Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics

Abstract

Biotinidase deficiency is an autosomal recessively inherited disorder of biotin recycling that is associated with neurologic and cutaneous consequences if untreated. Fortunately, the clinical features of the disorder can be ameliorated or prevented by administering pharmacological doses of the vitamin biotin. Newborn screening and confirmatory diagnosis of biotinidase deficiency encompasses both enzymatic and molecular testing approaches. These guidelines were developed to define and standardize laboratory procedures for enzymatic biotinidase testing, to delineate situations for which follow-up molecular testing is warranted, and to characterize variables that can influence test performance and interpretation of results.

Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil

“…We were fortunate to carry out sample collection in more than a million newborns for screening tests in the present study, as well as the enzymatic and molecular testing procedures in the same institution; this guaranteed a standard of quality and reliability of the results, since the enzymatic tests are susceptible to external interferers, as highlighted by several authors (Cowan et al, ; Strovel et al, ).…”

“…Additionally, borderline activity of biotinidase in well‐preserved samples is sometimes detected. Hence, sequencing BTD can be very useful for defining the status of the individuals and making decisions about life‐long treatment (Borsatto et al, ; Procter, Wolf, & Mao, ; Strovel, Cowan, Scott, & Wolf, ).…”

Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report

“…After the exome sequencing revealed the suspicious BTD genotype, to clarify whether the infant might have partial BTD, subsequent diagnostic enzyme testing was performed on a serum sample, which confirmed a low enzyme activity level consistent with a diagnosis of partial BTD (1.5 nmol/min/ml serum) (reference levels 3.5–13.8 nmol/min/ml serum). It should be noted that mean biotinidase activity has been reported at levels of 3.49 ± 0.72 SD nmol/min/ml serum in obligate heterozygotes with profound deficiency alleles (Strovel et al 2017), suggesting carrier status is insufficient to explain the reduced enzyme level. Based on the newborn's enzyme activity level, the baby was started on biotin supplementation.…”

“…It should be noted that it was the identification of the BTD variants in conjunction with NBS results that led to the diagnosis of partial BTD in the child, resulting in follow-up and reclassification of the variant, which would not normally have been reported as an incidental finding given its initial VUS classification. The combined phenotypic analysis and genotype results were necessary to effectively diagnose and treat the baby—a process now routinely recommended for certain metabolic diseases like BTD (Strovel et al 2017), but not possible for most other disorders. This case also illustrates the importance of functional testing in helping to decipher whether variants like the novel splice variant are disease causing.…”

Clinical Findings and BTD Gene Molecular Analysis Results of Patients Presenting with Suspicion of Biotinidase Deficiency

“…Klinik olarak, neonatal form (halokarboksilaz sentetaz eksikliği) ve infantil/juvenil form (biyotinidaz eksikliği) olmak üzere ikiye ayrılır (5). Biyotinidaz eksikliği (OMIM #253260), biyotinidaz üretiminden sorumlu Biyotinidaz (BTD) genindeki patojenik mutasyonların neden olduğu, geç başlangıçlı biotine duyarlı multipl karboksilaz eksikliği olarak da bilinen otozomal resesif geçişli bir hastalıktır (6). BTD geni kromozom 3q25 üzerinde bulunur ve 79 bp, 265 bp, 150 bp ve 1502 bp boyutlarında olmak üzere dört ekzon içerir.…”