Abstract
BackgroundBiotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity. Biotinidase activity, however, may be artifactually low due to enzyme lability, premature birth, and jaundice; this hinders both phenotypic classification and the decision to implement therapy. This study sought to characterize the clinical and genetic profile of a sample of Brazilian patients exhibiting reduced biotinidase activity.MethodsThis observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene.ResultsThe sample comprised 38 individuals with biochemical phenotypes defined a priori on the basis of biotinidase activity in serum/plasma (2 with profound deficiency, 9 with partial deficiency, 15 heterozygous, 1 borderline between partial deficiency and heterozygosity, 2 borderline between heterozygous and normal) or dried blood spot sample (n = 9, all with unspecified deficiency). Most patients were from Southern Brazil (n = 29/38) and were identified by neonatal screening (n = 33/38). Parental consanguinity was reported in two cases. The most commonly found genetic variants were c.1330G > C (p.D444H), c.755A > G (p.D252G), and c.[511G > A;1330G > C] (p.[A171T;D444H]), with allele frequencies of 50%, 9.4%, and 5.4% respectively. Three novel pathogenic variants were identified (c.119 T > C or p.L40P, c.479G > A or p.C160Y, and c.664G > A or p.D222N). Twenty-nine patients had two pathogenic variants detected (with cis/trans status ascertained in 26/29), six had only one variant, and three had no pathogenic variants detected. Genotyping confirmed the original phenotypic classification based on enzyme activity in 16/26 cases. Three polymorphic variants were identified in control individuals, of which two were nonpathogenic (c.1171C > T or p.P391S and c.1413 T > C or p.C471C, with a frequency of 1.5% and 5.5% respectively) and one pathogenic (c.1330G > C, frequency 4%).ConclusionsOur findings suggest that partial BD is the most common form of BD in Brazil, and expand current knowledge on the allelic heterogeneity of this condition.
Highlights
Biotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity
Thirty-three patients were identified by neonatal screening, of whom 27 were on biotin (10 mg/day); none had clinical manifestations suggestive of BD at the time of inclusion
We did not detect the variant p.Q456H, the profound BD allele most commonly found among children diagnosed by neonatal screening in the U.S [21], nor did we find any changes in exon 3
Summary
Biotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity. Biotinidase deficiency (BD, EC 3.5.1.12) is an autosomal recessive disease in which both the absorption of biotin from dietary sources and its reuse/recycling are impaired. The diagnosis of BD is confirmed by measurement of biotinidase activity in plasma or serum This test enables classification of patients as having profound (or total) BD (residual activity
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