Low Serum Biotinidase Activity in Children with Valproic Acid Monotherapy

Abstract

Summary:Purpose: 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 ‫ס‬ 25) was treated with VPA 28.7 ± 8.5 mg/kg/24 h, group B (n ‫ס‬ 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 g/ml, respectively. Fifty healthy children were the controls. Patients and controls underwent clinical and laboratory evaluations including liver function data, complete blood counts, NH 3 , 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.

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

“…However, there is indirect evidence linking PPA to alterations in fatty acid metabolism [137] , deficiencies in carnitine [125] and alterations in biotin [138] in autism. There are similar metabolic trends noted following exposure to valproate, a teratogenic risk factor in autism [57] . Furthermore PPA producing gut clostridial species have been found in a subset of patients with regressive ASD [40] .…”

“…A number of effects have been shown following PPA treatment, including catecholamine and proenkephalin gene induction [46] , cytoskeletal phosphorylation [47] , histone modulation [48] , second messenger metabolism [49] , impaired mitochondrial respiratory transport chain function [50,51] , modulation of gap junctions [52] and immune system activation [53] . There is also evidence of variable PPA metabolism in a number of metabolic disorders such as propionic and methylmalonic acidemia [54] , disorders of biotin [55] and B12 metabolism [56] , as well as following valproate [57] and ethanol exposure [58] . These disorders are associated with developmental delay, seizure and episodes of paroxysmal metabolic dysfunction resulting in increased oxidative stress and are to some degree reminiscent of autism [59,60] .…”

Epilepsy in Biotinidase Deficiency After Biotin Treatment

“…We would like to emphasize that valproic acid treatment impairs the liver mitochondrial function, resulting in a low biotinidase activity and/or biotin deficiency (Schulpis et al 2001), so we recommend avoiding it in patients with BD.…”

Alopecia Areata Universalis After Phenobarbital-Induced Anti-Convulsant Hypersensitivity Syndrome

“…For the treatment of alopecia, valproate induces alopecia in approximately 12-28% of patients and potentially inhibits liver mitochondrial biotinidase activity, but this is restored by biotin supplementation in some patients (Schulpis et al, 2001). Phenytoin may cause lupus-like symptoms, including alopecia (Mangalvedhekar et al, 2001).…”