Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

Fatemeh Norouzi Rostami; Hossein Sadeghi; Farzad Hashemi-Gorji; Sahand Tehrani Fateh; Reza Mirfakhraie; Parvaneh Karimzadeh; Milad Davarpanah; Sanaz Jamshidi; Rasoul Madannejad; Parinaz Moghimi; Mahdis Ekrami; Mohammad Miryounesi; Mohammad-Reza Ghasemi

doi:10.1016/j.heliyon.2024.e27434

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

Heliyon. 2024 Mar 6;10(6):e27434. doi: 10.1016/j.heliyon.2024.e27434. eCollection 2024 Mar 30.

Authors

Affiliations

¹ Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
² Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
³ Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁴ School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
⁵ Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁶ Department of Pediatric Neurology, School of Medicine, Pediatric Neurology Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁷ Students' Research Committee, Isfahan University of Medical Science, Isfahan, Iran.
⁸ School of Medicine, Islamic Azad University Tehran Medical Sciences, Tehran, Iran.

Abstract

Background and aims: The occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders.

Material and methods: The selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative.

Results: The first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene.

Conclusions: Collectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

Keywords: Novel mutations; SLC19A3; TPK1; Thiamine metabolism dysfunction syndrome; Whole-exome sequencing (WES).