title: Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: a treatable cause of Leigh syndrome.
abstract: Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.
authors.affiliation: 1 Department of Child Neurology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Juan Darío
authors.initials: JD
authors.lastname: Ortigoza-Escobar
authors.affiliation: 2 Department of Clinical Biochemistry, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Molero-Luis
authors.affiliation: 3 Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Arias
authors.affiliation: 5 Department of Molecular Biology, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular Severo Ochoa CSIC-UAM, IDIPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Oyarzabal
authors.affiliation: 6 Department of Paediatrics, Sahlgrenska Academy, Gothenburg University, Gothenburg Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darín
authors.affiliation: 1 Department of Child Neurology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Serrano
authors.affiliation: 1 Department of Child Neurology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Angels
authors.initials: A
authors.lastname: Garcia-Cazorla
authors.affiliation: 2 Department of Clinical Biochemistry, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Tondo
authors.affiliation: 2 Department of Clinical Biochemistry, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Hernández
authors.affiliation: 3 Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Garcia-Villoria
authors.affiliation: 2 Department of Clinical Biochemistry, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Casado
authors.affiliation: 3 Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Gort
authors.affiliation: 7 Department of Paediatrics, Paracelsus Medical University Salzburg, Salzburg 5020, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain 5 Department of Molecular Biology, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular Severo Ochoa CSIC-UAM, IDIPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodríguez-Pombo
authors.affiliation: 3 Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.affiliation: 2 Department of Clinical Biochemistry, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.affiliation: 1 Department of Child Neurology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 4 Centre for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain bperez@hsjdbcn.org.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez-Dueñas
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D013831:Thiamine / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000627:therapeutic use*; D013835:Thiamine Pyrophosphate / Q000378:metabolism
chemical_list: D015415:Biomarkers; D026901:Membrane Transport Proteins; D011768:Pyruvate Dehydrogenase Complex; C492291:SLC19A3 protein, human; D013835:Thiamine Pyrophosphate; D013831:Thiamine
keywords: Leigh syndrome; SLC19A3 gene; biotin thiamine responsive basal ganglia disease; mitochondrial disorders; striatal necrosis; thiamine transporter-2 deficiency