Biotinidase Deficiency 

  • Author: Ronald G Davis, MD, MPH, FAAP; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 27, 2012
 

Background

Biotinidase is a ubiquitous mammalian cell enzyme that occurs at high levels in the liver, serum, and kidney. The primary function is to cleave biotin from biocytin, preserving the pool of biotin for use as a cofactor for biotin dependent enzymes, namely the 4 human carboxylases.

Multiple carboxylase deficiency responsive to biotin administration was first described in 1971.[1, 2] Wolf and colleagues further characterized the infantile form of multiple carboxylase deficiency as biotinidase deficiency in the 1980s.[3, 4] The neonatal period is the usual period of presentation for multiple carboxylase deficiency,[5] and the infantile form is usually due to biotinidase deficiency.

Disease caused by complete or partial absence of the enzyme is associated with a wide spectrum of clinical manifestations, including abnormalities of the neurological,[6] dermatological, immunological, and ophthalmological systems. Despite its rarity, early recognition is crucial because expeditious treatment may reverse all of its manifestations.[7]

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Pathophysiology

Biotin is an imidazole derivative found in many natural foods,[8] and its structure is shown in the image below.

Biotin structure. Biotin structure.

Bacteria in the intestine synthesize large amounts of human biotin. It serves as a cofactor for human carboxylases, including pyruvate carboxylase, propionyl-coenzyme A (CoA) carboxylase, beta-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase.

Biotin is covalently bound to these enzymes. Under normal conditions it undergoes proteolytic metabolism to biocytin or biotinyl peptides. Cleavage of these breakdown products results in restoration of free biotin for continued cofactor functioning. Biotinidase affects this cleavage and its absence or deficiency impairs this step causing a deficiency of free biotin and slowing the functioning of the biotin-dependent carboxylases. The carboxylases serve important roles in intermediary metabolism and impairment causes abnormalities in fatty acid synthesis, amino acid catabolism, and gluconeogenesis. These abnormalities may manifest in various clinical and laboratory findings, which are presented below.

Evidence suggests that biotin is also important in cell signaling, gene expression, and chromatin structure. More than 2000 human genes depend on biotin for expression. One such process is regulation of transcription factor NF-α -B, which is important in prevention of all death. Biotin's effect on chromatin nucleic structure is based on its modulating effect on histones, which is a building block for chromatin.

Biotinidase deficiency typically accounts for the so-called late-onset multiple carboxylase deficiency. The early or neonatal onset of multiple carboxylase deficiency is more likely due to another biotin-responsive biochemical abnormality, holocarboxylase synthetase deficiency. This enzyme is responsible for covalently attaching biotin to the various apocarboxylases. The defect occurs in the Michaelis constant values of biotin, requiring greater amounts of free biotin to ensure binding.

Biotin dependency due to a novel inherited defect of biotin transport has recently been described. The underlying etiology of this defect remains unclear. Children with clinical and laboratory evidence of biotin deficiency who do not demonstrate a defect of biotinidase or holocarboxylase functioning may exhibit this presumably less common defect. This syndrome is also clinically responsive to biotin and may warrant empiric treatment of conditions that mimic biotinidase deficiency.

Biotin deficiency is generally seen in patients with biotinidase deficiency, in severely malnourished children in developing countries, and in individuals who consume large quantities of raw eggs, in whom avidin binds biotin and prevents absorption.

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Epidemiology

Frequency

United States

The incidence of profound biotinidase deficiency is estimated at 1 per 137,401 population. The combined incidence of partial and profound deficiencies is 1 per 61,067 population. In Virginia in 1986, Heard and colleagues determined that neonatal screening was cost effective.[9] Now screening for biotinidase deficiency is performed routinely in several states and around the world.

Mortality/Morbidity

If treated promptly, biotinidase deficiency may be asymptomatic. Prolonged symptoms prior to institution of biotin therapy may leave the patient with varying degrees of neurological sequelae, including mental retardation, seizures, and coma. Death may result from untreated profound biotinidase deficiency.

Sex

Males and females appear to be equally affected, which is consistent with an autosomal recessive pattern of inheritance.

Age

Profound biotinidase deficiency (< 10% of normal serum enzyme activity) typically presents in the first 6 months of life, although presentation in the neonatal period or after the first decade occurs.

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Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

Specialty Editor Board

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

Disclosure: Nothing to disclose.

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, New York

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

Disclosure: Genzyme Grant/research funds PI

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

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Biotin structure.
 
 
 
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