Mutational analysis for biotinidase deficiency of a Greek patients’ cohort ascertained through expanded newborn screening

Abstract

Late-onset multiple carboxylase deficiency, also known as biotinidase (BTD) deficiency, is an autosomal recessively inherited disorder of biotin metabolism. Its early diagnosis and treatment seems that it can even fully prevent its various clinical manifestations. Mutations in the BTD gene scattered throughout its coding region have been detected in patients ascertained either through newborn screening or clinically. From March 2010 up to June 2011, 18 954 Greek neonates were subjected to biochemical determination of BTD activity through a semiquantitative fluoroimmunoassay. Subsequently, the first cohort of our 'suspected' samples was further tested for the presence of aberrations associated either with partial or profound BTD deficiency through sequencing of the coding region of the BTD gene, including splice-site junctions. On the basis of the molecular data derived from the study of our first cohort of 'suspected' samples, a panel of four mutations, most frequently encountered in the Greek population, was created, and a rapid, reliable and cost-effective real-time-based genotyping assay for the detection of these mutations was developed. This is the first report about the BTD mutational spectrum in Greece, and it could be a beneficial utility in the differential clinical diagnosis of BTD deficiency.

High Incidence of Biotinidase Deficiency from a Pilot Newborn Screening Study in Minas Gerais, Brazil

“…Specific primers are available on request and were designed according to published papers (Pomponio et al 1997;Thodi et al 2011;M€ uhl et al 2001).…”

A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype–Phenotype Analysis

“…16 The BTD deficiency patients' clinical symptoms varied, which are based on the severity of mutation. 17 18…”

“…16 The BTD deficiency patients' clinical symptoms varied, which are based on the severity of mutation. 17,18 Interestingly, United States and certain countries have mandatory newborn screening (NBS) programs that successfully help prevent or treat BTD deficiency symptoms by giving pharmacological doses of biotin supplements. 7,17 The BTD deficiency is diagnosed among neonates.…”

Clinical utility gene card for: Biotinidase deficiency—update 2015

“…Finding known variants can be correlated with the biochemical enzymatic results (see 3.1.2 for explanations on classification of biotinidase deficiency according to enzymatic activity). 13,14 Severe variants, such as c.98_104delGCGGCTGinsTCC (p. Cys33Phefs*36), c.1368A4C (p. Gln456His) or c.1612C4T (p. Arg538Cys), are associated with profound biotinidase deficiency when they are homozygous or compound heterozygous with another severe variant. In contrast, the severity of the decrease in serum biotinidase enzyme activity due to milder variant c.1330G4C (p. Asp444His) depends on the variants to which it is combined: it results in 45-50% of mean normal serum biotinidase enzyme activity when homozygous, 20-25% of mean normal serum biotinidase enzyme activity or partial biotinidase deficiency when in trans with a variant with very low biotinidase enzyme activity or profound biotinidase deficiency.…”