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Biotinidase deficiency is an autosomal recessive disorder caused by mutations in the biotinidase gene (BTD). Age of onset and clinical phenotype vary among individuals depending on the amount of residual biotinidase activity. 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. The carrier frequency for biotinidase deficiency within the general population is about 1 in 120.
Untreated profound biotinidase deficiency typically manifests within the first decade of life as seizures, ataxia, developmental delay, hypotonia, sensorineural hearing loss, vision problems, skin rash, and/or alopecia. Partial biotinidase deficiency is associated with a milder clinical presentation, which may include cutaneous symptoms without neurologic involvement. Certain organic acidurias, such as holocarboxylase synthase deficiency, isolated carboxylase synthase deficiency and 3-methylcrotonylglycinuria, present similarly to biotinidase deficiency. Serum biotinidase levels can help rule out these disorders.
Treatment with biotin is successful in preventing the clinical features associated with biotinidase deficiency. In symptomatic patients, treatment will reverse many of the clinical features except developmental delay and vision and hearing complications. As a result, biotinidase deficiency is included in most newborn screening programs. This enables early identification and treatment of presymptomatic patients.
Molecular tests form the basis of confirmatory or carrier testing. When biotinidase enzyme activity is deficient, sequencing of the entire BTD gene (BTDZ / Biotinidase Deficiency, BTD Full Gene Analysis) allows for detection of disease-causing mutations in affected patients. Identification of familial mutations allows for testing of at-risk family members (FMTT / Familial Mutation, Targeted Testing).
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.
Preferred test for diagnosing biotinidase deficiency
Follow-up testing for certain organic acidurias
The reference range is 3.5 U/L to 13.8 U/L.
Partial deficiencies and carriers may occur at the low end of the reference range.
Values <3.5 U/L are occasionally seen in specimens from unaffected patients.
A diet high in biotin may result in normal clinical presentation even when the biotinidase level is low.
1. Zempleni J, Barshop BA, Cordonier EL, et al: Disorders of Biotin Metabolism. In The online Metabolic and Molecular Base of Inherited DiseaseEdited by D Valle, AL Beaudet, B Vogelstein, KW et al: New York, NY, McGraw-Hill; 2014. Available from: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62646613. Accessed August 24, 2015.
2. Wolf B: Biotinidase Deficiency. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al:. Seattle,WA, University of Washington, Seattle, 1993-2015 Available from: http://www.ncbi.nlm.nih.gov/books/NBK1322/