Biotinidase deficiency: clinical and genetic studies of 38 Brazilian patients
1 Post Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
2 BRAIN Laboratory, Center for Experimental Research (CPE), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
3 Post Graduate Program in Medicine: Medical Sciences, UFRGS, Porto Alegre, Brazil
4 Gene Therapy Center, CPE, HCPA, Porto Alegre, Brazil
5 Hospital Infantil Joana de Gusmão, Florianópolis, Brazil
6 Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, Porto Alegre, 90035-903, Brazil
7 Universidade Federal de Campina Grande, Campina Grande, Brazil
8 Medical Genetics Service, Hospital das Clínicas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
9 Universidade Estadual de Ciências da Saúde de Alagoas, Maceió, Brazil
10 CTN Diagnósticos, Porto Alegre, Brazil
11 Hospital Universitário-Universidade Federal de Santa Catarina, Florianópolis, Brazil
12 Department of Genetics, UFRGS, Porto Alegre, Brazil
BMC Medical Genetics 2014, 15:96 doi:10.1186/s12881-014-0096-3Published: 1 September 2014
Biotinidase 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.
This observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene.
The 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%).
Our 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.