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

Abstract

Objectives In the present study, we aimed to evaluate the genotype-phenotype relation in patients with biotinidase enzyme deficiency based on repeated biotinidase enzyme measurements. Methods The hospital file information of patients with biotinidase, enzyme deficiency was assessed retrospectively, and the relationship between the BTD gene mutations analysis results and biotinidase enzyme activity following the first and repeated enzyme activity assessments was analyzed. Results One-hundred-ten patients were included. In the first enzyme evaluation, profound biotinidase enzyme deficiency was identified in 15 (13.6 %), partial biotinidase enzyme deficiency in 63 (57.3 %), and heterozygous biotinidase enzyme deficiency in 32 (29.1 %) of the patients. The BTD genetic analysis revealed 42 (38.2 %) homozygous, 42 (38.2 %) heterozygous, and 26 (23.6 %) compound heterozygous variants. The most common homozygous variant, p.Asp444His, was evaluated with 130 repeated enzyme measurements and was consistent with a partial biotinidase enzyme deficiency in 55.4 % of cases, heterozygous biotinidase enzyme deficiency in 43.8 % of cases, and profound biotinidase enzyme deficiency in one (0.8 %) case. Clinical symptoms developed in 17 patients during follow-up, of which 70.6 % were related to neurodevelopment. The most common variant was homozygous p.Asp444His (29.4 %) among the patients who developed symptoms. Conclusions This is the first study to date to evaluate the genotype-phenotype relationship in patients with biotinidase deficiency through repeated measurements of biotinidase enzyme activity. The study reveals that biotinidase enzyme activity alone is inadequate for diagnosing biotinidase enzyme deficiency or evaluating disease severity, as genetic investigations are also required for a definitive diagnosis of biotinidase enzyme deficiency.

Diagnosis and Treatment of Newborns Referred to the Metabolism Department From the National Newborn Screening Program in Türkiye: A 5-Year Single-Center Experience

“…At our center, the level of biotinidase enzyme is studied using the fluorometric method. In which <0.7 U/L (<10%) was considered a profound deficiency, 0.7-2.1 U/L (10-30%) a partial deficiency, 2.1-5.1 U/L (30-70%) a heterozygous deficiency and>5.1 U/L (>70%) normal activity (14). Biotin treatment was started in patients who have a profound deficiency and partial deficiency for biotinidase activity.…”

“…Biotin was started in all of the patients in the present study whose biotinidase levels were lower than normal. The importance of repeated measurements of biotinidase activity and genetic analysis for a final diagnosis has been demonstrated (14). Biotin treatment was started and discontinued only after excluding a BD diagnosis in babies with no biallelic variant in their genetic analysis, and whose repeated measurements of biotinidase activity were within the normal range during follow-up.…”