Low serum biotinidase activity in children with valproic acid monotherapy

Purpose: Valproic acid (VPA) is an effective antiepileptic drug (AED), whic h is associated with dose-related adverse reactions such as skin rash, hair loss (alopecia), etc. Profound as well as partial biotinidase deficiency c auses dermatologic manifestations similar these. Therefore, it was of inter est to evaluate serum biotinidase activity in patients receiving VPA monoth erapy. Methods: Seventy-five patients with seizures, mean age, 8.6 years ( +/-1.9 years) were divided into three groups. Group A (n = 25) was treated with VP A 28.7 +/- 8.5 mg/kg/24 h, group B (n = 25) with 41.6 +/- 4.9 mg/kg/24 h, a nd group C with 54.5 +/- 5.8 mg/kg/24 h. Their "trough" VPA serum levels we re 40.9 +/- 13.2, 86.25 +/- 11.5, and 137 +/- 14.5 mug/ml, respectively. Fi fty healthy children were the controls. Patients and controls underwent cli nical and laboratory evaluations including liver function data, complete bl ood counts, NH3, and so on, after 45 days of VPA treatment. Biotinidase ser um levels were evaluated fluorometrically. Results: Liver function data were found elevated in the groups B and C. On the contrary, biotinidase activity was significantly statistically lowered (p < 0.001) in groups B and C (1.22 +/- 1.11, 0.97 +/- 0.07 mmol/min/L resp ectively), as compared with controls (5.20 +/- 0.90 mmol/min/L). Strong inv erse correlations were observed between liver enzymes and VPA blood levels with the activity of the enzyme. Additionally, no inhibitory effect on biot inidase activity was found, when the enzyme was incubated in vitro with hig h (1.2 mM) concentrations of the drug. Skin lesions (seborrheic rash, alope cia) were improved in our patients after biotin (10 mg/day) supplementation . Conclusions: It is suggested that VPA impairs the liver mitochondrial funct ion, resulting in a low biotinidase activity and or biotin deficiency. Biot in supplementation could restore some of the side effects of the drug.