Clinical, Biochemical and Genetic analysis of 6 North Indian families: Biotinidase deficiency in 86% of the children

Introduction: Biotinidase deficiency (BD) is an autosomal recessive, neurometabolic disorder of biotin metabolism caused by defects in BTD gene. Various clinical, biochemical parameters and genetic variant plays role in pathogenesis of BD. Methods: Children were suspected to have BD, were recruited from a tertiary care hospital. Serum biotinidase levels were measured. Urinary organic acids and acylcarnitine analysis in dried blood spots were done. Genetic testing was carried out using targeted Sanger sequencing. Results: Six families were recruited which included 11 symptomatic and 4 asymptomatic children, and 12 asymptomatic parents. Enzyme assay revealed 17 biotinidase deficient cases (15 children and 2 fathers), of which 13 children had profound biotinidase deficiency (<0.7nmol/min/mL), and 4 had partial biotinidase deficiency (0.7-2.1nmol/min/mL). The most common symptoms in profound BD were seizure (9/13), developmental delay (9/13), alopecia (5/13), and seborrheic dermatitis (3/13) followed by hypotonia, ataxia, and skin rash in few cases. The urinary organic acid revealed lactic acidosis with elevated secretion of 3-Hydroxyisovaleric acid in 3 cases. Elevated 3-hydroxyisovalerylcarnitine in dried blood spots was also observed in 3 cases. Genetic analysis showed homozygous pathogenic variant c.98_104 del7ins3del (p.C33Ffs*36) in at least 86% (13/15) of cases while (2/15) 14% cases showed heterozygous variant in our study. Conclusion: Exon 2 is hotspot region for pathogenic variations in the BTD gene. Family screening in children with BD is important for early detection of asymptomatic members, prenatal testing and early therapy.
Keywords: : Biotinidase deficiency, BTD variant, BTD gene ,genetic testing