Clinical Guidance

Genotype-phenotype correlations are not well established. However, certain genotypes correlate with profound biotinidase deficiency and others with partial biotinidase deficiency. There is a single report from Turkey in which symptomatic individuals with pathogenic null variants predicted to lead to profound enzyme deficiency had hearing loss, whereas those who had some residual enzyme activity did not . Profound biotinidase deficiency (10% mean normal serum biotinidase activity):

Source: GeneReviews — "Biotinidase Deficiency"

Penetrance

Almost all children with profound biotinidase deficiency become symptomatic or are at risk of becoming symptomatic if not treated. Several reports describe adults with profound biotinidase deficiency who have offspring who also have profound biotinidase deficiency identified by NBS but who have never had symptoms . In addition, several enzyme-deficient sibs of symptomatic individuals have apparently never exhibited symptoms. It is possible that these individuals would become symptomatic if stressed, such as with a prolonged infection.

Source: GeneReviews — "Biotinidase Deficiency"

Diagnostic Criteria

No consensus clinical diagnostic criteria for biotinidase deficiency have been published.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for biotinidase deficiency is primarily based on either fluorescent or colorimetric tests for biotinidase activity on dried blood spots. Putative positive samples have biotinidase activities below cutoff values established by the respective screening laboratory. Confirmational testing requires follow-up measurement of biotinidase activity in serum/plasma. Note: False positive newborn screening test results may occur in premature infants and in samples placed in plastic prior to sufficient drying.

Source: GeneReviews — "Biotinidase Deficiency"

Differential Diagnosis

Clinical features including vomiting, hypotonia, and seizures accompanied by metabolic ketolactic acidosis or mild hyperammonemia are often observed in inherited metabolic diseases. Individuals with biotinidase deficiency may exhibit clinical features that are misdiagnosed as other disorders (e.g., isolated carboxylase deficiency) before they are correctly identified . Other symptoms that are more characteristic of biotinidase deficiency (e.g., skin rash, alopecia) can also occur in children with nutritional biotin deficiency, holocarboxylase synthetase deficiency, zinc deficiency, or essential fatty acid deficiency . Nutritional biotin deficiency can usually be diagnosed by dietary history.

Source: GeneReviews — "Biotinidase Deficiency"

Management Guidelines

No clinical practice guidelines for biotinidase deficiency have been published. However, (full text) refers to some basic recommendations. When biotinidase deficiency is suspected during the diagnostic evaluation (i.e., due to decreased biotinidase activity on a newborn blood spot), biotin treatment should be initiated immediately. Biotinidase deficiency or other biotin-related disorders, such as holocarboxylase synthetase deficiency , should be excluded before biotin supplementation is discontinued.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an asymptomatic infant diagnosed with biotinidase deficiency following newborn screening, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Biotinidase Deficiency: Recommended Evaluations Following Initial Diagnosis Detected by Newborn Screening in an Asymptomatic Infant

System/Concern | Evaluation | Comment

Genetics/ Genetic counseling

| Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian |

Genetic counseling by genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of biotinidase deficiency to facilitate medical personal decision making

Constitutional

| Measurement of growth parameters | To screen for poor growth

Neurologic

| Neurologic eval | • To incl assessment for hypotonia seizures

• Consider EEG if seizures are a concern.

Hearing

| A...

Source: GeneReviews — "Biotinidase Deficiency"

Clinical Guidance

Raw eggs should be avoided because they contain avidin, an egg white protein that binds biotin, thus decreasing its bioavailability. However, thoroughly cooked eggs present no problem because heating inactivates avidin, rendering it incapable of binding biotin.

Source: GeneReviews — "Biotinidase Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Biotinidase Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to targeted and supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. Biotinidase Deficiency: Recommended Surveillance

Source: GeneReviews — "Biotinidase Deficiency"