Low serum biotinidase activity in children with valproic acid monotherapy.
OBJECTIVE
Valproic acid (VPA) is an effective antiepileptic drug (AED), which is associated with dose-related adverse reactions such as skin rash, hair loss (alopecia), etc. Profound as well as partial biotinidase deficiency causes dermatologic manifestations similar these. Therefore, it was of interest to evaluate serum biotinidase activity in patients receiving VPA monotherapy.


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 VPA 28.7 +/- 8.5 mg/kg/24 h, group B (n = 25) with 41.6 +/- 4.9 mg/kg/24 h, and group C with 54.5 +/- 5.8 mg/kg/24 h. Their "trough" VPA serum levels were 40.9 +/- 13.2, 86.25 +/- 11.5, and 137 +/- 14.5 microg/ml, respectively. Fifty healthy children were the controls. Patients and controls underwent clinical and laboratory evaluations including liver function data, complete blood counts, NH3, and so on, after 45 days of VPA treatment. Biotinidase serum 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 respectively), as compared with controls (5.20 +/- 0.90 mmol/min/L). Strong inverse correlations were observed between liver enzymes and VPA blood levels with the activity of the enzyme. Additionally, no inhibitory effect on biotinidase activity was found, when the enzyme was incubated in vitro with high (1.2 mM) concentrations of the drug. Skin lesions (seborrheic rash, alopecia) were improved in our patients after biotin (10 mg/day) supplementation.


CONCLUSIONS
It is suggested that VPA impairs the liver mitochondrial function, resulting in a low biotinidase activity and or biotin deficiency. Biotin supplementation could restore some of the side effects of the drug.
Schulpis
K H
KH
Institute of Child Health, Aghia Sophia Children's Hospital, Athens, Greece.
Karikas
G A
GA
Tjamouranis
J
J
Regoutas
S
S
Tsakiris
S
S
D000581:Amidohydrolases / Q000097:blood*; D043523:Biotinidase; D002648:Child; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D012016:Reference Values; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects*
D014635:Valproic Acid; D000581:Amidohydrolases; D043523:Biotinidase