Clinical Information

Biotinidase deficiency is an inherited metabolic disease caused by reduced levels of biotinidase, an enzyme that recycles biotin by releasing it from its metabolic product, biocytin, or exogenous dietary proteins. Biotin is a vitamin that serves as a coenzyme for 4 carboxylases that are essential for amino acid catabolism, gluconeogenesis, and fatty acid synthesis. Depletion of free biotin reduces carboxylase activity, resulting in secondary carboxylase deficiency. Depending on the amount of residual biotinidase activity, individuals can have either profound or partial biotinidase deficiency. Age of onset and clinical phenotype vary among individuals. Profound biotinidase deficiency occurs in approximately 1 in 137,000 live births and partial biotinidase deficiency occurs in approximately 1 in 110,000 live births, resulting in a combined incidence of about 1 in 61,000.

Untreated profound biotinidase deficiency (<10% of normal biotinidase activity) manifests within the first decade of life as seizures, hypotonia, neurosensory hearing loss, respiratory problems, and cutaneous symptoms including skin rash, alopecia, and recurrent viral or fungal infections. Among children and adolescents with profound biotinidase deficiency, clinical features include ataxia, sensorineural hearing loss, developmental delay, and eye problems such as optic neuropathy leading to blindness. Partial biotinidase deficiency (10%-30% of normal biotinidase activity) is associated with a milder clinical presentation, which may include cutaneous symptoms without neurologic involvement.

Treatment with biotin has been successful in both preventing and reversing the clinical features associated with biotinidase deficiency. As a result, biotinidase deficiency is included in most newborn screening programs in order to prevent disease. Biotinidase deficiency exhibits a similar clinical presentation to carboxylase and holocarboxylase synthetase deficiency. Therefore, measurement of the biotinidase enzyme is required to differentiate between these diseases and ensure proper diagnosis. Newborn screening for biotinidase deficiency involves direct analysis of the biotinidase enzyme from blood spots obtained shortly after birth. This enables early identification of potentially affected individuals and quick follow-up with confirmatory biochemical and molecular testing.

Biotinidase deficiency is inherited in an autosomal recessive manner, caused by mutations in the biotinidase gene (BTD). The carrier frequency for biotinidase deficiency in the general population is about 1:120. Several common mutations in the BTD gene have been identified, accounting for about 60% of affected individuals. Sequencing of the entire BTD gene detects other, less common, disease-causing mutations. While genotype-phenotype correlations are not well established, it appears that certain mutations are associated with profound biotinidase deficiency, while others are associated with partial deficiency.

The recommended first-tier test to screen for biotinidase deficiency is a biochemical test that measures biotinidase enzyme activity, either newborn screening or BIOTS / Biotinidase, Serum. Molecular tests form the basis of confirmatory or carrier testing. Individuals with decreased enzyme activity are more likely to have 2 identifiable mutations in the BTD gene by molecular genetic testing.