Management of a patient with holocarboxylase synthetase deficiency

Johan L K Van Hove, Sagi Josefsberg, Cynthia Freehauf, Janet A. Thomas, Le Phuc Thuy, Bruce A. Barshop, Michael Woontner, Donald M. Mock, Pei-Wen Chiang, Elaine Spector, Iván Meneses-Morales, Rafael Cervantes-Roldán, Alfonso León-Del-Río

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of the mutant protein with the pharmacokinetic factors of successful biotin treatment. A girl exhibited abnormal skin at birth, and developed in the first days of life neonatal respiratory distress syndrome and metabolic abnormalities diagnostic of multiple carboxylase deficiency. Enzyme assays showed low carboxylase activities. Fibroblast analysis showed poor incorporation of biotin into the carboxylases, and low transfer of biotin by the holocarboxylase synthetase enzyme. Kinetic studies identified an increased Km but a preserved Vmax. Mutation analysis showed the child to be a compound heterozygote for a new nonsense mutation Q379X and for a novel missense mutation Y663H. This mutation affects a conserved amino acid, which is located the most 3′ of all recorded missense mutations thus far described, and extends the region of functional biotin interaction. Treatment with biotin 100 mg/day gradually improved the biochemical abnormalities in blood and in cerebrospinal fluid (CSF), corrected the carboxylase enzyme activities, and provided clinical stability and a normal neurodevelopmental outcome. Plasma concentrations of biotin were increased to more than 500 nM, thus exceeding the increased Km of the mutant enzyme. At these pharmacological concentrations, the CSF biotin concentration was half the concentration in blood. Measuring these pharmacokinetic variables can aid in optimizing treatment, as individual tailoring of dosing to the needs of the mutation may be required.

Original languageEnglish (US)
Pages (from-to)201-205
Number of pages5
JournalMolecular Genetics and Metabolism
Volume95
Issue number4
DOIs
StatePublished - Dec 2008
Externally publishedYes

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Holocarboxylase Synthetase Deficiency
Biotin
biotin carboxylase
Cerebrospinal fluid
Missense Mutation
Pharmacokinetics
Mutation
Multiple Carboxylase Deficiency
Cerebrospinal Fluid
Enzymes
Newborn Respiratory Distress Syndrome
Blood
Nonsense Codon
Enzyme Assays
Mutant Proteins
Heterozygote
Enzyme activity
Fibroblasts
Molecular Biology
Therapeutics

Keywords

  • Biotin
  • Carboxylase
  • Holocarboxylase synthetase
  • Kinetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Van Hove, J. L. K., Josefsberg, S., Freehauf, C., Thomas, J. A., Thuy, L. P., Barshop, B. A., ... León-Del-Río, A. (2008). Management of a patient with holocarboxylase synthetase deficiency. Molecular Genetics and Metabolism, 95(4), 201-205. https://doi.org/10.1016/j.ymgme.2008.09.006

Management of a patient with holocarboxylase synthetase deficiency. / Van Hove, Johan L K; Josefsberg, Sagi; Freehauf, Cynthia; Thomas, Janet A.; Thuy, Le Phuc; Barshop, Bruce A.; Woontner, Michael; Mock, Donald M.; Chiang, Pei-Wen; Spector, Elaine; Meneses-Morales, Iván; Cervantes-Roldán, Rafael; León-Del-Río, Alfonso.

In: Molecular Genetics and Metabolism, Vol. 95, No. 4, 12.2008, p. 201-205.

Research output: Contribution to journalArticle

Van Hove, JLK, Josefsberg, S, Freehauf, C, Thomas, JA, Thuy, LP, Barshop, BA, Woontner, M, Mock, DM, Chiang, P-W, Spector, E, Meneses-Morales, I, Cervantes-Roldán, R & León-Del-Río, A 2008, 'Management of a patient with holocarboxylase synthetase deficiency', Molecular Genetics and Metabolism, vol. 95, no. 4, pp. 201-205. https://doi.org/10.1016/j.ymgme.2008.09.006
Van Hove JLK, Josefsberg S, Freehauf C, Thomas JA, Thuy LP, Barshop BA et al. Management of a patient with holocarboxylase synthetase deficiency. Molecular Genetics and Metabolism. 2008 Dec;95(4):201-205. https://doi.org/10.1016/j.ymgme.2008.09.006
Van Hove, Johan L K ; Josefsberg, Sagi ; Freehauf, Cynthia ; Thomas, Janet A. ; Thuy, Le Phuc ; Barshop, Bruce A. ; Woontner, Michael ; Mock, Donald M. ; Chiang, Pei-Wen ; Spector, Elaine ; Meneses-Morales, Iván ; Cervantes-Roldán, Rafael ; León-Del-Río, Alfonso. / Management of a patient with holocarboxylase synthetase deficiency. In: Molecular Genetics and Metabolism. 2008 ; Vol. 95, No. 4. pp. 201-205.
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