Molecular characterisation of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation

This study characterises the spectrum of biotinidase mutations in 21 patien ts (17 families) with profound biotinidase deficiency (BD) and 13 unrelated patients with partial BD using a denaturing gradient gel electrophoretic m utation screening and selective sequencing approach. In 29 from 30 unrelate d families we found biallelic mutations including four common mutations, D4 44H (frequency 23.3%), G98:d7i3(20.0%), Q456H(20.0%), T532M (15.0%) and nin e rare mutations (V62M, R157H, A171T+D444H, C423W, D543H, L279W, N172S, V10 9G, 12236G-A) with frequencies less than 5.0%. Only three profound BD patie nts with G98:d7i3/G98:d7i3 and Q456H/Q456H genotypes and residual biotinida se activities of 0.0%, and 0.9% of normal activity developed clinical sympt oms before biotin supplementation at 8 weeks of age. All other patients rem ained asymptomatic within the first months of life or even longer without t reatment. Two patients homozygous for the frameshift mutation G98:d7i3 had no measurable residual enzyme activity. Twelve patients with partial BD had the D444H mutation in at least one allele. We conclude that, based on muta tion analysis and biochemical examinations of the enzyme, it is currently n ot clearly predictable whether an untreated patient will develop symptoms o r not, although it seems that patients with activities lower than 1% are at a high risk for developing symptoms of the disease early in life.