title: Biotinidase deficiency: clinical and genetic studies of 38 Brazilian patients.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.forename: Taciane
authors.initials: T
authors.lastname: Borsatto
authors.forename: Fernanda
authors.initials: F
authors.lastname: Sperb-Ludwig
authors.forename: Louise L C
authors.initials: LL
authors.lastname: Pinto
authors.forename: Gisele R De
authors.initials: GR
authors.lastname: Luca
authors.forename: Francisca L
authors.initials: FL
authors.lastname: Carvalho
authors.forename: Carolina F M De
authors.initials: CF
authors.lastname: Souza
authors.forename: Paula F V De
authors.initials: PF
authors.lastname: Medeiros
authors.forename: Charles M
authors.initials: CM
authors.lastname: Lourenço
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Lo Filho
authors.forename: Eurico C
authors.initials: EC
authors.lastname: Neto
authors.forename: Pricila
authors.initials: P
authors.lastname: Bernardi
authors.forename: Sandra
authors.initials: S
authors.lastname: Leistner-Segal
authors.forename: Ida V
authors.initials: IV
authors.lastname: Schwartz
mesh_terms: D043523:Biotinidase / Q000235:genetics*; D028921:Biotinidase Deficiency / Q000235:genetics* / Q000473:pathology*; D001938:Brazil; D003430:Cross-Sectional Studies; D005091:Exons; D005260:Female; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D015997:Neonatal Screening; D020641:Polymorphism, Single Nucleotide
chemical_list: D043523:Biotinidase