High Incidence of Partial Biotinidase Deficiency in the First 3 Years of a Regional Newborn Screening Program in Italy

Abstract

Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not recycled. BD meets the major criteria for a population screening program. Newborn bloodspot screening (NBS) allows early diagnosis of BD, thus preventing the high morbidity and mortality associated with untreated disease. Both profound and partial BD variant can be detected by NBS test, and serum enzyme activity and/or mutational analysis are required for definitive diagnosis. In Italy, BD is included in the screening panel for inborn errors of metabolism (IEMs) that has been declared mandatory in 2016. We analyzed the data of the first 3 years of the NBS for BD in our region (Abruzzo, Italy), with the aim to describe the outcomes of this recently introduced screening program. In over 26,393 newborns screened, we found 2 carriers and 16 cases with genotype associated with partial BD. Since the serum biotinidase assay has been recently introduced in our algorithm, only three of our newborns met the criteria of genetic and biochemical confirmation, with an incidence of 1:8797, which is in the high range of what has been reported in the literature. All affected infants carried the 1330G>C (D444H) variant in compound heterozygosis, with variants known to be associated with profound BD. A variant previously not described and likely pathogenic was found in one newborn. None of the infants had signs or symptoms. The study of the distribution of the enzyme activity in our population allowed us to validate the adopted cutoff with which the program has a positive predictive value of 18% and to analyze some preanalytical factors influencing biotinidase activity: A correlation of the enzyme activity with gestational age and time at specimen collection was found. Lower mean values of enzyme activity were found in infants born in the summer.

Identification of Novel and Recurrent Variants in BTD, GBE1, AGL and ASL Genes in Families with Metabolic Disorders in Saudi Arabia

“…The p. Asp424His variant has previously been reported in Asian [ 21 ] and Brazilian populations [ 22 ]. Biotinidase deficiency is associated with the BTD gene, which is an autosomal recessive disorder [ 23 ]. A missense variant is a common mechanism associated with Biotinidase deficiency, and the rate of benign missense variants is relatively low [ 24 ].…”

A different approach to the evaluation of the genotype-phenotype relationship in biotinidase deficiency: repeated measurement of biotinidase enzyme activity

“…[1; 2] In general, clinical ndings are related to the degree of residual enzyme activity. [2] Alopecia, eczema, seborrheic dermatitis-like rashes, viral and fungal infections due to immunological dysfunction, hypotonia, ataxia, seizures, developmental delay, conjunctivitis, vision problems (such as optic atrophy) and neurosensory deafness may be seen in patients with profound enzyme de ciency. [1] While other ndings may regress with biotin therapy, optic atrophy and neurosensory deafness are irreversible.…”

“…[1] While other ndings may regress with biotin therapy, optic atrophy and neurosensory deafness are irreversible. [2] More than 200 variants of the BTD gene have been reported, most of which have a loss of more than 90% of biotinidase enzyme activity. [2] There have been many studies to date evaluating the relationship between genotypes and phenotypes in biotinidase enzyme de ciency, however biotinidase enzyme activity measurements were made only once or twice in most of them.…”

“…[2] More than 200 variants of the BTD gene have been reported, most of which have a loss of more than 90% of biotinidase enzyme activity. [2] There have been many studies to date evaluating the relationship between genotypes and phenotypes in biotinidase enzyme de ciency, however biotinidase enzyme activity measurements were made only once or twice in most of them. [2][3][4][5][6][7][8][9][10][11][12][13] As biotinidase enzyme activity measurements may be affected by such external factors as age, prematurity, neonatal jaundice and the temperature of the sample during storage or transport, [1; 4; 14; 15] it is suggested that a diagnosis of biotinidase enzyme de ciency should be based on multiple measurements of plasma biotinidase enzyme activity.…”

“…[2] There have been many studies to date evaluating the relationship between genotypes and phenotypes in biotinidase enzyme de ciency, however biotinidase enzyme activity measurements were made only once or twice in most of them. [2][3][4][5][6][7][8][9][10][11][12][13] As biotinidase enzyme activity measurements may be affected by such external factors as age, prematurity, neonatal jaundice and the temperature of the sample during storage or transport, [1; 4; 14; 15] it is suggested that a diagnosis of biotinidase enzyme de ciency should be based on multiple measurements of plasma biotinidase enzyme activity. [4] We believe that repeated measurement of biotinidase enzyme activity during the clinical follow-up of patients with biotinidase enzyme de ciency can lead to a better evaluation of the genotype and phenotype relationship and the exclusion of external factors.…”