Biotinidase Deficiency 

Updated: Jul 27, 2018
Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD 

Overview

Background

Biotinidase (BTD, [OMIM 609019]), 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 (OMIM 253260) 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]

Pathophysiology

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.

Epidemiology

Frequency

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]

Mortality/Morbidity

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.

Sex

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

Age

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]

Prognosis

With immediate treatment and proper continuance and compliance of care, patients with biotinidase deficiency have an excellent prognosis and potential for a normal lifestyle and lifespan.[19]

Patient Education

Supporting Organizations

CLIMB (Children Living with Inherited Metabolic Diseases)

Genetic and Rare Diseases (GARD) Information Center

NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Biotinidase Deficiency Family Support Group

  • Dr. Barry Wolf
  • Chair, Department of Medical Genetics
  • Henry Ford Hospital
  • 2799 West Grand Blvd., CFP-4
  • Detroit, MI 48202
  • Phone: (313) 916-3116
  • Email:  bwolf1@hfhs.org
 

Presentation

History

Partial biotinidase deficiency (10%-30% mean normal serum biotinidase activity) is associated with an increased risk of developing clinical symptoms that are similar to those seen in children who have a profound deficiency. However, symptom presentation appears to be correlated with metabolic stressors (eg, illness, fever, fasting), and these children may not be symptomatic or only mildly symptomatic until then.

Metabolic deterioration during stress can be a useful clue in diagnosing a partial deficiency, although this type of clinical decline does occur with other inborn errors of metabolism. If there is concern, laboratory studies that specifically measure biotinidase activity should be obtained. In addition, diagnostic clarification is further made with symptom response to biotin treatment.

Sudden death is reported in association with presumed biotinidase deficiency, possibly due to seizures and/or brain stem dysfunction. Therefore, the diagnosis of biotinidase deficiency should be considered when evaluating an infant who died from sudden infant death syndrome (SIDS),[20] especially if there are family members who have possible clinical signs of partial biotinidase deficiency or are known to be heterozygous for a BTD gene mutation.

Clinical signs and symptoms of biotinidase deficiency vary. Consider biotinidase deficiency in patients who present with symptoms such as intractable seizures, hypotonia, spastic paraparesis, acidosis, unexplained visual loss or visual field loss, unexplained sensorineural hearing loss, alopecia, persistent rash, or failure to thrive.[21]

Neurologic sequelae

In a retrospective study published in 1993, 38% of patients with biotinidase deficiency presented with seizures, often in combination with other clinical features indicative of biotinidase deficiency. Approximately 55% of these patients had seizures at some point during the clinical review period. Seizures were described as generalized, tonic-clonic, clonic or myoclonic. Infantile spasms were also reported.[22]

Among patients with biotinidase deficiency, seizures or other neurologic manifestations (typically unresponsive to conventional therapies) quickly respond to pharmacologic doses of biotin. Most neurologic symptoms respond well to treatment with biotin; however, severe permanent neurologic sequelae can result from untreated biotinidase deficiency.

Other neurologic sequelae may include the following:

  • Developmental delay
  • Ataxia
  • Neuropathy
  • Auditory nerve dysfunction (sensorineural hearing loss)
  • Optic nerve atrophy and scotomata
  • Spastic paraparesis (an uncommon presentation)

Respiratoryabnormalities

Respiratory difficulties are common. Apnea, hyperventilation, and laryngeal stridor are observed. Stridor and breathing pattern abnormalities possibly result from dysfunction of medullary breathing centers affected by metabolic imbalance. Progression to other bulbar symptoms, such as swallowing difficulties, can occur.

Hair/Dermatoses

Clinical manifestations, such as loss of hair color (achromotrichia), loss of hair (alopecia), and an eczematous, scaly perioral/facial rash, can be quite striking. The rash distribution is described as periorificial and can be mistaken for eczema, seborrheic dermatitis, or the dermatoses of zinc deficiency.

Immunologic dysfunction

Abnormalities in cellular immunity can result from biotin deficiency. Chronic, potentially lethal fungal infections and recurrent viral infections characterize immunologic dysfunction. Immunologic dysfunction is ameliorated with proper biotin treatment.

Metabolic abnormalities

Profound biotinidase deficiency can cause metabolic ketoacidosis or organic acidosis.

Physical

Eye

Conjunctivitis and/or sudden vision loss may be presenting signs. Comprehensive ophthalmologic examination by a trained ophthalmologist may reveal optic atrophy and scotomata (alteration in visual fields).

Hair andskin

Clinical findings such as achromotrichia, alopecia, and an eczematous scaly perioral/facial rash can be striking. The rash distribution is described as periorificial, indicating a propensity for the rash to affect areas surrounding body orifices. Rashes may be mistaken for eczema, seborrheic dermatitis, or the dermatoses observed in zinc deficiency. Recalcitrance to conventional treatments for these dermatoses should lead the medical provider to diagnostically consider an inborn error of metabolism, including biotinidase deficiency. Initiation of biotin treatment leads to clinical improvement of alopecia and the periorificial rash within days to months.

Causative explanations for the dermatologic findings may be abnormal fatty acid synthesis and metabolism, possibly secondary to carboxylase dysfunction. Chronic candidiasis may also develop (as part of immunologic dysfunction).

Neurodevelopmental abnormalities

Infants may present with hypotonia and delay in developmental milestones. Older children may present with developmental delay and ataxia.

Twenty to 30% of symptomatic patients have sensorineural hearing loss. Of these patients, 76% of untreated children with profound biotinidase deficiency have sensorineural hearing loss that will not resolve or improve, but instead remains static, despite initiation of biotin treatment.[23]

Visual loss with progressive optic neuropathy can develop in isolation or in association with spastic paraparesis. Treatment with biotin therapy has demonstrated resolution of ocular findings and improvement of spastic paraparesis.[24, 25]

Causes

Biotinidase deficiency is a genetic disorder that results from an autosomal-recessive Mendelian inheritance pattern. Both biological parents must contribute the biotinidase gene mutation for this deficiency to occur in offspring, as two altered gene copies are required. Biotinidase deficiency heterozygous carriers can be identified via mutation assay.

The gene that encodes biotinidase, called BTD, is cytogenetically located on the short arm (p) of chromosome 3, band 25.1 (3p25.1). The most common BTD mutation, 98_104del7ins3, is present in about 50% of symptomatic children. A less common BTD mutation, Arg538 R→C, has also been described. The BTD mutation known to cause partial deficiency is p.D444H.[13]

As of 2012, Wolf has described 150 novel mutations of BTD.[26] His research cites the difficulty of correlating genotypes with phenotypes, indicating that age at onset of clinical signs and the patient's disease path primarily depend on the amount of functioning biotinidase present.

Prenatal testing via BTD gene analysis can identify the causative mutation(s), identify carriers of a mutated gene, and diagnose biotinidase deficiency via mutation assay.[1]

Complications

Failure to recognize and treat patients with biotinidase deficiency may cause permanent neurologic, ocular, and auditory damage. Immunologic disruption due to abnormal leukocyte function may result in fulminant fungal infections (ie, candidiasis). Complications can lead to death.

Studies on early recognition and treatment have repeatedly demonstrated that neonates identified through newborn metabolic screening and treated before they exhibit clinical signs of biotinidase deficiency were healthy and developmentally appropriate upon later examination. Children treated following the development of clinical signs of biotinidase deficiency were more likely to have residual neurologic impairments.[27]

Routine preventive guidelines for infants and children have been established by the Michigan Quality Improvement Consortium.[28]

 

DDx

Diagnostic Considerations

Consider sepsis, meningitis, or toxic exposure in a child who presents with intractable seizures or severe metabolic disruption.

If serum laboratory testing indicates hyperammonemia and/or lactic acidosis, other inborn errors of metabolism should be considered.

Symptoms of biotinidase deficiency in neonates may make it difficult to differentiate holocarboxylase synthetase deficiency from biotinidase deficiency (see Pathophysiology), as patients with holocarboxylase synthetase deficiency also respond clinically well to biotin treatment.

 

Workup

Laboratory Studies

In neonates, biotinidase deficiency is identified via newborn metabolic screening (activity assay). Mutational assay identifies the BTD mutation.

When biotinidase deficiency is suspected in a patient, obtain laboratory studies to test for an inborn error of metabolism.

Recommended serum tests include the following:

  • Arterial blood gas (ABG)

  • Serum chemistries

  • Ammonia level

  • Biotinidase, carnitine, and acylcarnitine profiles
  • Serum amino acids (SAA)

Recommended urine tests include the following:

  • Urine ketones

  • Urine organic acids (UOA)

Illness or catabolic stress can induce metabolic disruption. Obtaining laboratory studies at this time may give clues to the etiology of a metabolic disorder. These clues may resolve in an otherwise healthy child, especially in patients who have partial biotinidase enzyme activity. Affected children may have ketolactic acidosis, organic aciduria, and/or mild hyperammonemia.[1]

Imaging Studies

Magnetic resonance imaging (MRI) is the neuroimaging study of choice to evaluate a child with a possible inborn error of metabolism. Children with biotinidase deficiency may show cerebral edema, low attenuation of white matter signal, cerebral atrophy, and compensatory ventricular enlargement.[29]

Magnetic resonance spectroscopy (MRS) helps determine functional brain metabolism. Some hospital facilities have access to MRS, and using this tool may help delineate the nature of the brain disorder in vivo.

Positron emission tomography (PET) scanning is used to demonstrate changes in cerebral metabolic activity before and after administration of biotin therapy.

Computerized tomography (CT) scanning may demonstrate bilateral basal ganglia calcifications that may not be as easily observed on MRI.

Other Tests

Electroencephalography

Electroencephalography (EEG) findings prior to biotin treatment demonstrate poor organization of background and absence of typical sleep morphology.

Ictal manifestations have been described as diffuse polyspike discharges at the onset of seizures (myoclonic) followed by rhythmic diffuse spike and wave discharges during clinical presentation of a generalized tonic-clonic seizure.[22]

EEG findings vary and may normalize completely after biotin therapy.

Ophthalmologic testing

An experienced ophthalmologist should perform a dilated funduscopic examination to evaluate for optic nerve atrophy and scotomata.

Visual field testing and visual evoked potentials (VEPs) may help determine the degree of optic nerve injury in affected patients.

Audiologic testing

Perform audiologic testing in all children, as hearing deficits in symptomatic children are common and can persist after treatment.

Brainstem auditory evoked response (BAER) potentials may help delineate hearing impairment in young children or in patients with development or speech delay.

Histologic Findings

The extent of pathologic central nervous system (CNS) lesions in patients with biotinidase deficiency vary based on the severity of their clinical condition prior to death. Findings are similar to those found in Leigh syndrome or Wernicke encephalopathy, although the pathologic lesions in the CNS appear more widespread.

Myelin appears to be more severely affected than neurons or axonal processes. Poorly delineated necrotic lesions affect the pons, hypothalamus, hippocampus, and medulla. Microscopically, these areas show microcavitation, capillary proliferation, and gliosis.

Severe cerebral edema may be evident in many major white matter tracts.

 

Treatment

Medical Care

Therapy for biotinidase deficiency is oral biotin, typically prescribed at a starting dose of 5-10 mg/d. Treatment is with free biotin. Bound biotin contained in oral multivitamin supplements does not treat the body deficiency.

Some patients require higher daily doses of free biotin. If the enzymatic defect is present but a healthy clinical response does not occur with lower doses, a high-dose therapy is considered (up to 40 mg/d).

Treatment with free biotin is lifelong in patients with profound deficiency. Patients with a partial deficiency (10%-25% activity remaining) may not require lifelong treatment. Both patient populations, however, require knowledgeable continuity of care to address ongoing medical care and treatment approach.

Children with residual neurologic disease may require medical interventions for developmental delay, spasticity, and bulbar dysfunction, in addition to oral biotin treatment. Spasticity and dystonia associated with inborn errors of metabolism have been treated with intrathecal baclofen and neurotoxins.[30]

Consultations

A pediatric neurologist, metabolic disorder specialist, and geneticist should assist in the patient’s workup and evaluation.[31]

A pediatric neurologist and a pediatrician skilled in the evaluation of a child who is delayed and neurologically impaired should establish continuity of care and perform follow-up examinations, as well as procedures to document residual neurological insult. Children with residual neurologic injury as noted with spasticity or dystonia should receive ongoing physical therapy to prevent long-term orthopedic deterioration.

A medical genetics team, including a genetic counselor, should be referred to explain the genetics of biotinidase deficiency and to offer support and resources to patients and family members.

 

Medication

Medication Summary

Biotin is the drug of choice (DOC) for biotinidase deficiency.

Vitamins and cofactors

Class Summary

Organic substances are required by the body in small amounts for various metabolic processes. They are used clinically for the prevention and treatment of specific deficiency states. Biotin is the DOC for biotinidase deficiency.

Biotin

An essential coenzyme in fat metabolism and in other carboxylation reactions. Biotin deficiency may result in the urinary excretion of organic acids and changes in skin and hair. Functions as a coenzyme or a prosthetic group in all 4 of the body's carboxylases. Each of these carboxylases maintain critical roles in intermediary metabolism. In these enzymes, biotin serves as a carrier for CO2.