Biotinidase deficiency: A treatable neurometabolic disorder

Background

Biotinidase (E.C. 3.5.1.12) is an enzyme which recycles biotin, a coenzyme of four carboxylases involved in fatty acid synthesis, amino acid catabolism and gluconeogenesis. Biotinidase deficiency (OMIM #253260) causes a reduction in free biotin leading to multiple carboxylase deficiency. In its severe form, children may have seizures, delayed development, respiratory issues, cutaneous manifestations, hearing and visual loss. The milder phenotype may manifest symptoms only when stressed, such as during infections.

Case presentation

We describe two infants who presented aged two and five months respectively, with generalised seizures, mild gross motor delay, elevated plasma and cerebrospinal fluid lactate levels. Moderate increases in propionylcarnitine and 3-hydroxyisovalerylcarnitine on plasma acylcarnitine profile suggested multiple carboxylase deficiency. Further testing confirmed biotinidase deficiency. Retrospective qualitative analysis of the newborn screening dried blood spot cards in both patients showed reduced biotinidase enzyme activity. Molecular analysis confirmed pathogenic homozygous variants in the BTD gene. They were commenced on oral biotin with no further seizures observed in either patient. Patient 1 also made significant developmental gains and achieved age-appropriate milestones by 12 months. At five years of age, he has receptive and expressive language delays.

Discussion/conclusion

Early identification and treatment of biotinidase deficiency can prevent lifelong complications and major disabilities, hence should be considered as an important differential of seizures and neurodevelopmental delay. Currently, biotinidase deficiency is not one of the conditions screened for in newborns in Australia, however with the evolving demographics due to robust immigration, the New South Wales Newborn Screening Program has reconsidered its inclusion in our screening program.