Biotinidase Deficiency

Description

Other Names

Multiple carboxylase deficiency, late onset

Diagnosis Coding

ICD-10

D81.810, Biotinidase deficiency

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

Description

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 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. If biotin supplementation is instituted before the condition has fully developed, prognosis is excellent.

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.

Prevalence

The prevalence is estimated to be 1:60,000 overall; 1:130,000 for profound deficiency; 1:110,000 for partial deficiency; and 1:120 for carrier (heterozygous for BTD mutation) frequency. [Wolf: 1991] The incidence of biotinidase deficiency is estimated to be 1:67,766 for profound deficiency and 1:24,957 for partial deficiency. [Therrell: 2014]

Genetics

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]

Prognosis

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). 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]

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.

Practice Guidelines

There are no published practice guidelines for the management of biotinidase deficiency. The guideline below were 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.

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

Helpful Articles

PubMed search for biotinidase in children, last 5 years

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

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.

Screening

Of Family Members

Siblings of affected children should be screened 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. Typical findings are listed below.

Profound biotinidase deficiency:
  • Typical age of onset is 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
Partial biotinidase deficiency (symptoms may only present after a significant physical stress such as illness or infection):
  • Hypotonia
  • Paraparesis/myelopathy on spine MRI
  • Skin rashes
  • Hair loss

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. Individuals with biotinidase deficiency can have metabolic ketoacidosis, organic aciduria, and possibly mild hyperammonia, although children can have isolated neurological presentation due to the high sensitivity of the brain to biotin deficiency.

Differential Diagnosis

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

Pathway block: Individuals who have a block in the synthetic pathway of all or one of the carboxylases for which biotinidase serves as a cofactor might present similarly to biotinidase deficiency. These entities are identified through biochemical testing of enzyme activity.

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 neurological complications of children with biotinidase deficiency.

Pearls & Alerts

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 urine 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.

History & Examination

Family History

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

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.

Developmental & Educational Progress

An individual with biotinidase 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

Annual ophthalmologic and audiologic evaluation are indicated for potential vision and hearing deficits. Hearing loss, if present, does not usually respond well to biotin supplementation.

Laboratory Testing

Quantitative biotinidase activity, urine organic acids, plasma acylcarnitine profile, serum ammonia, blood pH, and ketones are generally included in the diagnostic workup.

Immunological testing looking for cellular immunologic abnormalities that may be present in children with profound and partial deficiency may be performed.

Imaging

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

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant 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

Avoid uncooked eggs

Uncooked eggs contain the protein avidin, an inhibitor of the biotinidase enzyme.

Biotin dosing

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

Systems

Nutrition/Growth/Bone

In individuals with profound biotinidase deficiency, 5-20 mg of oral biotin daily are recommended. Monitoring 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 1-5 mg of biotin daily. [Wolff: 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 compete deficiency (usually by measurement of enzyme activity and DNA testing) becomes essential.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Yearly visits to monitor treatment and assess progress are recommended.

Pediatric Ophthalmology (see Services below for relevant providers)

Annual evaluation is indicated for potential vision deficits.

Audiology (see Services below for relevant providers)

Annual evaluation is indicated for potential hearing deficits.

Frequently Asked Questions

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.

Issues Related to Biotinidase Deficiency

Resources

Information for Clinicians

Newborn Screeening Newsletter: Biotinidase (UDOH) (PDF Document 226 KB)
Five pages of details about screening, pathophysiology, and management of biotinidase deficiency written by Dr. Nicola Longo; Utah Department of Health Newborn Screening Program 2005.

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.

Resources for Biotinidase Deficiency (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Helpful Articles

PubMed search for biotinidase in children, 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

Algorithms/Care Processes

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.

Care/Action 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.

Information & Support for Families

Family Diagnosis Page

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)
A clearinghouse for newborn screening information. Provides resources about screening at the local, state, and national levels and ways for people to share their viewpoints and questions about newborn screening; supported by the U.S. Department of Health and Human Services.

Support National & Local

Biotinidase Deficiency Family Support Group
Support group site with information, links, and a "Family Center" with an email forum, chance to meet other families, and read stories.

Services for Patients & Families in Montana

Select services for a different state: ID, NM, NV, RI, UT

Audiology

See all Audiology services providers (38) in our database.

Newborn Screening Programs

See all Newborn Screening Programs services providers (3) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (6) in our database.

Pediatric Metabolic Genetics

See all Pediatric Metabolic Genetics services providers (1) in our database.

Pediatric Ophthalmology

See all Pediatric Ophthalmology services providers (14) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors & Reviewers

Initial Publication: January 2014; Last Update: July 2012
Current Authors and Reviewers (click on name for bio):
Authors: Nicola Longo, MD, Ph.D.
Lynne M. Kerr, MD, PhD
Authoring history
(Limited detail is available on authoring dates before 2014.)
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.
Worldwide survey of neonatal screening for biotinidase deficiency.
J Inherit Metab Dis. 1991;14(6):923-7. PubMed abstract

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

Wolff DJ, Van Dyke DL, Powell CM.
Laboratory guideline for Turner syndrome.
Genet Med. 2010;12(1):52-5. PubMed abstract / Full Text