Balasubramaniam Shanti, Lewis B, Mock D M, Said H M, Tarailo-Graovac M, Mattman A, van Karnebeek C D, Thorburn D R, Rodenburg R J, Christodoulou J
Metabolic Unit, Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA, Australia.
School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
JIMD Rep. 2017;33:99-107. doi: 10.1007/8904_2016_559. Epub 2016 Jul 22.
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.
Leigh综合征（LS），即亚急性坏死性脑脊髓病，是一种具有遗传异质性、呈无情进行性发展的毁灭性神经退行性疾病，通常在婴儿期或幼儿期发病。对于那些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。我们描述了一名3岁男孩的独特Leigh样综合征表现，其在新生儿筛查（NBS）中3-羟基异戊酰肉碱（C5-OH）升高。随后C5-OH和丙酰肉碱（C3）的血浆水平持续升高以及尿标志物波动提示多种羧化酶缺乏症（MCD）。全羧化酶合成酶（HLCS）和生物素酶（BTD）编码基因的酶学检查和突变分析均正常，排除了MCD。生物素摄取研究正常，排除了生物素转运蛋白缺乏症。他13个月大时的临床特征包括精神运动发育迟缓、中枢性肌张力减退、肌病、生长发育迟缓、低瓜氨酸血症、代谢性酮乳酸酸中毒反复失代偿发作以及一次高氨血症发作。尽管生化指标没有改善，但从13个月大开始进行生物素治疗后，患者的活动能力、警觉性增强，并达到了新的发育里程碑进展。全外显子组测序（WES）分析未能识别出任何其他可能导致所观察到表型的变异，除了最初通过线粒体DNA（mtDNA）测序检测到的纯合（100%）m.8993T>G变异。低瓜氨酸血症已在患有m.8993T>G变异和其他线粒体疾病的患者中报道。然而，此前仅有另一例具有这种纯合突变的患者报道过C3和C5-OH的血浆水平持续升高。我们建议在对类似MCD的生化紊乱进行诊断评估时尽早考虑m.8993T>G变异，特别是当与NBS及后续确诊试验中的低瓜氨酸血症相关时。口服生物素试验也是必要的。
