2. Academic Validation
  3. Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4

Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4

  • Orphanet J Rare Dis. 2021 Sep 29;16(1):403. doi: 10.1186/s13023-021-02028-4.
Yuanying Chen # 1 2,  Boliang Fang # 3,  Xuyun Hu 1 2,  Ruolan Guo 1 2,  Jun Guo 1 2,  Kenan Fang 4,  Jingwen Ni 4,  Wei Li 1 2,  Suyun Qian 5,  Chanjuan Hao 6 7
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 2 Henan Key Laboratory of Pediatric Inherited and Metabolic Diseases, Henan Children's Hospital, Zhengzhou Hospital of Beijing Children's Hospital, Zhengzhou, China.
  • 3 Pediatric Intensive Care Unit, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 4 Pediatric Intensive Care Unit, Luoyang Maternal and Child Health Hospital, Luoyang, China.
  • 5 Pediatric Intensive Care Unit, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China. [email protected].
  • 6 Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China. [email protected].
  • 7 Henan Key Laboratory of Pediatric Inherited and Metabolic Diseases, Henan Children's Hospital, Zhengzhou Hospital of Beijing Children's Hospital, Zhengzhou, China. [email protected].
  • # Contributed equally.
PMID: 34587972 DOI: 10.1186/s13023-021-02028-4
Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords

Compound heterozygosity; Exome sequencing; Functional study; SLC25A19; Thiamine metabolism dysfunction syndrome 4; Thiamine pyrophosphate.

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