Management of a patient with holocarboxylase synthetase deficiency - PubMed (original) (raw)

Case Reports

doi: 10.1016/j.ymgme.2008.09.006. Epub 2008 Oct 29.

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

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Case Reports

Management of a patient with holocarboxylase synthetase deficiency

Johan L K Van Hove et al. Mol Genet Metab. 2008 Dec.

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 100mg/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.

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Figures

Figure 1

Figure 1. Biotinylation of the carboxylases

Legend: In the first lane, control normal fibroblasts grown in normal medium (NF-B) show a band of pyruvate carboxylase PC at 128 kDa, and a doublet of 3-methylcrotonyl-CoA carboxylase-alpha subunit (MCC) (76 kDa) and propionyl-CoA carboxylase-alpha subunit (PCC) (72 kDa). These bands are reduced in intensity in patient’s fibroblasts (B-PF). In biotin depleted medium (D), the signal intensities are further reduced in control fibroblasts(D-NF), and virtually unnoticeable in patient’s fibroblasts (D-PF).

Figure 2

Figure 2. Biotinylation activity

Legend: The amount of 3H-biotin incorporated into using p-67, a peptide containing the last 67 amino acids of the alpha subunit of propionyl-CoA carboxylase. Extracts from mutant cells catalyzed the incorporation of ten times less biotin into p-67 than normal fibroblasts.

Figure 3

Figure 3. Alignment of Holocarboxylase synthetase

Legend: Multi-species alignment of the peptide sequence according to the Ensemble website at

www.ensemble.org/

, and from reference . The highlighted amino acid is where the Y663H mutation occurred.

References

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