m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening
m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening
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DOI：
10.1007/8904_2014_332
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Hickey, Scott
中科院分区：
文献类型：
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作者：
Mori, Mari;Mytinger, John R.;Hickey, Scott
瓜氨酸是扩大新生儿筛查（NBS）测量的代谢物之一。虽然低瓜氨酸血症可以作为近端尿素循环酶（如鸟氨酸转氨基甲酰基酶（OTC））缺乏的标志，但在美国只有少数几个州的新生儿筛查项目正式报告了由于低阳性预测值而需要进一步检查的低瓜氨酸值。我们报告一例男性婴儿谁被发现有低瓜氨酸血症的NBS。在通过DNA测序排除近端尿素循环障碍后，他的NBS结果被认为是假阳性。4个月大时，他出现了营养不良、发育不良、呼吸暂停和婴儿痉挛，并发展为顽固性癫痫发作，以及持续的低瓜氨酸血症。他被诊断为Leigh综合征，这是由于母亲遗传了同质m.8993T>G突变的ATPase 6基因。他的母亲之前被诊断为脑瘫，由于同一突变的异质性，同时被诊断为神经病变、共济失调和视网膜色素变性（NARP）。她有进行性肌肉无力、共济失调和言语运动障碍。m.8993T>G突变导致线粒体ATP合成酶缺乏，并可能破坏CPS1对瓜氨酸的合成。除了近端尿素循环障碍外，对持续性低果糖血症婴儿的评估还应包括检测m.8993T >g突变和其他导致线粒体功能障碍的疾病。
Citrulline is among the metabolites measured by expanded newborn screening (NBS). While hypocitrullinemia can be a marker for deficiency of proximal urea cycle enzymes such as ornithine transcarbamylase (OTC), only a handful of state newborn screening programs in the United States officially report a low citrulline value for further work-up due to low positive predictive value. We report a case of a male infant who was found to have hypocitrullinemia on NBS. After excluding proximal urea cycle disorders by DNA sequencing, his NBS result was felt to be a false positive. At 4 months of age, he developed poor feeding, failure to thrive, apnea and infantile spasms with a progression to intractable seizures, as well as persistent hypocitrullinemia. He was diagnosed with Leigh syndrome due to a maternally inherited homoplasmic m.8993T>G mutation in the ATPase 6 gene. His mother, who had previously been diagnosed with cerebral palsy, was concurrently diagnosed with neuropathy, ataxia, and retinitis pigmentosa (NARP) due to heteroplasmy of the same mutation. She had progressive muscle weakness, ataxia, and speech dyspraxia. The m.8993T>G mutation causes mitochondrial ATP synthase deficiency and it is hypothesized to undermine the synthesis of citrulline by CPS1. In addition to proximal urea cycle disorders, the evaluation of an infant with persistent hypocitrullinemia should include testing for the m.8993T>G mutation and other disorders that cause mitochondrial dysfunction.