Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases
Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases
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DOI：
10.3390/jcm8070991
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发表时间：
2019-07-01
影响因子：
3.9
通讯作者：
Pitceathly, Robert D. S.
中科院分区：
文献类型：
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作者：
Bugiardini, Enrico;Pope, Simon;Pitceathly, Robert D. S.
TPK 1突变是一种罕见的，但潜在的治疗，硫胺素缺乏症的原因。由于与其他代谢和神经系统疾病存在表型重叠，诊断具有挑战性。我们报告一例TPK 1相关的疾病表现为Leigh样综合征，并回顾了焦磷酸硫胺素（TPP）血液测量的诊断效用。先证者为一名35岁男性，在4个月大时出现反复发作的感染后脑病。他随后出现癫痫、学习困难、感觉神经性听力损失、痉挛和吞咽困难。有一个积极的家族史利综合征的哥哥。血浆乳酸升高（3.51 mmol/L），脑MRI显示双侧基底节高信号，提示Leigh综合征。线粒体呼吸链复合物I、II+III和IV的组织化学和分光光度分析正常。肌肉线粒体DNA的遗传分析为阴性。先证者的全外显子组测序证实了TPK 1：c中的复合杂合变体。426G>C（p.Leu142Phe）和c. 258+1G>A（p.？）。血液TPP水平降低，为变体的有害作用提供了功能证据。我们强调临床和生物信息学的挑战，诊断罕见的遗传疾病和生化分析的持续效用，尽管在DNA测序技术的重大进展，调查新的，潜在的致病性，遗传变异。血液TPP测量代表了TPK 1相关疾病的快速且具有成本效益的诊断工具。
TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases.