Clinico-pathological and molecular spectrum of biotinidase deficiency- experience from a lower middle-income country

Background: The aim of this study was to evaluate the clinical, biochemical, and molecular analysis of Pakistani patients with biotinidase deficiency (BD). Methods: Medical charts, urine organic acid (UOA) chromatograms, and biotinidase (BTD) enzyme activity of 113 suspected BD cases and BTD gene results of BTD enzyme deficient patients presenting at the Biochemical Genet-ics Clinic, AKUH from January 2010 to December 2019 were reviewed. Details were collected on a pre-structured questionnaire. SPSS 22 was used for data analysis. Results: BD was found in 33 (29.23%) cases, 28 being profound and 5 partial BD. The median age of BD diagnosis was 171 days (IQR: 81 - 1,022.75) and 300 days (IQR: 25 - 1,540) for the profound and partial BD, respectively. The median BTD levels in the partial BD and profound BD groups were 35 U (IQR: 25.5 - 62.5) and 15 U (IQR: 11 - 17), respectively. UOA analysis exhibited sensitivity, specificity, and agreement of 52.94%, 86.05%, and 76.67% with BTD enzyme activity. The BTD sequencing revealed seven recurrent homozygous single nucleotide variants (SNVs) and small indels. These variants include three frameshift, protein truncating variants and four missense variants. We report two novel protein truncating variants, c.929GinsA, p.S310fs∗14 and c.394insA, p.T132Nfs∗30 and one missense variant, c.416G>A, p.S139N that had not been reported in BD associated literature and clinical databases. Conclusions: Thirty-three cases of BD from a single center indicates a high frequency of BD in Pakistan. Late di-agnosis emphasizes the need for increased clinical awareness and preferably screening for BD in this population.