Eleven novel mutations and clinical characteristics in seven Chinese patients with thiamine metabolism dysfunction syndrome.

• 影响指数: 2.465
• 发表时间: Oct 2020
• 来源期刊: Eur J Med Genet
• DOI: 10.1016/j.ejmg.2020.104003
• PMID: 32679198
• 文章类型: Case Reports
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Li D,Song J,Li X,Liu Y,Dong H,Kang L,Liu Y,Zhang Y,Jin Y,Guan H,Zhou C,Yang Y

关键词: Clinical exome sequencing; Leigh syndrome; SLC19A3; SLC25A19; TPK1; Thiamine metabolism dysfunction syndrome (THMD)

Mesh: Asians; Biotin / therapeutic use; Brain / diagnostic imaging pathology; Brain Diseases / diagnosis diagnostic imaging genetics physiopathology; Child, Preschool; DNA, Mitochondrial / genetics; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Ketoglutaric Acids / urine; Leigh Disease / diagnosis diagnostic imaging genetics physiopathology; Magnetic Resonance Imaging; Male; Membrane Transport Proteins / genetics; Metabolic Diseases / diagnosis diagnostic imaging genetics physiopathology; Mitochondrial Membrane Transport Proteins / genetics; Thiamin Pyrophosphokinase / genetics; Thiamine / genetics metabolism therapeutic use

Abstract

Thiamine metabolism dysfunction syndrome (THMD) comprises a group of clinically and genetically heterogeneous encephalopathies with autosomal recessive inheritance. Four genes, SLC19A3, SLC25A19, SLC19A2, and TPK1, are associated with this disorder. This study aimed to explore the clinical, biochemical and molecular characteristics of seven Chinese patients with THMD. Targeted next-generation sequencing of mitochondrial DNA and nuclear DNA was used to identify the causative mutations. The patients presented with subacute encephalopathy between the ages of 1-27 months. Brain magnetic resonance imaging (MRI) revealed abnormalities in the basal ganglia, indicating Leigh syndrome. Urine α-ketoglutarate in five patients was elevated. In four patients, five novel mutations (c.1276_1278delTAC, c.265A > C, c.197T > C, c.850T > C, whole gene deletion) were found in SLC19A3, which is associated with THMD2. In two patients, four novel mutations (c.194C > T, c.454C > A, c.481G > A, and c.550G > C) were identified in SLC25A19, supporting a diagnosis of THMD4. In one patient, two novel mutations (c.395T > C and c.614-1G > A) were detected in TPK1, which is indicative of THMD5. The patients received thiamine, biotin, and symptomatic therapy, upon which six patients demonstrated clinical improvement. Our findings expanded the phenotypic and genotypic spectrum of THMD, with eleven novel mutations identified in seven Chinese patients. Early diagnosis and treatment have a significant impact on prognosis.