Biotin dependency due to a defect in biotin transport.

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.

[1]  D. Mock,et al.  Lymphocyte propionyl-CoA carboxylase is an early and sensitive indicator of biotin deficiency in rats, but urinary excretion of 3-hydroxypropionic acid is not. , 2002, The Journal of nutrition.

[2]  J. Saudubray,et al.  Branched-chain organic acidurias. , 2002, Seminars in neonatology : SN.

[3]  J. Zempleni,et al.  Proliferation of peripheral blood mononuclear cells causes increased expression of the sodium-dependent multivitamin transporter gene and increased uptake of pantothenic acidopen star , 2001, The Journal of nutritional biochemistry.

[4]  G. Kearns,et al.  The clearance and metabolism of biotin administered intravenously to pigs in tracer and physiologic amounts is much more rapid than previously appreciated. , 2001, The Journal of nutrition.

[5]  V. Ganapathy,et al.  Human Placental Na+-dependent Multivitamin Transporter , 1999, The Journal of Biological Chemistry.

[6]  J. Zempleni,et al.  Mitogen-induced proliferation increases biotin uptake into human peripheral blood mononuclear cells. , 1999, The American journal of physiology.

[7]  H. Said.  Cellular uptake of biotin: mechanisms and regulation. , 1999, The Journal of nutrition.

[8]  D. Mock.  Biotin status: which are valid indicators and how do we know? , 1999, The Journal of nutrition.

[9]  J. Zempleni,et al.  Advanced analysis of biotin metabolites in body fluids allows a more accurate measurement of biotin bioavailability and metabolism in humans. , 1999, The Journal of nutrition.

[10]  J. Zempleni,et al.  Uptake and metabolism of biotin by human peripheral blood mononuclear cells. , 1998, The American journal of physiology.

[11]  V. Ganapathy,et al.  Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. , 1998, The Journal of biological chemistry.

[12]  G. Buck,et al.  Mutations in the Human Biotinidase Gene That Cause Profound Biotinidase Deficiency in Symptomatic Children: Molecular, Biochemical, and Clinical Analysis , 1997, Pediatric Research.

[13]  V. Ganapathy,et al.  Characterization of a sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin and lipoate in human placental choriocarcinoma cells. , 1997, Placenta.

[14]  D. Mock.  Determinations of biotin in biological fluids. , 1997, Methods in enzymology.

[15]  D. Mock,et al.  Urinary biotin analogs increase in humans during chronic supplementation: the analogs are biotin metabolites. , 1997, The American journal of physiology.

[16]  H. Said,et al.  Uptake of biotin by human hepatoma cell line, Hep G2: A carrier‐mediated process similar to that of normal liver , 1994, Journal of cellular physiology.

[17]  D. B. Mccormick,et al.  Cellular Assimilation of Water-Soluble Vitamins in the Mammal: Riboflavin, B6, Biotin, and C , 1993, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[18]  D. Horne,et al.  Biotin transport in human liver basolateral membrane vesicles: a carrier-mediated, Na+ gradient-dependent process. , 1992, Gastroenterology.

[19]  P. Ozand,et al.  A Patient With Propionic Acidemia Managed With Continuous Insulin Infusion and Total Parenteral Nutrition , 1992, Journal of Child Neurology.

[20]  B. Wolf,et al.  Biotin uptake, utilization, and efflux in normal and biotin-deficient rat hepatocytes. , 1991, Biochemical medicine and metabolic biology.

[21]  E. Coligan.  Current protocols in immunology , 1991 .

[22]  B. Wolf,et al.  Biotin uptake in cultured hepatocytes from normal and biotin-deficient rats. , 1990, Biochemical medicine and metabolic biology.

[23]  D. Horne,et al.  Transport of biotin in basolateral membrane vesicles of rat liver. , 1990, The American journal of physiology.

[24]  E. R. Baumgartner,et al.  Na(+)-dependent biotin transport into brush-border membrane vesicles from rat kidney. , 1990, The American journal of physiology.

[25]  S. Weintraub,et al.  Quantification of urinary 3-hydroxyisovaleric acid using deuterated 3-hydroxyisovaleric acid as internal standard. , 1989, Biomedical & environmental mass spectrometry.

[26]  K. Roth,et al.  On the uptake of biotin by the rat renal tubule. , 1988, Biochemical medicine and metabolic biology.

[27]  R. Podevin,et al.  Biotin uptake mechanisms in brush-border and basolateral membrane vesicles isolated from rabbit kidney cortex. , 1986, Biochimica et biophysica acta.

[28]  D. B. Mccormick,et al.  Biotin Uptake by Isolated Rat Liver Hepatocytes a , 1985, Annals of the New York Academy of Sciences.

[29]  J. Thoene,et al.  BIOTINIDASE DEFICIENCY IN JUVENILE MULTIPLE CARBOXYLASE DEFICIENCY , 1983, The Lancet.

[30]  B. Wolf,et al.  Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. , 1983, Clinica chimica acta; international journal of clinical chemistry.

[31]  J. Thoene,et al.  Impaired intestinal absorption of biotin in juvenile multiple carboxylase deficiency. , 1983, The New England journal of medicine.

[32]  J. Thoene,et al.  Biotin-responsive carboxylase deficiency associated with subnormal plasma and urinary biotin. , 1981, The New England journal of medicine.

[33]  W. Nyhan,et al.  Deficiency of propionyl-Co A carboxylase and methylcrotonyl-Co A carboxylase in a patient with methylcrotonylglycinuria. , 1977, Clinica chimica acta; international journal of clinical chemistry.

[34]  M. Utter,et al.  PYRUVATE CARBOXYLASE. I. NATURE OF THE REACTION. , 1963, The Journal of biological chemistry.

[35]  Y. Najean.  [Blood physiology]. , 1958, Gazette medicale de France.