Biotinidase biochemical and molecular analyses: Experience at a large reference laboratory

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Biotinidase deficiency results from absent biotinidase activity, impairing biotin recycling and causing neurological and cutaneous symptoms.
• Early biotin supplementation is crucial for preventing irreversible neurological damage in profound deficiency (enzyme activity <10% mean normal).
• Molecular testing complements biochemical analysis for diagnosis and management of biotinidase deficiency.

Purpose of the Study:

• To correlate biochemical phenotype (enzyme activity) with biotinidase gene (BTD) genotype in patients.
• To review how genotype-phenotype correlations inform on BTD variant severity.
• To assess the utility of molecular testing alongside enzyme activity for diagnosis and carrier screening.

Main Methods:

• Analysis of biotinidase enzyme activity and BTD gene sequencing results.
• Study included 407 patients with samples submitted between 2008 and 2020.
• Correlation of identified BTD variants with measured enzyme activity levels.

Main Results:

• Identified 84 BTD variants, including 19 novel ones; c.1330G>C was most common overall.
• In patients with profound deficiency (<10% MN activity), the c.528G>T variant was most frequent.
• The c.1330G>C variant was most common in patients with enzyme activity >10% MN.

Conclusions:

• Enzyme activity alone suffices for diagnosing profound biotinidase deficiency.
• Molecular testing is essential for accurate carrier screening and differentiating partial deficiency from carrier status.
• Genotype-phenotype correlation refines understanding of BTD variant impact and aids clinical management.