Biotinidase Deficiency: Primary Care Guide to a Positive Newborn Screen

Guidance for primary care clinicians receiving a positive newborn screen result

Biotinidase is an autosomal recessive inherited disorder in which the body is unable to reuse and recycle biotin, a B complex vitamin found in foods such as liver, egg yolks, nuts, and milk. Biotinidase is responsible for the extraction of biotin from ingested dietary sources and the breakdown of endogenous proteins. Biotin is an essential cofactor for several carboxylase enzymes that process proteins, fats, or carbohydrates. Variants in the BTD gene can be subcategorized as profoundly deficient (<10% activity) or partially deficient (10-30% activity). Typically, symptoms do not appear until 3-4 months of age, distinguishing it from the related condition, holocarboxylase/multiple carboxylase deficiency. Biotin therapy is highly effective.

Other Names

Multiple carboxylase deficiency, late-onset

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Decreased activity of biotinidase, an enzyme that releases biotin (vitamin H or vitamin B7) from proteins

Tested By

Colorimetric, semiquantitative enzyme assay

False positives may occur in premature infants, and if the sample is exposed to excessive heat.

Clinical Characteristics

With treatment, clinical outcomes are excellent, with no observable symptoms in cases of profound and partial deficiency.

Without treatment, outcomes depend on the inherent severity of disease. In those with a profound biotinidase deficiency, developmental delays, eczematous rash, alopecia, hearing and vision loss, seizures, and, in rare cases, death may result if untreated.

Although the neonate is usually asymptomatic, initial signs/symptoms may include:

• Seizures
• Hypotonia
• Eczematoid rash
• Alopecia
• Conjunctivitis
• Candidiasis
• Ataxia
• Hypoglycemia

Older children may manifest:

• Paresis
• Developmental delay
• Neurosensory hearing loss
• Optic atrophy and scotomata
• Recurrent viral and fungal infections

For partial biotinidase deficiency, the majority will not develop any symptoms, even without treatment. Some providers may still recommend treating because symptoms can develop at any age, particularly during an intercurrent illness.

Incidence

The incidence of biotinidase deficiency is 1:60,000 overall¹, 1:130,000 for profound deficiency, and 1:110,00 for partial deficiency. Carrier (heterozygous for BTD mutation) frequency is about 1:120.

Inheritance

Autosomal recessive

Next Steps After a Positive Screen

• Contact the family and evaluate the infant for poor feeding, lethargy, and hypotonia. Most newborns are asymptomatic.
• Provide emergency treatment and referral if symptoms are present.

Confirming the Diagnosis

• To confirm the diagnosis of biotinidase deficiency, work with Newborn Screening Services.
• Follow-up testing will include quantitative enzyme assay on serum/plasma. A panel of 5 common BTD mutations detects approximately 60% of disease-causing mutations and can identify a specific mutation responsible for partial biotinidase deficiency (p.D444H). Full-gene sequencing is available and can identify up to 99% of causative mutations.
• Genetic testing is possible for at-risk family members who may develop late-onset symptoms. Carriers can be diagnosed with 95% accuracy by enzyme assay, but DNA testing is superior for this purpose.

If the Diagnosis is Confirmed

• For evaluation and ongoing collaborative management, consult Medical Genetics.
• Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill.
• Start oral biotin at 5mg bid and ensure continuation for life in patients with profound biotinidase deficiency. Patients with partial deficiency might require lower doses after the first year of life.
• For those identified after irreversible consequences, assist in management, particularly with low vision aids, hearing aids or cochlear implants, and developmental and educational interventions.

Declaration of Conflicting Interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

References

1. Wolf B. Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab. 2010;100(1):6-13. doi:10.1016/j.ymgme.2010.01.003

Article History

The Medical Home Portal published this article in May 2023, and Topical Reviews in Pediatrics (TRIP) reprinted it in July  2025.. The Medical Home Portal, retired in July 2024, provided diagnosis and management information for pediatric conditions, guidance for immediate steps after a positive newborn screen result, and in-depth family education to improve outcomes for children with complex medical care needs. The full archive can be found at the Medical Home Portal Archive. 

Topical Reviews in Pediatrics (TRIP) includes archival and updated content from the Medical Home Portal and features new, contemporary topics in pediatrics.   

• 2023 update: Brian J. Shayota^A; Nancy C. Rose, MD^R
• 2015 update: Kimberly Hart, MS, LCGC^A
• 2012 update: Kimberly Hart, MS, LCGC^A
• 2007 first publication: Nicola Longo, MD, Ph.D.^A

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

Stay Informed

Be the first to know about the release of each new issue. Click here–> Subscribe for Notifications