骼肌的线粒体呼吸链活性正常（未显示）。怀疑是MEGDEL综合征。在确定MEGDEL综合征的分子基础（即描述SERAC1突变[1]）之前就已经进行了整个外显子组测序，发现SERAC1中已经报道了纯合突变[1]。通过适当的亲本分离的Sanger测序证实了该突变（c.1822_1828Δ+Δ10del17ins9）。 2.讨论临床和神经放射学[7]报道约40名已报告的MEGDEL患者相对均一。但是，还报道了一些其他的，最初没有描述的特征，例如新生儿肝病[8]，视神经萎缩，小头畸形和肌阵挛性癫痫[9]。这些附加功能均不可用

Transient neonatal renal failure and massive polyuria in MEGDEL syndrome

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