Interpretive Handbook

Test 89012 :
Biotinidase Deficiency, BTD Full Gene Analysis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 in 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.

Useful For Suggests clinical disorders or settings where the test may be helpful

Second-tier test for confirming biotinidase deficiency (indicated by biochemical testing or newborn screening)


Carrier testing of individuals with a family history of biotinidase deficiency, but disease-causing mutations have not been identified in an affected individual

Interpretation Provides information to assist in interpretation of the test results

An interpretative report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A small percentage of individuals who are carriers or have a diagnosis of biotinidase deficiency may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of biotinidase deficiency. For carrier testing, it is important to first document the presence of a BTD gene mutation in an affected family member. 


In some cases, DNA alterations of undetermined significance may be identified.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Kaye CI, Committee on Genetics: Newborn screening fact sheets. Pediatrics 2006 Sep;118(3):e934-e963

2. Moslinger D, Muhl A, Suormala T, et al: Molecular characterization and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies. Eur J Pediatr 2003 Dec;162 Suppl 1:S46-49 Epub 2003 Nov 20

3. Nyhan WL, Barshop B, Ozand PT: Multiple carboxylase deficiency/biotinidase deficiency. In Altas of Metabolic Diseases. Second edition. New York, Oxford University Press, 2005, pp 42-48

4. Wolf B, Jensen KP, Barshop B, et al: Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. Hum Mutat 2005 Apr;25(4):413