Biotinidase Deficiency

Overview

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. Deficiency can be partial or profound.

Biotin is attached to the amino acid lysine in our body and food. Biotinidase detaches biotin from lysine 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. Although patients usually appear perfectly normal at birth, they can develop irreversible hearing and vision loss if untreated. With biotin supplementation before the condition has fully developed, prognosis is excellent.

Other Names & Coding

Multiple carboxylase deficiency, late onset
ICD-10 coding

D81.810, Biotinidase deficiency

ICD-10 for Biotinidase Deficiency (icd10data.com) provides further coding details.

Prevalence

Newborn screening data in the United States indicate that the incidence is about 1:67,766 for profound deficiency and 1:24,957 for partial deficiency. [Therrell: 2014]

Genetics

Biotinidase deficiency is caused by mutations in the BTD gene and inheritance is autosomal recessive. 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]

Prognosis

With treatment, clinical outcomes are excellent. Without treatment, outcomes depend on the inherent severity of disease. In the severe form (profound biotinidase deficiency with enzyme activity <10% of normal), neurologic injury, seizures, hearing loss, and blindness may result. Symptoms usually occur after a few months of life when the biotin transferred from the mom to the baby via the placenta becomes depleted. 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). 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] In partial biotinidase deficiency, symptoms are usually triggered when the requirement for biotin increases (stress, infections, or fever).

Practice Guidelines

The guideline below was developed to standardize laboratory procedures for enzymatic biotinidase testing, delineate situations for which follow-up molecular testing is warranted, and characterize variables that can influence test performance and interpretation of results. There are no published practice guidelines for the management of biotinidase deficiency.

Cowan TM, Blitzer MG, Wolf B.
Technical standards and guidelines for the diagnosis of biotinidase deficiency.
Genet Med. 2010;12(7):464-70. PubMed abstract

Roles of the Medical Home

Although most children with biotinidase deficiency who take supplements will have no clinical or developmental problems, they may need more supplementation when physically stressed or going through puberty. The medical home should be alert to problems that may reflect inadequate biotin supplementation or noncompliance.

Clinical Assessment

Overview

Though usually diagnosed by newborn screening, partial or profound biotinidase deficiency should be considered in any child presenting with consistent clinical and biochemical findings. Annual preventive health visits with the medical home routine and follow-up visits with metabolic genetics, ophthalmology, and audiology are indicated.

Pearls & Alerts for Assessment

Test when indicated, despite a normal newborn screen

Even if their newborn screen was reported normal, individuals presenting with symptoms suggestive of biotinidase deficiency should be tested.

False positive newborn screens

Improper handling of the specimen, prematurity, and blood transfusion may give false positive newborn screens for biotinidase activity.

Symptoms despite biotin therapy

Occasionally, individuals will exhibit a return of symptoms despite biotin therapy. Biotin levels in serum or plasma acylcarnitine profile and urine organic acids may help determine if compliance is an issue. Biotinidase enzyme activity can be determined even after a child has been started on biotin.

Screening

For the Condition

Screening for biotinidase deficiency is part of every state’s newborn screening program. See Biotinidase Deficiency.

Of Family Members

Screen siblings of affected children for low biotinidase activity, even if they've had no symptoms. Individuals with low biotinidase activity, particularly those with partial biotinidase activity, may show symptoms only when physically stressed.

Presentations

Many children with biotinidase deficiency remain asymptomatic for a long time. Children with complete biotinidase deficiency are at high risk of developing symptoms and may manifest any or all of the findings associated with the condition.

Some children may have 1 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.

Diagnostic Criteria

Diagnosis is based on biochemical criteria. Newborn screening testing consists of a colorimetric test for biotinidase activity. Positive results are confirmed by a serum/plasma test for biotinidase enzyme activity and with DNA testing that detects a specific variant (p.D444H) in partial deficiency. Individuals with biotinidase deficiency can have metabolic ketoacidosis, organic aciduria, and possibly mild hyperammonemia, although children can have isolated neurological presentation due to the high sensitivity of the brain to biotin deficiency.

Clinical Classification

Affected children may have partial or profound biotinidase deficiency based on enzymatic activity in serum

Characteristics associated with profound biotinidase deficiency include:
  • Typical age of onset of 3.5 months, with a range from near birth to 10 years
  • Seizures
  • Hypotonia
  • Breathing problems
  • Developmental delays
  • Hearing loss
  • Vision loss and eye abnormalities
  • Ataxia
  • Skin rashes
  • Hair loss
  • Frequent candidiasis
Characteristics associated with partial biotinidase deficiency include:
  • Symptoms may only present after a significant physical stress such as illness or infection
  • Hypotonia
  • Paraparesis/myelopathy on spine MRI
  • Skin rashes
  • Hair loss

Differential Diagnosis

Biotin deficiency: Although unusual, children who eat a large number of raw eggs or have been receiving hyperalimentation without biotin supplementation may present with biotin deficiency and low serum levels of biotin.

Multiple carboxylase deficiency: Multiple carboxylase deficiency causes the same biochemical abnormalities of biotinidase deficiency. The enzyme is unable to insert biotin in the enzymes that need it. Patients with multiple carboxylase deficiency have metabolic acidosis and chemical imbalance but are less prone to the neurological complications of children with biotinidase deficiency. These patients can present at birth and be diagnosed by biochemical abnormalities in the plasma acylcarnitine profile.

History & Examination

Current & Past Medical History

Children, especially those with profound deficiency, can have seizures. These can be myoclonic, focal, generalized tonic-clonic, and/or infantile spasms. They will usually respond well to biotin supplementation.

Hearing loss might be one of the manifestations of biotinidase deficiency.

During puberty, individuals may develop alopecia that responds to increased biotin supplementation.

Family History

As an autosomal recessive condition, no family history of biotinidase deficiency is expected.

Developmental & Educational Progress

An individual with biotinidase deficiency may present with developmental delays and/or learning problems. Developmental and educational progress may be affected by inadequate compliance with biotin supplementation.

Physical Exam

General

Children with untreated deficiency may be developmentally delayed and have visual and/or auditory inattention.

In children with proper supplementation, general and neurologic exams should remain normal. Neurologic or other problems that preceded treatment may improve, but those children may continue to have disabilities that should be managed to optimize functional outcomes. See Cerebral Palsy module.

Growth Parameters

Height, weight, and OFC may be low for age.

Skin

Eczematous skin rashes, cutaneous skin infections, and hair loss may be present.

Chest

Stridor, hyperventilation, and apnea may be present in untreated children.

Neurologic Exam

Hypotonia is common. In children with partial biotinidase deficiency, a myelopathy with spasticity may be present. Children who present at an older age may have ataxia.

Testing

Sensory Testing

Ophthalmologic and audiologic evaluation can be performed as clinically indicated for vision and hearing deficits. Hearing loss, if present, does not usually respond well to biotin supplementation.

Laboratory Testing

Quantitative biotinidase activity and DNA testing for specific mutations in the related gene are generally included in the diagnostic workup.

Other testing (plasma acylcarnitine profile, urine organic acids, immunological testing) is performed if clinically indicated.

Imaging

Imaging is not part of the diagnostic evaluation of children identified through newborn screening. However, MRI abnormalities can appear in untreated children with biotinidase deficiency and may respond to biotin supplementation.

Genetic Testing

Two types of genetic testing can be performed in biotinidase deficiency. Targeted mutational analysis identifies the most common variants causing complete or partial deficiency. Full gene sequencing is useful for the identification of private mutations that are very common in this condition.

Specialty Collaborations & Other Services

Pediatric Metabolic Genetics (see Services below for local providers)

Refer to confirm the diagnosis, initiate supplementation, and collaborate with the medical home. Yearly follow-up with metabolic genetics is recommended.

Treatment & Management

Pearls & Alerts for Treatment & Management

Avoid uncooked eggs

Uncooked eggs contain the protein avidin that binds free biotin. This is not a usual cause of biochemical problems.

Biotin dosing

The optimal dose of biotin is not known, but recommended dosages seem to be safe and effective and need to be continued for life.

Systems

Nutrition/Growth/Bone

In individuals with profound biotinidase deficiency, 5-20 mg of oral biotin daily are recommended. Plasma acylcarnitine profile and urine organic acids may be useful when there is concern about the adequacy of supplementation. Abnormal acylcarnitines and urine organic acids suggest inadequate supplementation, although normal values do not confirm that supplementation is adequate. Anecdotal reports suggest that individuals may need higher doses of biotin during puberty. Biotin in foods is bound and not available to individuals with biotinidase deficiency. Biotin is available as a capsule or tablet that may be opened or crushed and administered with liquid or food for young children.

Individuals with partial biotinidase deficiency should be maintained on 5 mg of biotin daily. [Wolf: 2010] Some clinics give biotin only once per week after 1 year of age in patients with partial biotinidase deficiency. Especially in these cases, differentiation between partial and complete deficiency (usually by measurement of enzyme activity and DNA testing) becomes essential.

Specialty Collaborations & Other Services

Pediatric Metabolic Genetics (see Services below for local providers)

Yearly visits to monitor treatment and assess progress are recommended.

Pediatric Ophthalmology (see Services below for local providers)

Evaluation is indicated for potential vision deficits if there is clinical suspicion.

Audiology (see Services below for local providers)

Evaluation is indicated for potential hearing deficits if there are suggestive symptoms.

Issues Related to Biotinidase Deficiency

Ask the Specialist

How is biotinidase deficiency diagnosed?

Most children with biotinidase deficiency are diagnosed by newborn screening tests. Quantitative biotinidase levels can also be tested if there are concerns in older children.

Resources for Clinicians

On the Web

Biotinidase Deficiency (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information for the condition; National Center for Biotechnology Information, U.S. National Library of Medicine.

Genetics in Primary Care Institute (AAP)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American Academy of Pediatrics.

Helpful Articles

PubMed search for biotinidase in children and adolescents, last 5 years

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

Clinical Tools

Care, Action, & Self-Care Plans

ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (PDF Document 400 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Care Processes & Protocols

Confirmatory Algorithms for Elevated C5 Acylcarnitine (ACMG)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Resources for Patients & Families

Information on the Web

Biotinidase Deficiency (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; U.S. National Library of Medicine.

Baby's First Test (Genetic Alliance)
Clearinghouse for local, state, and national newborn screening education, programs, policies, and resources. Also, provides many ways for people to connect and share their viewpoints and questions about newborn screening; supported by the U.S. Department of Health and Human Services.

Resources for Biotinidase Deficiency (Disease InfoSearch)
Compilation of information, articles, and links to support.

Services for Patients & Families in Idaho (ID)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: October 2011; last update/revision: May 2019
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Authoring history
2011: first version: Lynne M. Kerr, MD, PhDA; Nicola Longo, MD, Ph.D.R
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Cowan TM, Blitzer MG, Wolf B.
Technical standards and guidelines for the diagnosis of biotinidase deficiency.
Genet Med. 2010;12(7):464-70. PubMed abstract

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text

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