High frequency of biotinidase deficiency in Italian population identified by newborn screening

Silvia Funghini; Rodolfo Tonin; Sabrina Malvagia; Anna Caciotti; Maria Alice Donati; Amelia Morrone; Giancarlo la Marca

doi:10.1016/j.ymgmr.2020.100689

High frequency of biotinidase deficiency in Italian population identified by newborn screening

Mol Genet Metab Rep. 2020 Dec 5:25:100689. doi: 10.1016/j.ymgmr.2020.100689. eCollection 2020 Dec.

Authors

Silvia Funghini¹, Rodolfo Tonin², Sabrina Malvagia¹, Anna Caciotti², Maria Alice Donati³, Amelia Morrone^{2

4}, Giancarlo la Marca^{1

5}

Affiliations

¹ Newborn Screening, Biochemical & Pharmacology Lab, Clinic of Paediatric Neurology, A. Meyer Children's Hospital, Firenze, Italy.
² Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Firenze, Italy.
³ Metabolic and Muscular Unit, Meyer Childrens' Hospital, Firenze, Italy.
⁴ Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Italy.
⁵ Department of Experimental Clinical and Biomedical Sciences, University of Florence, Firenze, Italy.

Abstract

The biotinidase (BTD) enzyme is essential for recycling biotin, a water-soluble B-complex vitamin that is the coenzyme of four carboxylases involved in fatty acid synthesis, amino acid catabolism and gluconeogenesis. If untreated, total or partial BTD deficiencies lead to an autosomal recessive inherited organic aciduria whose clinical features, mainly presenting in the first years of life, include, seizures, skin rash, and alopecia. Based on residual BTD enzyme activity it is possible to identify partial or total biotinidase deficiency. The incidence of profound and partial biotinidase deficiency worldwide is estimated to be about 1 in 60.000. We report twelve years of experience in the newborn screening of biotinidase deficiency on 466.182 neonates. When a positive screening result occurred, a clinical evaluation was made of the patient and genetic counselling was offered to the family. Molecular analysis the BTD gene was carried out in all recalled neonates. Newborn screening lead to the identification of 75 BTD deficiencies with an incidence of about 1:6.300 births, ten times higher than the reported worldwide incidence. BTD deficiency was confirmed at a genomic level in all patients, demonstrating a high frequency of the p.(Asp444His) amino acid substitution and the complex allele p.(Ala171Thr)/p.(Asp444His) in the analyzed Italian newborns. Four new mutations (two small deletions, one stop mutation and one missense mutation) and a new combined allelic alteration were identified. Our data suggests that there is a high incidence of the biotinidase defect in the Italian population, most likely due to the high frequency of certain mutations.

Keywords: BTD gene; BTD, Biotinidase; Biotinidase deficiency; Biotinidase deficiency incidence; C5-OH, 3-OH-isovalerylcarnitine; DBS, Dried blood spot; DNA, DeoxyriboNucleic Acid; GC–MS, Gas chromatography–mass spectrometry; HGMD, Human Gene Mutation Database; IQ, Intelligence Quotient; LC-MS/MS, Liquid Chromatography Tandem Mass Spectrometry; MCD; Multiple carboxylase deficiency; Newborn screening; PCR, Polymerase Chain Reaction; WISC, Wechsher Intelligence Scale for Children.