title: Biotin-thiamine responsive basal ganglia disease: Identification of a pyruvate peak on brain spectroscopy, novel mutation in SLC19A3, and calculation of prevalence based on allele frequencies from aggregated next-generation sequencing data.
abstract: Biotin-thiamine responsive basal ganglia disease is an inborn error of metabolism caused by mutations in SLC19A3, encoding a transporter of thiamine across the plasma membrane. We report a novel mutation identified in the homozygous state in a patient with typical brain MRI changes. In addition, this patient had markedly elevated CSF pyruvate, a low lactate-to-pyruvate molar ratio, and an abnormal pyruvate peak at 2.4 ppm on brain magnetic resonance spectroscopy. Using aggregated exome sequencing data, we calculate the carrier frequency of mutations in SLC19A3 as 1 in 232 individuals in the general population, for an estimated prevalence of the disease of approximately 1 in 215,000 individuals. The disease is thus more frequent than previously recognized, and the presence of a pyruvate peak on spectroscopy could serve as an important diagnostic clue.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|Division of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia.|The George Washington University School of Medicine, Washington, District of Columbia.
authors.forename: Carlos R
authors.identifier: http://orcid.org/0000-0002-2697-1046
authors.initials: CR
authors.lastname: Ferreira
authors.affiliation: The George Washington University School of Medicine, Washington, District of Columbia.|Division of Diagnostic Imaging and Radiology, Children's National Health System, Washington, District of Columbia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Whitehead
authors.affiliation: Division of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia.
authors.forename: Eyby
authors.initials: E
authors.lastname: Leon
mesh_terms: D001479:Basal Ganglia / Q000503:physiopathology*; D001480:Basal Ganglia Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging* / Q000503:physiopathology; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D019289:Pyruvic Acid / Q000378:metabolism; D013057:Spectrum Analysis; D013831:Thiamine / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human; D019289:Pyruvic Acid; D013831:Thiamine
keywords: SLC19A3; biotin-thiamine responsive basal ganglia disease; magnetic resonance spectroscopy; pyruvate; thiamine metabolism dysfunction syndrome 2; thiamine transporter-2 deficiency