硫胺素代谢功能障碍综合征4(THMD4,OMIM#613710)是一种常染色体隐性遗传性疾病,由编码线粒体硫胺素焦磷酸(TPP)转运蛋白的SLC25A19缺乏引起。这种疾病的特征是双侧纹状体退化和进行性多发性神经病,并伴有不明原因的发烧。报道的病例数量有限以及缺乏相关基因变异的功能注释继续限制诊断。
我们报告了3例来自两个无关家系的脑病,这些家系在不明原因的发热后具有基底节信号改变。为了区别于其他类型的脑病,如急性坏死性脑病,进行外显子组测序,和四个新的杂合变异,即,c.169G>A(p。Ala57Thr),c.383C>T(p。Ala128Val),c.76G>A(第Gly26Arg),和c.745T>A(p。Phe249Ile),在SLC25A19中鉴定。使用Sanger测序确认所有变体。为了确定这些变异的致病性,进行了功能研究。我们发现线粒体TPP水平在SLC25A19变体的存在下显著降低,表明突变的SLC25A19蛋白的TPP转运活性受损。因此,结合临床表型,遗传分析,和功能研究,这些变异被认为可能是致病的.
外显子组测序分析使分子诊断以及提供潜在的病因。进一步的研究将能够阐明SLC25A19蛋白的功能。我们的调查为罕见疾病的精确诊断和临床决策提供了关键的分子证据。
Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of
SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis.
We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in
SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of
SLC25A19 variants, indicating that TPP transport activities of mutated
SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic.
Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of
SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease.