Leigh-Like Syndrome Due to Homoplasmic m.8993T> Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)
Leigh-Like Syndrome Due to Homoplasmic m.8993T> Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)
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DOI：
10.1007/8904_2016_559
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Christodoulou, J.
中科院分区：
文献类型：
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作者：
Balasubramaniam, Shanti;Lewis, B.;Christodoulou, J.
Leigh综合征(LS)，或亚急性坏死性脑脊髓病，是一种遗传异质性的、无情的进行性、破坏性的神经退行性疾病，通常出现在婴儿或儿童早期。对于不符合严格诊断标准但具有类似Leigh综合征特征的个体，可考虑诊断为Leigh样综合征。我们描述了一例新生儿筛查(NBS)中3-羟基异戊基肉碱(C5-OH)升高的3岁男孩的Leigh样综合征的独特表现。随后持续升高的C5-OH和丙酰肉碱(C3)以及波动的尿标志物提示多发性羧基酶缺乏症(MCD)。正常的酶学和全羧酶合成酶(HLCS)和生物素酶(BTD)基因突变分析排除了MCD。除生物素转运体缺乏症外，生物素摄取研究正常。他在13个月大时的临床特征包括精神运动迟缓、中枢性低眼压、肌病、发育迟缓、低瓜氨酸血症、反复发作代谢性失代偿伴代谢性酮酸中毒和一次高氨血症。从13个月大开始的生物素治疗与患者活跃度、警觉性和达到新的发育里程碑有关，尽管缺乏生化改善。除了线粒体DNA(MtDNA)序列最初检测到的同质(100%)m.8993T>；G变异外，整个外显子序列(WES)分析没有发现任何其他可能导致观察到的表型的变异。已有报道在m.8993T>；G变异和其他线粒体疾病的患者中出现低核氨酸血症。然而，C3和C5-OH的持续性血浆升高之前只在另一例这种同质突变的患者中被报道过。我们建议在MCD样生化紊乱的早期诊断评估中考虑m.8993T>；G变异，特别是在国家统计局和随后的确证试验中与低瓜氨酸血症相关的时候。口服生物素试验也是有必要的。
Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS). Subsequent persistent plasma elevations of C5-OH and propionylcarnitine (C3) as well as fluctuating urinary markers were suggestive of multiple carboxylase deficiency (MCD). Normal enzymology and mutational analysis of genes encoding holocarboxylase synthetase (HLCS) and biotinidase (BTD) excluded MCD. Biotin uptake studies were normal excluding biotin transporter deficiency. His clinical features at 13 months of age comprised psychomotor delay, central hypotonia, myopathy, failure to thrive, hypocitrullinemia, recurrent episodes of decompensation with metabolic keto-lactic acidosis and an episode of hyperammonemia. Biotin treatment from 13 months of age was associated with increased patient activity, alertness, and attainment of new developmental milestones, despite lack of biochemical improvements. Whole exome sequencing (WES) analysis failed to identify any other variants which could likely contribute to the observed phenotype, apart from the homoplasmic (100%) m.8993T>G variant initially detected by mitochondrial DNA (mtDNA) sequencing.Hypocitrullinemia has been reported in patients with the m.8993T>G variant and other mitochondrial disorders. However, persistent plasma elevations of C3 and C5-OH have previously only been reported in one other patient with this homoplasmic mutation. We suggest considering the m.8993T>G variant early in the diagnostic evaluation of MCD-like biochemical disturbances, particularly when associated with hypocitrullinemia on NBS and subsequent confirmatory tests. An oral biotin trial is also warranted.