Management of a patient with holocarboxylase synthetase deficiency

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, 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.

Holocarboxylase synthetase deficiency pre and post newborn screening

“…HCLS is responsible for covalently linking biotin to propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase (3-MCC), pyruvate carboxylase and acetyl-CoA carboxylase (see Fig. 1 ) [1] , [2] . Failure to attach biotin causes reduced activity of these biotin-dependent carboxylases and results in multiple carboxylase deficiency.…”

“…Failure to attach biotin causes reduced activity of these biotin-dependent carboxylases and results in multiple carboxylase deficiency. The typical presentation described in the medical literature is of neonatal onset within hours to weeks of birth with emesis, hypotonia, lethargy, seizures, metabolic ketolactic acidosis, hyperammonemia, developmental delay, skin rash and alopecia [1] . Left untreated, infants will progress to profound metabolic acidosis, cerebral edema, coma and death.…”

Neonatal dermatological emergencies

“…Poor incorporation of biotin into the carboxylases, and low transfer of biotin by the holocarboxylase synthetase enzyme are demonstrated by fibroblast analysis. [49] Treatment: The dosage of biotin is usually high 20-40 mg/day and sometimes 100 mg/day may be required. The signs and symptoms resolve completely following biotin therapy.…”

“…The biotin supplementation is required for life long. [48,49] E. Kasabach-Merritt phenomenon Kasabach-Merritt phenomenon (KMP) is a clinical syndrome of thrombocytopenic coagulopathy in association with vascular tumor. It is usually seen in infants lesser than 3 months of age.…”

Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency

“…The majority of HLCS patients respond to biotin therapy. However, a few patients show only a partial or very limited response to biotin therapy depending on the genotype (Peters et al 2000;Santer et al 2003;Wilson et al 2005;Van Hove et al 2008). Thus, obtaining a molecular diagnosis can result in optimized management by providing a better understanding of the underlying enzyme defect and the extent to which a response to biotin therapy is anticipated.…”