title: Biotin dependency due to a defect in biotin transport.
abstract: We describe a 3-year-old boy with biotin dependency not caused by biotinidase, holocarboxylase synthetase, or nutritional biotin deficiency. We sought to define the mechanism of his biotin dependency. The child became acutely encephalopathic at age 18 months. Urinary organic acids indicated deficiency of several biotin-dependent carboxylases. Symptoms improved rapidly following biotin supplementation. Serum biotinidase activity and Biotinidase gene sequence were normal. Activities of biotin-dependent carboxylases in PBMCs and cultured skin fibroblasts were normal, excluding biotin holocarboxylase synthetase deficiency. Despite extracellular biotin sufficiency, biotin withdrawal caused recurrent abnormal organic aciduria, indicating intracellular biotin deficiency. Biotin uptake rates into fresh PBMCs from the child and into his PBMCs transformed with Epstein Barr virus were about 10% of normal fresh and transformed control cells, respectively. For fresh and transformed PBMCs from his parents, biotin uptake rates were consistent with heterozygosity for an autosomal recessive genetic defect. Increased biotin breakdown was ruled out, as were artifacts of biotin supplementation and generalized defects in membrane permeability for biotin. These results provide evidence for a novel genetic defect in biotin transport. This child is the first known with this defect, which should now be included in the identified causes of biotin dependency.
authors.affiliation: Regional Metabolic Service, Kaiser Permanente, Los Angeles, California, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mardach
authors.forename: Janos
authors.initials: J
authors.lastname: Zempleni
authors.forename: Barry
authors.initials: B
authors.lastname: Wolf
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Cannon
authors.forename: Michael L
authors.initials: ML
authors.lastname: Jennings
authors.forename: Sally
authors.initials: S
authors.lastname: Cress
authors.forename: Jane
authors.initials: J
authors.lastname: Boylan
authors.forename: Susan
authors.initials: S
authors.lastname: Roth
authors.forename: Stephen
authors.initials: S
authors.lastname: Cederbaum
authors.forename: Donald M
authors.initials: DM
authors.lastname: Mock
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D001692:Biological Transport; D001710:Biotin / Q000172:deficiency*; D043523:Biotinidase; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D002262:Carboxy-Lyases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002461:Cell Line, Transformed; D002675:Child, Preschool; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000031:analogs & derivatives* / Q000652:urine; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D043586:Methylmalonyl-CoA Decarboxylase; D011766:Pyruvate Carboxylase / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000235:genetics / Q000652:urine; D027981:Symporters / Q000172:deficiency*; D014631:Valerates / Q000652:urine
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D027981:Symporters; D014631:Valerates; C119981:biotin transporter; D019344:Lactic Acid; C004961:beta-hydroxyisovaleric acid; D001710:Biotin; C031601:hydracrylic acid; D000581:Amidohydrolases; D043523:Biotinidase; D002262:Carboxy-Lyases; D019735:Carbon-Carbon Ligases; D011766:Pyruvate Carboxylase; C021573:methylcrotonoyl-CoA carboxylase; D043586:Methylmalonyl-CoA Decarboxylase