Biotinidase Deficiency - Description

Other Names

Multiple carboxylase deficiency, late onset


277.6, deficiency of circulating enzymes


Biotin is a cofactor in important carboxylase enzymes required to process proteins, fats, and carbohydrates. Biotin is processed by the enzyme biotinidase, in the absence of which biotin cannot be extracted from ingested sources or recycled from endogenous sources (by protein degradation) and is not available for use as a cofactor. Biotinidase deficiency results from a mutation in the BTD gene. Biotinidase Deficiency (GeneReviews)

Biotin is attached to the amino acid lysine within our body and in the food that we eat. Biotinidase detaches biotin from them and generates free biotin that can be attached to many enzymes, called carboxylases, and possibly used in other chemical reactions. Biotin is an essential cofactor for Acetyl-CoA, Propionyl-CoA, 3-Methylcrotonyl-CoA, and pyruvate carboxylase. None of these enzymes will work properly without biotin. In addition, biotin is essential for brain and nerve function.

The developing brain is particularly sensitive to biotin deficiency. Patients usually appear perfectly normal at birth, but can develop irreversible hearing and vision loss if untreated. With treatment, clinical outcomes are excellent. Without treatment, outcomes depend on the inherent severity of disease in the affected patient. In the severe form (profound biotinidase deficiency with enzyme activity <10% of normal), neurologic injury, seizures, hearing loss, blindness, and death may result. Symptoms may develop as soon as the first week of life or as late as 10 years of age (mean age of 3 1/2 months). The natural history and outcomes for untreated children with this disorder are only partially known. [Wolf: 2010]

Some children may have only one sign or symptom, others many. Initial signs/symptoms may include:
  • seizures
  • hypotonia
  • hyperventilation, laryngeal stridor, and/or apnea
  • eczematoid rash
  • alopecia
  • conjunctivitis
  • candidiasis
  • ataxia

Older children may manifest:
  • limb weakness
  • paresis and spasticity consistent with a myelopathy [Wiznitzer: 2003]
  • developmental delay
  • neurosensory hearing loss
  • optic atrophy and scotomata
  • recurrent viral and fungal infections

Children with untreated partial biotinidase deficiency (10-30% of normal enzyme activity) may manifest any of the above symptoms, though generally they will be mild and occur only with concomitant stressors, such as prolonged infection.


Inheritance is autosomal recessive and due to mutations in the BTD gene. The BTD gene is small and has only 4 exons, allowing for rapid sequencing. Many mutations are known to cause profound deficiency but a single mutation (p.D444H) is responsible for almost all cases of partial deficiency. [Wolf: 2010]


If biotin supplementation is instituted before the condition has fully developed, prognosis is excellent. Optic atrophy, deafness, and developmental delay, if present before the condition is discovered, do not respond to biotin supplementation, although seizures and skin problems will usually respond quickly. [Wolf: 2010]


1/60,000 overall; 1/130,000 for profound deficiency and 1/110,000 for partial deficiency; carrier (heterozygous for BTD mutation) frequency is about 1/120 [Wolf: 1991]

Biotinidase Deficiency Module Authors

Authors: Nicola Longo, MD, PhD - 7/2012
Lynne M Kerr, MD, PhD - 7/2012
Content Last Updated: 7/2012

The authors listed above are responsible for the overall Biotinidase Deficiency Module. Authors contributing to individual pages in the module are listed on those pages.

Page Bibliography

Wiznitzer M, Bangert BA.
Biotinidase deficiency: clinical and MRI findings consistent with myelopathy.
Pediatr Neurol. 2003;29(1):56-8. PubMed abstract

Wolf B.
Clinical issues and frequent questions about biotinidase deficiency.
Mol Genet Metab. 2010;100(1):6-13. PubMed abstract

Wolf B.
Worldwide survey of neonatal screening for biotinidase deficiency.
J Inherit Metab Dis. 1991;14(6):923-7. PubMed abstract