TY - JOUR
T1 - Management of a patient with holocarboxylase synthetase deficiency
AU - Van Hove, Johan L.K.
AU - Josefsberg, Sagi
AU - Freehauf, Cynthia
AU - Thomas, Janet A.
AU - Thuy, Le Phuc
AU - Barshop, Bruce A.
AU - Woontner, Michael
AU - Mock, Donald M.
AU - Chiang, Pei Wen
AU - Spector, Elaine
AU - Meneses-Morales, Iván
AU - Cervantes-Roldán, Rafael
AU - León-Del-Río, Alfonso
N1 - Funding Information:
We thank Christopher Korch at the UCDHSC Cancer Center Molecular Core Laboratory for assistance with sequencing. This work was supported by a grant from the National Institutes of Health to D.M. Mock R-01:DK36823, and to E. Spector 5 P30 HD004024-39 for the MRDD Research Center, and by a grant from Consejo Nacional de Ciencia y Tecnología (CONACyT 48862) to A. León Del Río.
PY - 2008/12
Y1 - 2008/12
N2 - 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.
AB - 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.
KW - Biotin
KW - Carboxylase
KW - Holocarboxylase synthetase
KW - Kinetics
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U2 - 10.1016/j.ymgme.2008.09.006
DO - 10.1016/j.ymgme.2008.09.006
M3 - Article
C2 - 18974016
AN - SCOPUS:56149089771
SN - 1096-7192
VL - 95
SP - 201
EP - 205
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -