Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released

Condition: Biotinidase Deficiency
Mode(s) of Inheritance: Autosomal Recessive
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
BTD0009665 (biotinidase deficiency)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: BTD 0009665 (OMIM:253260)
Neurological complications / Biotin therapy
Cutaneous manifestations / Biotin therapy

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Worldwide screening of biotinidase deficiency (BTD) has estimated an incidence of 1/137,401 for profound BTD and 1/109,921 for partial BTD, with a combined incidence of 1/61,067. Based on US newborn screening outcome data from 2007 to 2008, the incidence of profound biotinidase deficiency is estimated at 1/80,000 births and that of partial biotinidase deficiency 1/31,000-1/40,000. Incidence estimates are higher in Hispanic and lower in African American populations.
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Clinical Features
(Signs / symptoms)
BTD is an inborn error of metabolism due to reduced activity of biotinidase, an enzyme essential for recycling biotin. Profound BTD is due to <10% of mean normal serum biotinidase activity, while partial BTD is due to 10-30% of mean enzyme activity. If untreated, patients with profound BTD usually exhibit neurologic abnormalities (seizures, hypotonia, ataxia, developmental delay, and sensorineural vision problems and hearing loss), cutaneous abnormalities (alopecia, skin rash, and/or candidiasis), and respiratory problems. Metabolically, patients may also have ketolactic acidosis, organic academia, and mild hyperammonemia. A milder expression of these symptoms may occur in patients with partial BTD.
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Natural History
(Important subgroups & survival / recovery)
Symptoms of untreated profound BTD usually appear between ages 1 week and 10 years, with a mean age of 3.5 months. In a few cases, individuals with profound BTD have remained asymptomatic or developed symptoms after adolescence. Patients with partial BTD are typically asymptomatic, but may develop symptoms such as hypotonia, skin rash, and hair loss during periods of stress (e.g., illness, infection, fever, or fasting). Individuals who are diagnosed before they develop symptoms and are treated with biotin have normal development. Symptomatic individuals improve with biotin therapy, with the exception of vision problems, hearing loss, and developmental delay which are usually irreversible.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening:
To establish the extent of disease and needs in an individual diagnosed with BTD, the following evaluations are recommended:
•History of seizures, balance problems, feeding problems, breathing problems, loss of hair, fungal infections, skin rash, and conjunctivitis
•Physical examination for hypotonia, ataxia, eye findings, eczematous skin rash, alopecia, conjunctivitis, breathing abnormalities, thrush, and candidiasis
•Evaluation for sensorineural hearing loss and psychomotor deficits
•Identification of biochemical abnormalities such as metabolic ketolactic acidosis, hyperammonemia and organic aciduria
•Identification of cellular immunologic abnormalities
•Quantitative determination of biotinidase enzyme activity in serum/plasma
•Medical genetics consultation. (Tier 4)
Information specific to treatment of an individual diagnosed as an adult was not identified. All individuals with profound BTD, even those with some residual biotinidase enzyme activity, should have lifelong treatment with biotin (typical dosage is 5-10mg per day). Because there is no known toxicity for biotin, children with partial BTD are usually treated with 1-10mg oral biotin per day. Biotin is an effective treatment of BTD. Children with BTD identified by newborn screening will remain asymptomatic with biotin therapy. All symptomatic children with BTD have improved after treatment with biotin. The biochemical abnormalities and seizures rapidly resolve after biotin therapy, followed by improvement of cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between onset and initiation of treatment. Some treated children have rapidly achieved developmental milestone, whereas others have continued to show developmental delay. (Tier 3)
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Information specific to surveillance of an individual diagnosed as an adult was not identified. All children with BTD should undergo:
•Ophthalmologic examination and auditory testing: annually for profound BTD and every 2 years for partial BTD
•Regularly scheduled appointments with primary care physicians or as needed
•Evaluation by a medical geneticist or metabolic specialist: annually for profound BTD and every 2 years for partial BTD. (Tier 4)
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Circumstances to Avoid
Raw eggs should be avoided because they contain avidin, an egg-white protein that binds biotin, thus decreasing its bioavailability. (Tier 4)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Mutations
Mutations in BTD are detected in ~99% of BTD cases. Thus mutations associated with BTD are expected to have a similar prevalence as BTD, roughly 1/61,000. The carrier frequency in the general population is approximately 1/120. (Tier 3)
(Include any high risk racial or ethnic subgroups)
Almost all children with profound BTD become symptomatic or are risk of becoming symptomatic if not treated. However, several adults with profound BTD have been identified through family studies, but have never had symptoms. (Tier 4)
Information on the penetrance of mutations was not available for the Adult context.
Information on the penetrance of mutations was not available for the Adult context.
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not identified.
Some children with profound BTD may manifest only a single symptom, whereas others exhibit multiple neurologic and cutaneous findings. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified were medical exams, blood screenings, and biotin therapy, which are low intensity and minimally invasive.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Both profound and partial BTD are usually identified by newborn screening in states where offered. However, occasionally a child who has not been screened or has been mistakenly thought to have normal biotinidase activity on newborn screening will present with clinical symptoms. (Tier 4)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. B Wolf. Biotinidase Deficiency. 2000 Mar 24 [Updated 2016 Jun 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from:
2. Biotinidase deficiency. Orphanet encyclopedia,
3. Kury S, Ramaekers V, Bezieau S, Wolf B. Clinical utility gene card for: biotinidase deficiency. Eur J Hum Genet. (2012) 20(5).
4. Cowan TM, Blitzer MG, Wolf B. Technical standards and guidelines for the diagnosis of biotinidase deficiency. Genet Med. (2010) 12(7):464-70.
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