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Biotinidase Deficiency

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
Updated: May 06, 2016


Biotinidase (BTD), a ubiquitous mammalian cell enzyme, is present in high levels in the serum, liver, and kidneys. Its primary enzymatic function is to cleave the vitamin biotin (also known as coenzyme R, vitamin H, or vitamin B7) from the organic compound, biocytin. Biotin is recycled in the body when biotinidase liberates biotin from endogenous and dietary proteins. Recycling maintains a pool of biotin to serve as a critical cofactor for gluconeogenesis, fatty acid synthesis, and branched chain amino acid catabolism. In biotinidase deficiency, biotin-dependent enzymes are affected, namely the 4 human carboxylases: acetyl-CoA carboxylase, propionyl-CoA carboxylase, β-methylcrotonyl-CoA carboxylase, and pyruvate CoA carboxylase. Biotinidase deficiency diminishes or prevents biotin recycling and coenzyme activity required for stable metabolic function.[1]

Multiple carboxylase deficiency (MCD) is one of many metabolic disorders that occur in the absence of the coenzyme activity of biotin. Known genetic causes of multiple carboxylase deficiency include holocarboxylase synthetase (HCS) deficiency and biotinidase deficiency. These enzyme deficiencies render the body unable to reuse and recycle the vitamin biotin.

Holocarboxylase synthetase deficiency is typically diagnosed in neonates. Older infants with multiple carboxylase deficiency usually have biotinidase deficiency. Both enzyme deficiencies are known to be treatment-responsive to biotin supplements.[2]

The role of biotin to treat carboxylase deficiencies was first recognized over 40 years ago. In 1971, patients diagnosed with beta-methylcrotonylglycinuria, a carboxylase deficiency, were clinically responsive to supplemental biotin treatment.[3, 4] Ten years later, Wolf and colleagues further characterized a neonatal form of multiple carboxylase deficiency due to biotin deficiency.[5, 6]

This inborn error of metabolism can result from either partial or complete absence of biotinidase. Biotinidase deficiency has a wide range of clinical manifestations, as it affects the human neurologic,[7] ophthalmologic, dermatologic, and immunologic systems. Despite its rarity, early recognition is imperative because expeditious treatment may prevent or minimize clinical insult.[8]



Biotin is one of the water-soluble B-complex vitamins.[9] This imidazole derivative[9] is present in various food sources, such as raw egg yolk, milk, organ meats (liver, kidney), brewer’s yeast, Swiss chard, and leafy green vegetables,[10] Endogenous biotin is synthesized by colonic microflora in the large intestine.

Biotin’s chemical structure is shown in the image below.

Biotin structure. Biotin structure.

Biotin is a coenzyme for, and covalently bound to, the 4 human carboxylases: pyruvate carboxylase, propionyl-CoA carboxylase, beta-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase. Under normal conditions, biotinidase cleaves biotin from biocytin or biotinyl-peptides to produce free biotin and lysine. This cleavage restores free biotin to continue cofactor enzymatic activity. Biotinidase deficiency or absence impairs biotin production, leading to a free biotin deficiency and resulting in decreased metabolic activity of the biotin-dependent carboxylases.

Biotin-dependent carboxylases have essential roles in the intracellular processes by which nutritive material is converted into cellular components, a process defined as intermediary metabolism. Metabolic impairment leads to abnormalities in fatty acid synthesis, amino acid catabolism, and gluconeogenesis. Consequently, various anomalous clinical and laboratory findings occur.

Biotin is also important for cell signaling, gene expression, and chromatin structure. More than 2000 human genes depend on biotin for expression. One such dependent process is regulating transcription factor NF-α-B, which is important in preventing cell death. Biotin's role in chromatin nucleic structure is based on its modulating effect on histones, the building blocks for chromatin.

Neonatal-onset multiple carboxylase deficiency most likely results from holocarboxylase synthetase deficiency (another biotin-responsive metabolic abnormality). Holocarboxylase synthetase activates and covalently binds biotin to four apo-carboxylases. Multiple carboxylase deficiency due to lack of biotinidase typically presents in infancy at age 3-6 months.

In 2002, a case report cited biotin dependency due to an inherited defect of biotin transport.[2] Children who have clinical and laboratory evidence of biotin deficiency, but do not demonstrate deficiencies in holocarboxylase synthetase or biotinidase, may have this less-common defect. This transport disorder is clinically responsive to biotin, suggesting that conditions that clinically mimic biotinidase deficiency warrant empiric trial treatment with biotin.

Dietary biotin deficiency occurs in severely malnourished children and in persons who consume large quantities of raw egg whites (about 20 per day) because avidin (egg-white protein) binds biotin, decreasing the bioavailability of this vitamin in the gastrointestinal tract. Cooked egg whites do not impair its absorption.




Profound biotinidase deficiency has an incidence of about 1 per 137,400 population; partial biotinidase deficiency affects about 1 per 110,000 population. The combined overall incidence of profound and partial deficiencies is about 1 per 61,000 population.[11]

In populations with an increased rate of consanguinity, the incidence of biotinidase deficiency is higher. This is evident in countries such as Turkey and Saudi Arabia. Cowan et al reported that the incidence appears to be higher in Hispanic infants born in the western United States.[12] A lower incidence has been cited in the African-American population.

Carrier frequency (people who are heterozygous for biotinidase gene mutation) in the general population is about 1 in 120.[13]

In 1986, Heard and Annison determined that newborn metabolic screening for biotinidase deficiency was justified as being cost effective,[14] given that the test enabled early detection and, consequently, prevention of reversible and irreversible clinical insults. A benefit for the public’s greater good was demonstrated.

Today, newborn metabolic screening for biotinidase deficiency is performed routinely in all 50 states in the United States[15] and in more than 25 nations worldwide.[13, 16] Biotinidase deficiency is detected via the newborn metabolic screen. This serological test uses a colorimetric semiquantitative assessment of biotinidase activity and includes a follow-up quantitative measurement of biotinidase activity for each newborn.[1]


If treated promptly with free biotin supplementation, patients with biotinidase deficiency can be without clinical sequelae. The prognosis is excellent if therapy is started early, before the onset of clinical symptoms. Lifelong oral treatment with free biotin is required.

Symptoms present prior to the initiation of biotin therapy may reflect varying degrees of neurologic findings, including mental retardation, seizures, and coma. Death may ensue from untreated profound biotinidase deficiency.


Males and females are equally affected, as the genetic etiology is autosomal recessive. Two copies of the altered BTD gene are required.


Profound biotinidase deficiency (< 10% mean normal serum enzyme activity) typically presents within the first 6 months of life, although the age of onset can vary.[17, 18] The age range of symptom presentation is from the first week of life through age 10 years, with the mean age of onset at age 3.5 months.[13]

Contributor Information and Disclosures

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.


Ronald G Davis, MD, MPH, FAAP Assistant Clinical Professor, Child Neurology, Florida State University; Owner and Medical Director of Pediatric Neurology, PA and Pediatric Neurology Epilepsy Center of Central Florida; Medical Director of Epileptology, Arnold Palmer Hospital for Women and Children in Orlando, Florida; Medical Director, Central Florida Muscular Dystrophy Association Clinic

Ronald G Davis, MD, MPH, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose. Marc P DiFazio, MD Associate Professor, Department of Neurology, Uniformed Services University of the Health Sciences; Director, Pediatric Subspecialty Services, Shady Grove Adventist Hospital for Children

Marc P DiFazio, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Cerebral Palsy and Developmental Medicine, American Academy of Neurology, Child Neurology Society, and Movement Disorders Society

Disclosure: Nothing to disclose.

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Biotin structure.
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