A Case of Thiamine Metabolism Dysfunction Syndrome-2 With Special Emphasis on Management and Prenatal Genetic Counseling

Background: Thiamine metabolism dysfunction syndrome-2 (THMD-2) (OMIM #607483) is an autosomal recessive metabolic disorder characterized by episodic-encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. Affiliated tissues include brain, and related phenotypes are global developmental delay and ptosis. Family history: A female child of age 1-year 9-months born to 3rd-degree consanguineous parent presented with developmental delay, motor regression post fever at 15-months of age. Her antenatal and birth history was uneventful. Investigations: On clinical examination, NBS for IEM was done by TMS showed positive report. MRI brain showed multiple T2 FLAIR hyperintensities without diffusion restriction. EEG report showed normal study. Genetic testing was done to confirm the diagnosis. Results: Whole exome sequencing report revealed Likely pathogenic variant of SLC19A3 gene mutation in homozygous condition causing Thiamine metabolism dysfunction syndrome-2. Genetic Counselling: THMD-2 is an autosomal recessive metabolic disorder caused due to the homozygous or compound heterozygous mutation in the SLC19A3 gene which encodes a thiamine transporter. If both parents are known to be heterozygous for SLC19A3 pathogenic variant, there would be a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected child. Administration of high doses of biotin, and sometimes thiamine, during these crises results in partial or complete improvement within days. Carrier testing and prenatal testing and preimplantation genetic testing for pregnancies at increased risk are possible if the SLC19A3 pathogenic variants in the family have been identified.
Keywords: Biotin, Seizures, Genomics, Consanguinity, SLC19A3