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Biotinidase Deficiency

Synonyms: Late-Onset Biotin-Responsive Multiple Carboxylase Deficiency, Late-Onset Multiple Carboxylase Deficiency
, MD, PhD
Chairman, Department of Medical Genetics
Henry Ford Hospital
Detroit, Michigan

Initial Posting: ; Last Update: December 5, 2013.

Summary

Disease characteristics. If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.

Diagnosis/testing. Individuals with profound biotinidase deficiency have less than 10% of mean normal serum biotinidase enzyme activity. Individuals with partial biotinidase deficiency have 10%-30% of mean normal serum biotinidase enzyme activity. Both profound and partial biotinidase deficiency are usually identified by newborn screening in states where such screening is offered. BTD is the only gene in which mutations are known to cause biotinidase deficiency.

Management. Treatment of manifestations: All symptomatic children with profound biotinidase deficiency improve when treated with 5-10 mg of oral biotin per day. All individuals with profound biotinidase deficiency, even those who have some residual enzymatic activity, should have lifelong treatment with biotin. Children with vision problems may benefit from vision aids; those with hearing loss will usually benefit from hearing aids or cochlear implants, and those with developmental deficits from appropriate interventions.

Prevention of primary manifestations: Children with biotinidase deficiency identified by newborn screening should remain asymptomatic if biotin therapy is instituted early and they are continuously maintained on therapy.

Surveillance: Annual vision and hearing evaluation, physical examination, and periodic assessment by a metabolic specialist.

Agents/circumstances to avoid: Raw eggs because they contain avidin, an egg-white protein that binds biotin and decreases the bioavailability of the vitamin.

Evaluation of relatives at risk: Testing of asymptomatic sibs of a proband ensures that biotin therapy for affected sibs can be instituted in a timely manner.

Genetic counseling. Biotinidase deficiency is inherited in an autosomal recessive manner. With each pregnancy, a couple who has had one affected child has a 25% chance of having an affected child, a 50% chance of having a child who is an asymptomatic carrier, and a 25% chance of having an unaffected child who is not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

The working group of the American College of Medical Genetics Laboratory Quality Assurance Committee has established technical standards and guidelines for the diagnosis of biotinidase deficiency [Cowan et al 2010; click Image guidelines.jpg for full text]. Clinical issues and frequently asked questions about biotinidase deficiency have been addressed in a recent review [Wolf 2010].

Testing Strategy

Biotinidase deficiency may be suspected and confirmed in three clinical scenarios [Wolf 2012]:

Newborn Positive on NBS

Infants with either profound biotinidase deficiency or partial biotinidase deficiency are usually identified by newborn screening in states in which it is offered [McVoy et al 1990, Suormala et al 1990]. In such states, biotinidase deficiency can be detected in virtually 100% of affected infants (see National Newborn Screening Status Report).

Newborn screening utilizes a small amount of blood obtained from a heel prick for a colorimetric test for biotinidase activity [Heard et al 1984, Wolf et al 1985b, Heard et al 1986, Wolf 1991]:

  • False positive test results may occur in premature infants and in samples placed in plastic prior to sufficient drying.
  • Measurement of biotinidase activity in serum/plasma is warranted in infants whose initial screening tests are abnormal.
  • Note: Although most individuals with biotinidase deficiency exhibit metabolic ketolactic acidosis, organic aciduria, and mild hyperammonemia, the absence of organic aciduria or metabolic ketoacidosis does not exclude the diagnosis of biotinidase deficiency in a symptomatic child.

The diagnosis of biotinidase deficiency is established in a newborn whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on detection of either deficient biotinidase enzyme activity in serum/plasma or biallelic mutations in BTD.

  • Biotinidase enzyme activity in serum is most commonly determined colorimetrically by measuring the release of p-aminobenzoate from N-biotinyl-p-aminobenzoate, a biocytin analog [Wolf et al 1983a]. Deficient biotinidase activity has also been shown in extracts of leukocytes and fibroblasts [Wolf & Secor McVoy 1983]. Biotinidase activity is also determined fluorimetrically by measuring the release of aminoquinoline from biotinyl-6-aminoquinoline [Wastell et al 1984]. (Other assays for biotinidase activity in serum and tissues measure the hydrolysis of biocytin or other biotinyl derivatives.)

    Profound biotinidase deficiency is lower than 10% mean normal serum enzyme activity.

    Partial biotinidase deficiency is 10%-30% of mean normal serum biotinidase activity.

    Note: With appropriate controls, biochemical testing is definitive for confirming the diagnosis. It is important that a normal unrelated control sample and samples from the parent(s) accompany the serum/plasma sample from the proband to the diagnostic laboratory for accurate interpretation of enzymatic results [Neto et al 2004]. An increasing problem of enzymatic deterioration (false positives) is almost certainly the result of inadequate storage of samples either prior to shipping to commercial laboratories or at some laboratories [Wolf 2003].
  • Molecular genetic testing of BTD is warranted when the results of enzymatic testing are ambiguous, such as in differentiating profound biotinidase deficiency from partial biotinidase deficiency and in differentiating heterozygosity for profound biotinidase deficiency from partial biotinidase deficiency.

Note: Because genotype/phenotype correlations in biotinidase deficiency are not well established, decisions regarding treatment should be based on the results of enzyme activity rather than molecular genetic testing.

Table 1. Summary of Molecular Genetic Testing Used in Biotinidase Deficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
BTDTargeted mutation analysis 4p.Cys33PhefsTer36
p.Gln456His
p.Arg538Cys
p.Asp444His
p.[Ala171Thr;Asp444His] 5
~60% 6
Sequence analysisSequence variants 7, 8~99%
Deletion/duplication analysis 9Partial- and whole-gene deletions/duplicationsUnknown, none reported 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Targeted mutation panels may vary by laboratory.

5. Real-time PCR of DNA from the blood spot of a newborn screen card can be used to identify a panel of common BTD mutations [Dobrowolski et al 2003]. p.Cys33PhefsTer36 and p.Arg538Cys occurred in both symptomatic individuals and children identified by newborn screening, but occurred in symptomatic individuals at a significantly greater frequency. The other common mutant alleles, p.Gln456His and p.[Ala171Thr;Asp444His], occurred only in the newborn screening group in the Norrgard et al [1999] study (see Genotype-Phenotype Correlations).

6. Pomponio et al [1997a], Norrgard et al [1999]

7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8. Almost all individuals with partial biotinidase deficiency have the mutation p.Asp444His in one allele of BTD in combination with a mutation for profound deficiency in the other allele [Swango et al 1998].

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. No large deletions have been reported in BTD. Based on the high sensitivity of BTD sequence analysis, a screening test for large deletions may not be warranted.

Newborn with Previously Affected Sib

An infant at risk for biotinidase deficiency should be treated at birth pending results of the definitive biotinidase enzyme activity assay and/or molecular genetic testing.

Older Child or Adult with Signs and Symptoms Suggestive of Biotinidase Deficiency

Children or adults with untreated profound biotinidase deficiency usually exhibit one or more of the following features, which are also observed in children with many other inherited metabolic disorders:

  • Seizures
  • Hypotonia
  • Respiratory problems including hyperventilation, laryngeal stridor, and apnea
  • Developmental delay
  • Hearing loss
  • Vision problems, such as optic atrophy

More specific features of profound biotinidase deficiency include the following:

  • Eczematous skin rash
  • Alopecia
  • Conjunctivitis
  • Candidiasis
  • Ataxia

Older children and adolescents may exhibit limb weakness, paresis, and scotomata.

Children or adults with untreated partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may exhibit any of the above symptoms, but usually the symptoms are mild and occur only when the child is stressed, such as with a prolonged infection.

Children and adults with signs and/or symptoms of biotinidase deficiency should have the diagnosis confirmed by either enzyme activity assay and/or molecular genetic testing.

Clinical Description

Natural History

Individuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development. Neurologic problems occur only in those individuals with biotinidase deficiency who have recurrent symptoms and metabolic compromise prior to biotin treatment.

Profound biotinidase deficiency. Symptoms of untreated profound biotinidase deficiency usually appear between ages one week and ten years, with a mean age of three and one-half months [Wolf et al 1985c].

Some children with biotinidase deficiency manifest only a single symptom, whereas others exhibit multiple neurologic and cutaneous findings.

The most common neurologic features of individuals with untreated, profound biotinidase deficiency are seizures and hypotonia [Wolf et al 1983a, Wolf et al 1985c, Wastell et al 1988, Wolf 1995, Wolf 2011]. The seizures are usually myoclonic but may be grand mal and focal; some children have infantile spasms [Salbert et al 1993b]. Some untreated children have exhibited spinal cord involvement characterized by progressive spastic paresis and myelopathy [Chedrawi et al 2008]. Older affected children often have ataxia and developmental delay.

Sensorineural hearing loss and eye problems (e.g., optic atrophy) have also been described in untreated children [Wolf et al 1983b, Taitz et al 1985, Salbert et al 1993a, Weber et al 2004]. Approximately 76% of untreated symptomatic children with profound biotinidase deficiency have sensorineural hearing loss that usually does not resolve or improve but remains static with biotin treatment [Wolf et al 2002b].

Many symptomatic children with biotinidase deficiency exhibit a variety of central nervous system abnormalities on MRI or CT of the brain [Wolf et al 1983b, Wastell et al 1988, Lott et al 1993, Salbert et al 1993b, Grunewald et al 2004]. These findings may improve or become normal after biotin treatment.

Cutaneous symptoms include skin rash, alopecia, and recurrent viral or fungal infections caused by immunologic dysfunction. Respiratory problems, such as hyperventilation, laryngeal stridor, and apnea can occur. One death initially thought to be caused by sudden infant death syndrome was subsequently attributed to biotinidase deficiency [Burton et al 1987].

A number of children with profound biotinidase deficiency were asymptomatic until adolescence, when they developed sudden loss of vision with progressive optic neuropathy and spastic paraparesis [Ramaekers et al 1992, Lott et al 1993, Ramaekers et al 1993]. After several months of biotin therapy, the eye findings resolved and the spastic paraparesis improved. In other individuals with enzyme deficiency, paresis and eye problems have occurred during early adolescence [Tokatli et al 1997, Wolf et al 1998]. Several reports describe adults with profound biotinidase deficiency who have offspring who also have profound biotinidase deficiency identified by newborn screening, but who have never had symptoms [Wolf et al 1997, Baykal et al 2005].

Partial biotinidase deficiency. One child with partial biotinidase deficiency who was not treated with biotin exhibited hypotonia, skin rash, and hair loss during an episode of gastroenteritis at approximately age six months. When treated with biotin, the symptoms resolved. Individuals with partial biotinidase deficiency may develop symptoms only when stressed, such as during infection.

Outcome with biotin treatment. An outcome study of children with biotinidase deficiency indicates that biotin treatment is effective in preventing symptoms [Möslinger et al 2001, Weber et al 2004]. Möslinger et al [2003] stated that children with profound deficiency who have less than 1% biotinidase activity should be treated with biotin, but those with greater than 1% to 10% biotinidase activity may not need treatment. A child with 1% to 10% biotinidase activity may be just as likely to develop symptoms as one with total loss of enzyme activity [Wolf 2002]. It is therefore strongly recommended that all children with profound biotinidase deficiency, regardless of the residual biotinidase enzyme activity, be treated with biotin.

Genotype-Phenotype Correlations

Genotype/phenotype correlations are not well established. Deletions, insertions, or nonsense mutations usually result in complete absence of biotinidase enzyme activity, whereas missense mutations may or may not result in complete loss of biotinidase enzyme activity. Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms. Regardless of their molecular genetic test results, all individuals with deficient biotinidase enzyme activity require biotin treatment.

Although genotype-phenotype correlations are not well established, in one study, children with symptoms of profound biotinidase deficiency with null mutations were more likely to develop hearing loss than those with missense mutations, even if not treated for a period of time [Sivri et al 2007].

Certain genotypes correlate with partial biotinidase deficiency and others with complete biotinidase deficiency:

  • Most mutations in BTD cause complete loss or near-complete loss of biotinidase enzyme activity. These alleles are considered profound biotinidase deficiency alleles; a combination of two such alleles, whether homozygous or compound heterozygous, results in the individual having profound biotinidase deficiency. Such individuals are likely to develop symptoms if not treated with biotin.
  • Individuals with one profound biotinidase deficiency allele and a normal allele are heterozygotes or carriers of profound biotinidase deficiency. Parents of children with profound biotinidase deficiency are in this group. No heterozygous parents of children with profound or partial biotinidase deficiency have ever exhibited symptoms [B Wolf, personal observation]. Such individuals do not need biotin therapy.
  • Individuals who are compound heterozygotes for the p.Asp444His mutation and a mutation that results in profound biotinidase deficiency are expected to have approximately 20%-25% of mean normal serum biotinidase enzyme activity or partial biotinidase deficiency [Swango et al 1998]. Individuals in this group are routinely treated with biotin [McVoy et al 1990].
  • One BTD allele with both the p.Asp444His and p.Ala171Thr mutations in cis configuration, p.[Ala171Thr;Asp444His] (see Table 1), results in an allele causing profound biotinidase deficiency. An individual with an allele having these two mutations in cis configuration combined with another allele with a mutation for profound biotinidase deficiency has profound biotinidase deficiency and requires biotin therapy [Norrgard et al 1998].
  • Individuals who are homozygous or have two alleles for the p.Asp444His mutation are expected to have approximately 45%-50% of mean normal serum biotinidase enzyme activity. This is similar to the activity of heterozygotes for profound biotinidase deficiency. Such individuals do not need biotin therapy.
  • Several adults with profound biotinidase deficiency have never had symptoms and have never been treated [Wolf et al 1997] whereas some children with the same mutations have been symptomatic. Therefore, it has been speculated that some children with profound biotinidase deficiency may exhibit mild or no symptoms if left untreated. However, it is recommended that these children be treated nonetheless [Möslinger et al 2003].

Penetrance

Almost all children with profound biotinidase deficiency become symptomatic or are at risk of becoming symptomatic if not treated. Several adults with profound biotinidase deficiency identified through family studies have never exhibited symptoms. In addition, several enzyme-deficient sibs of symptomatic children have apparently never exhibited symptoms. It is possible that these individuals would become symptomatic if stressed, such as with a prolonged infection.

Nomenclature

Profound and partial biotinidase deficiency is the accepted nomenclature for this disorder. Individuals with partial biotinidase deficiency were previously described as having late-onset or juvenile multiple or combined carboxylase deficiency.

Biotinidase deficiency should not be confused with holocarboxylase synthetase deficiency, previously called early-onset or infantile multiple or combined carboxylase deficiency.

Prevalence

Based on the results of worldwide screening of biotinidase deficiency [Wolf 1991], the incidence of the disorder is:

  • One in 137,401 for profound biotinidase deficiency;
  • One in 109,921 for partial biotinidase deficiency;
  • One in 61,067 for the combined incidence of profound and partial biotinidase deficiency.

The incidence of biotinidase deficiency is generally higher in populations with a high rate of consanguinity (e.g., Turkey, Saudi Arabia). The incidence appears to be increased in the Hispanic population [Cowan et al 2012] and it may be lower in the African American population.

Carrier frequency in the general population is approximately one in 120.

Differential Diagnosis

Clinical features including vomiting, hypotonia, and seizures accompanied by metabolic ketolactic acidosis or mild hyperammonemia are often observed in inherited metabolic diseases. Individuals with biotinidase deficiency may exhibit clinical features that are misdiagnosed as other disorders, such as isolated carboxylase deficiency, before they are correctly identified [Suormala et al 1985, Wolf 1992]. Other symptoms that are more characteristic of biotinidase deficiency (e.g., skin rash, alopecia) can also occur in children with nutritional biotin deficiency, holocarboxylase synthetase deficiency, zinc deficiency, or essential fatty acid deficiency. See Figure 1.

Figure 1

Figure

Figure 1. The biotin cycle

Free biotin enters the cycle from dietary sources or from the cleavage of biocytin or biotinyl-peptides by the action of biotinidase. The free biotin is then covalently attached to the various apocarboxylases, (more...)

Biotin deficiency. Biotin deficiency can usually be diagnosed by dietary history. Individuals with biotin deficiency may have a diet containing raw eggs or protracted parenteral hyperalimentation without biotin supplementation.

Low-serum biotin concentrations are useful in differentiating biotin and biotinidase deficiencies from holocarboxylase synthetase deficiency, but it is important to know the method used for determining the biotin concentration. Only methods that distinguish biotin from biocytin or bound biotin yield reliable estimates of free biotin concentrations.

Isolated carboxylase deficiency. Urinary organic acid analysis is useful for differentiating isolated carboxylase deficiencies from the multiple carboxylase deficiencies that occur in biotinidase deficiency and holocarboxylase synthetase deficiency:

  • Beta-hydroxyisovalerate is the most commonly elevated urinary metabolite in biotinidase deficiency, holocarboxylase synthetase deficiency, isolated beta-methylcrotonyl-CoA carboxylase deficiency, and acquired biotin deficiency.
  • In addition to beta-hydroxyisovalerate, elevated concentrations of urinary lactate, methylcitrate, and beta-hydroxypropionate are indicative of the multiple carboxylase deficiencies.

The multiple carboxylase deficiencies are biotin responsive, whereas the isolated carboxylase deficiencies are not. A trial of biotin can be useful for discriminating between the disorders.

Isolated carboxylase deficiency can be diagnosed by demonstrating deficient enzyme activity of one of the three mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts grown in low biotin-containing medium and normal activity of the other two carboxylases.

Holocarboxylase synthetase deficiency. Both biotinidase deficiency and holocarboxylase synthetase deficiency are multiple carboxylase deficiencies. Both are biotin responsive.

The symptoms of biotinidase deficiency and holocarboxylase synthetase deficiency are similar, and clinical differentiation is often difficult.

The age of onset of symptoms may be useful for distinguishing between holocarboxylase synthetase deficiency and biotinidase deficiency. Holocarboxylase synthetase deficiency usually presents with symptoms before age three months, whereas biotinidase deficiency usually presents after age three months; however, there are exceptions for both disorders.

Organic acid abnormalities in biotinidase deficiency and holocarboxylase synthetase deficiency are similar and may be reported as consistent with multiple carboxylase deficiency. However, the tandem mass spectroscopic methodology that is being incorporated into many newborn screening programs should identify metabolites that are consistent with multiple carboxylase deficiency. Because most children with holocarboxylase synthetase deficiency excrete these metabolites in the newborn period, the disorder should be identifiable using this technology.

Definitive enzyme determinations are required to distinguish between the two disorders. Biotinidase activity is normal in serum of individuals with holocarboxylase synthetase deficiency; therefore, the enzymatic assay of biotinidase activity used in newborn screening is specific for biotinidase deficiency and does not identify children with holocarboxylase synthetase deficiency.

Both biotinidase deficiency and holocarboxylase synthetase deficiency are characterized by deficient activities of the three mitochondrial carboxylases in peripheral blood leukocytes prior to biotin treatment. In both disorders, these activities increase to near-normal or normal after biotin treatment.

Individuals with holocarboxylase synthetase deficiency have deficient activities of the three mitochondrial carboxylases in extracts of fibroblasts that are incubated in medium containing only the biotin contributed by fetal calf serum (low biotin), whereas individuals with biotinidase deficiency have normal carboxylase activities in fibroblasts. The activities of the carboxylases in fibroblasts of individuals with holocarboxylase synthetase deficiency become near-normal to normal when cultured in medium supplemented with biotin (high biotin).

Sensorineural hearing loss (see Deafness and Hereditary Hearing Loss Overview). Sensorineural hearing loss has many causes. Biotinidase deficiency can be excluded as a cause by determining biotinidase enzyme activity in serum. This test should be performed specifically on children with hearing loss who are exhibiting other clinical features consistent with biotinidase deficiency.

Ataxia (see Hereditary Ataxia Overview). Ataxia has multiple causes. Biotinidase deficiency can be excluded as a cause by determining biotinidase enzyme activity in serum. The test should be performed especially on children with ataxia who are exhibiting other clinical features consistent with biotinidase deficiency.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with biotinidase deficiency, the following evaluations are recommended:

  • History of seizures, balance problems, feeding problems, breathing problems, loss of hair, fungal infections, skin rash, conjunctivitis
  • Physical examination for hypotonia, ataxia, eye findings such as optic atrophy, eczematous skin rash, alopecia, conjunctivitis, breathing abnormalities such as stridor, thrush, and/or candidiasis
  • Evaluation for sensorineural hearing loss and psychomotor deficits
  • Identification of biochemical abnormalities such as metabolic ketolactic acidosis, hyperammonemia, and organic aciduria
  • Identification of cellular immunologic abnormalities
  • Quantitative determination of biotinidase enzyme activity in serum/plasma
  • Medical genetics consultation

Treatment of Manifestations

Although newborn screening for biotinidase deficiency has resulted in almost complete ascertainment of children with biotinidase deficiency in the United States and in many other countries, occasionally a child who has not been screened or has been mistakenly thought to have normal biotinidase activity on newborn screening will present with clinical symptoms. These children may become metabolically compromised and require hydration, occasionally bicarbonate for acidosis, and procedures to ameliorate hyperammonemia. Once it is recognized that the child has a multiple carboxylase deficiency, administration of biotin - or a multivitamin “cocktail” containing biotin - can rapidly resolve the metabolic derangement and improve many of the clinical symptoms within hours to days.

Compliance with biotin therapy (see Prevention of Primary Manifestations) improves symptoms in symptomatic individuals.

Some features such as optic atrophy, hearing loss, or developmental delay may not be reversible; they should be addressed with ophthalmologic evaluations and intervention, hearing aids or cochlear implants, and appropriate interventions for developmental deficits.

Prevention of Primary Manifestations

All individuals with profound biotinidase deficiency, even those who have some residual biotinidase enzyme activity, should be treated with biotin independent of their genotype [Wolf 2003].

Biotinidase deficiency is treated by supplementation with oral biotin in free form as opposed to the bound form. Children with biotinidase deficiency identified by newborn screening will remain asymptomatic with compliance to biotin therapy.

All symptomatic children with biotinidase deficiency have improved after treatment with 5-10 mg oral biotin per day.

Biotin is usually dispensed as a tablet or a capsule, most of which is filler and not the biotin which is minute relative to the quantity of filler. To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. Note that the contents of the tablet or capsule should not be put into a bottle because the mixture will stick to the bottle and/or fail to pass through the nipple, thus delivering inconsistent doses.

Although biotin occasionally is dispensed as a solution or syrup, these liquid preparations are not recommended because the mixture - which is a suspension - tends to settle (especially upon refrigeration) and to grow bacteria upon storage. The liquid preparations usually do not provide a consistent dose and should not be added to milk in a bottle.

The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays.

Only a few anecdotal reports exist regarding symptoms in children with partial biotinidase deficiency who were not treated with biotin. Because there is no known toxicity for biotin, children with partial deficiency are usually treated with 1-10 mg oral biotin per day.

Biotin therapy is lifelong.

More data are required to determine the dosage of biotin that is necessary for older children with either profound or partial biotinidase deficiency, but essentially all children have tolerated 10 mg/day of oral biotin with no side effects. Anecdotally, two girls with profound biotinidase deficiency developed hair loss during adolescence that resolved following increase of their biotin dosages from 10 mg per day to 15 or 20 mg per day.

A protein-restricted diet is not necessary.

Prevention of Secondary Complications

There are no known adverse side effects from pharmacologic doses of biotin. In fact, the major problem is the lack of treatment or non-compliance with prescribed treatment.

Surveillance

For all children with biotinidase deficiency:

  • Yearly ophthalmologic examination and auditory testing for individuals with profound deficiency and every two years for those with partial deficiency
  • Regularly scheduled appointments with primary care physicians or as needed
  • Yearly evaluation by a medical geneticist or metabolic specialist for individuals with profound deficiency and every two years for those with partial deficiency

Symptomatic children with residual clinical problems should be seen as directed by the appropriate sub-specialists:

  • Evaluation of urinary organic acids if return of symptoms with biotin therapy (most commonly the result of non-compliance)

    Note: Measurement of biotin concentrations in blood or urine is not useful except to determine compliance with therapy.

Agents/Circumstances to Avoid

Raw eggs should be avoided because they contain avidin, an egg-white protein that binds biotin, thus decreasing its bioavailability. (Thoroughly cooked eggs present no problem because heating inactivates avidin, rendering it incapable of binding biotin.)

Evaluation of Relatives at Risk

Sibs who have never been tested, even if asymptomatic, should have biotinidase enzyme testing.

Any relative with symptoms consistent with biotinidase deficiency should have biotinidase enzyme testing.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The only special pregnancy management considerations for a woman who is carrying a baby with biotinidase deficiency or is at risk of having a baby with biotinidase deficiency is consideration of biotin supplementation of the mother. An optimal prenatal dose has not been determined.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Biotinidase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of a child with biotinidase deficiency are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an individual with biotinidase deficiency has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Sibs of an individual with biotinidase deficiency should be tested for the deficiency even if they do not exhibit symptoms.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • All offspring of an individual with biotinidase deficiency are obligate carriers.
  • The risk of biotinidase deficiency occurring in the offspring of an individual with biotinidase deficiency is essentially zero if the reproductive partner is not heterozygous for the enzyme deficiency.
  • Based on a carrier frequency of approximately one in 120 in the general population, the empiric risk to an individual with biotinidase deficiency of having a child with the disorder is one in 240.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Biochemical genetic testing. Carriers (heterozygotes) usually have serum enzyme activity levels intermediate between those of affected and those of normal individuals [Wolf et al 1983a]. Using serum enzyme activity, heterozygosity can be diagnosed with approximately 95% accuracy [Weissbecker et al 1991]. However, if the disease-causing mutations in the family have been identified, molecular testing is preferred.

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Biochemical testing. Prenatal diagnosis for pregnancies at increased risk is possible through measurement of biotinidase enzyme activity in cultured amniotic fluid cells and in amniotic fluid obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation [Secor McVoy et al 1984, Chalmers et al 1994].

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like biotinidase deficiency) do not affect intellect and for which treatment is available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified. However, because immediate biotin treatment of a newborn child with biotinidase deficiency apparently prevents all symptoms, requests for PGD for biotinidase deficiency will likely be very uncommon.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Biotinidase Deficiency: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
BTD3p25​.1BiotinidaseBiotinidase Deficiency (BTD)
BTD @ LOVD
BTD

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Biotinidase Deficiency (View All in OMIM)

253260BIOTINIDASE DEFICIENCY
609019BIOTINIDASE; BTD

Normal allelic variants. The human gene encoding biotinidase consists of four exons, designated 1-4, with sizes of 79 bp, 265 bp, 150 bp, and 1502 bp, respectively [Knight et al 1998]. Intron 1, separating exons 1 and 2, is at least 12.5 kb; intron 2 is 6.2 kb, and intron 3 is 0.7 kb. Two putative translation initiation codons exist in the gene; one is encoded within exon 1 and the other within exon 2, which contains the N-terminal methionine of the mature enzyme. The presence of an intron between the two possible initiation codons could allow for alternative splicing, which could produce transcripts encoding a protein with a 41- or a 21-residue signal peptide.

The nucleotide sequence upstream of exons 1 and 2 has been examined for putative promoter elements. Promoter features identified from -600 to +400 are consistent with the ubiquitous expression of biotinidase with characteristics of a CpG island, lack of a TATA element, six consensus methylation sites, and three initiator (Inr) sequences, which are thought to be important in transcription initiation of TATA-less promoters. A consensus sequence for the liver-specific transcription factor HNF-5 is present at -352. The nucleotide sequence 5' of exon 2, which contains the second putative ATG initiation codon, has features associated with housekeeping genes but does contain a consensus sequence for the liver-specific transcription factor C/EBP within 300 bp of the 5' end of exon 2.

Normal allelic variants have been found among individuals with normal biotinidase activity.

Pathogenic allelic variants. Pindolia et al [2010] have compiled mutations causing biotinidase deficiency.

A new continually updated database of current mutations has been established [Procter et al 2013]. See www.arup.utah.edu.

Approximately 100 mutations have been described in symptomatic children with profound biotinidase deficiency, including the following [Pomponio et al 1997a, Muhl et al 2001, Wolf et al 2002a]:

Multiple mutations have been reported in children identified by newborn screening who had profound biotinidase deficiency [Norrgard et al 1999]. Of this group, two mutations occurred most commonly:

  • A p.Gln456His missense mutation
  • p.[Ala171Thr;Asp444His] [Norrgard et al 1997, Norrgard et al 1998]:
    • p.[Ala171Thr;Asp444His] (p.Asp444His in cis configuration with the p.Ala171Thr mutation) results in a profound biotinidase deficiency allele.
    • An allele with the double mutation combined with a second allele for profound biotinidase deficiency causes profound biotinidase deficiency.
    • Individuals who are compound heterozygous for the p.Asp444His mutation and a mutation that results in profound biotinidase deficiency are expected to have approximately 20%-25% of mean normal serum biotinidase activity (i.e., partial biotinidase deficiency) [Swango et al 1998].
    • Individuals who are homozygous for the p.Asp444His mutation are expected to have approximately 50% of mean normal serum biotinidase deficiency. This is similar to the activity of heterozygotes for profound biotinidase deficiency.

Several of these pathogenic allelic variants are included in OMIM 253260 (see Table B).

Table 2. Selected BTD Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.98_104delinsTCC
(G98del3ins)
p.Cys33PhefsTer36NM_000060​.2
NP_000051​.1
c.511G>Ap.Ala171Thr
c.1330G>Cp.Asp444His
c.1368A>Cp.Gln456His
c.1612C>Tp.Arg538Cys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Biotinidase is essential for the recycling of the vitamin biotin [Wolf et al 1985a]. Biotinidase has been shown to have biotinyl-hydrolase and biotinyl-transferase activities (see Abnormal gene product) [Hymes & Wolf 1996].

The cDNA for human biotinidase from a human cDNA hepatic library has two possible ATG initiation codons and an open reading frame of 1629 bp, relative to the first ATG codon [Cole et al 1994]. The cDNA encodes for a mature protein of 543 amino acids with a molecular mass of 56,771 d. The amino terminus of the mature serum biotinidase is in the same reading frame with both of the ATG codons, consistent with the two putative signal peptides.

Northern blot analysis, using a 2000-bp probe consisting of the cDNA sequence, revealed that the biotinidase message is present in human lung, liver, skeletal muscle, kidney, pancreas, heart, brain, and placenta under the hybridization conditions used.

The author and several other investigators have purified human biotinidase to homogeneity from plasma [Craft et al 1985, Chauhan & Dakshinamurti 1986, Wolf et al 1987]. The enzyme is a monomeric sialylated glycoprotein with a molecular weight of 76-77 kd. Normal serum or plasma biotinidase has at least nine isoforms (four major and five minor isoforms) between pH 4.15 and 4.35 observed by isoelectric focusing [Hart et al 1991].

There are six potential N-linked glycosylation sites (N-X-T/S) in the deduced amino acid sequence. Glycosylation of the protein could increase its mass by 13 to 19 kd; the molecular mass of the glycosylated enzyme is thus estimated at between 70 and 76 kd, which is consistent with that of the glycosylated serum enzyme reported by the author's laboratory and other investigators [Craft et al 1985, Chauhan & Dakshinamurti 1986, Wolf et al 1987, Oizumi et al 1989]. Most of the microheterogeneity observed on isoelectric focusing results from differences in the degree of sialylation.

Biotinidase is a thiol enzyme that migrates to the α1-region on agarose electrophoresis. The serum enzyme has a pH optimum of 5-6 when biocytin or biotinyl-p-aminobenzoate (artificial substrate) is the substrate [Pispa 1965, Craft et al 1985, Chauhan & Dakshinamurti 1986]. Biocytin is cleaved more readily than larger biotinyl-peptides [Craft et al 1985]. Biotinidase apparently does not cleave biotin from intact holocarboxylases at acid pH. The biotinyl-binding site of biotinidase is specific for the ureido group of the biotinyl moiety of various substrates [Knappe et al 1963, Chauhan & Dakshinamurti 1986]. Biotinidase plays a role in the processing of dietary protein-bound biotin [Heard et al 1984, Wolf et al 1985a] and has recently been shown to transfer biotin from biocytin to nucleophiles, such as histones [Hymes et al 1995]; the physiologic significance of the latter activity is not known.

Abnormal gene product. Biotinidase is essential for the recycling of the vitamin biotin [Wolf et al 1985a]. Biotinidase has been shown to have biotinyl-hydrolase and biotinyl-transferase activities [Hymes & Wolf 1996]:

  • Biotinyl-hydrolase activity. Hymes and Wolf [1996] have determined that both the polyclonal and monoclonal antibodies react on immunoblot with biotinidase in extracts of normal fibroblasts and lymphoblasts. These antibodies react with normal serum biotinidase that has been sialylated by treatment with neuraminidase. Individuals with profound biotinidase deficiency can be classified into at least nine distinct biochemical phenotypes on the basis of the presence or absence of cross-reacting material (CRM) to biotinidase, the number of isoforms, and the distribution frequency of the isoforms. All CRM-positive individuals had normal-size serum biotinidase on SDS-immunoblots. None of the individuals with CRM had an abnormal Km of the substrate for the enzyme. No relationship exists between the age of onset or severity of symptoms and the isoform patterns or CRM status of the symptomatic children. The isoform patterns of children identified by newborn screening are not different from those of symptomatic children.
    Hart et al [1992b] have performed biochemical and immunologic characterization of biotinidase in sera from children with partial biotinidase deficiency. All individuals had CRM in their sera. Individuals with partial biotinidase deficiency can be classified into six distinct biochemical phenotypes on the basis of the number of isoforms and the distribution frequency of the isoforms. Kinetic studies were performed on samples from these individuals and were found to be normal in all cases. The isoform patterns observed in the individuals with partial biotinidase deficiency were not different from those of individuals with profound biotinidase deficiency who had CRM.
  • Biotinyl-transferase activity. More than 100 children with profound biotinidase deficiency were assessed for biotinyl-transferase activity and the presence of CRM to antibodies prepared against purified serum biotinidase [Hymes et al 1995]. Sera from all of the symptomatic individuals studied (both CRM-negative and CRM-positive) had no biotinyl-transferase activity. Sera from children detected by newborn screening who were CRM-negative had no biotinyl-transferase activity, whereas a large group of the CRM-positive children had varying degrees of transferase activity. Statistically, a significant difference in biotinyl-transferase activity exists between the population of symptomatic enzyme-deficient children and the population of children who were identified by newborn screening. Hart et al [1992a] have previously shown a difference in the biotinyl-hydrolase activity between the symptomatic and newborn screening group. The significance of these differences is not yet known. These differences may indicate variations in the domains of the enzyme resulting from different mutations. The authors do not know if all children with profound biotinidase deficiency who are detected by newborn screening will become symptomatic. Transfer of biotin to histones, which may represent a physiologic function, may ultimately be a criterion for determining which children with profound enzyme deficiency are likely to become symptomatic.

References

Published Guidelines/Consensus Statements

  1. Cowan TM, Blitzer MG, Wolf B; Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee. Technical standards and guidelines for the diagnosis of biotinidase deficiency. Available online. Accessed 11-27-13. [PubMed: 20539236]

Literature Cited

  1. Baykal T, Gokcay G, Gokdemir Y, Demir F, Seckin Y, Demirkol M, Jensen K, Wolf B. Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. J Inherit Metab Dis. 2005;28:903–12. [PubMed: 16435182]
  2. Burton BK, Roach ES, Wolf B, Weissbecker KA. Sudden death associated with biotinidase deficiency. Pediatrics. 1987;79:482–3. [PubMed: 3822661]
  3. Chalmers RA, Mistry J, Docherty PW, Stratton D. First trimester prenatal exclusion of biotinidase deficiency. J Inherit Metab Dis. 1994;17:751–2. [PubMed: 7707701]
  4. Chauhan J, Dakshinamurti K. Purification and characterization of human serum biotinidase. J Biol Chem. 1986;261:4268–75. [PubMed: 3949811]
  5. Chedrawi AK, Ali A, Al Hassnan ZN, Faiyaz-Ul-Haque M, Wolf B. Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol. 2008;23:1043–8. [PubMed: 18645204]
  6. Cole H, Reynolds TR, Lockyer JM, Buck GA, Denson T, Spence JE, Hymes J, Wolf B. Human serum biotinidase. cDNA cloning, sequence, and characterization. J Biol Chem. 1994;269:6566–70. [PubMed: 7509806]
  7. Cowan TM, Blitzer MG, Wolf B. Technical standards and guidelines for the diagnosis of biotinidase deficiency. Genet Med. 2010;12:464–70. [PubMed: 20539236]
  8. Cowan TM, Kazerouni NN, Dharajiya N, Lorey F, Roberson M, Hodgkinson C, Schrijver I. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012;106:485–7. [PubMed: 22698809]
  9. Craft DV, Goss NH, Chandramouli N, Wood HG. Purification of biotinidase from human plasma and its activity on biotinyl peptides. Biochemistry. 1985;24:2471–6. [PubMed: 3925986]
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  11. Grunewald S, Champion MP, Leonard JV, Schaper J, Morris AA. Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics. 2004;35:211–6. [PubMed: 15328559]
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  14. Hart PS, Hymes J, Wolf B. Biochemical and immunological characterization of serum biotinidase in partial biotinidase deficiency. Pediatr Res. 1992b;31:261–5. [PubMed: 1561012]
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  23. McVoy JR, Levy HL, Lawler M, Schmidt MA, Ebers DD, Hart PS, Pettit DD, Blitzer MG, Wolf B. Partial biotinidase deficiency: clinical and biochemical features. J Pediatr. 1990;116:78–83. [PubMed: 2295967]
  24. Möslinger D, Mühl A, Suormala T, Baumgartner R, Stöckler-Ipsiroglu S. Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies. Eur J Pediatr. 2003;162 Suppl 1:S46–9. [PubMed: 14628140]
  25. Möslinger D, Stockler-Ipsiroglu S, Scheibenreiter S, Tiefenthaler M, Muhl A, Seidl R, Strobl W, Plecko B, Suormala T, Baumgartner ER. Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr. 2001;160:277–82. [PubMed: 11388594]
  26. Muhl A, Moslinger D, Item CB, Stockler-Ipsiroglu S. Molecular characterisation of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation. Eur J Hum Genet. 2001;9:237–43. [PubMed: 11313766]
  27. Neto EC, Schulte J, Rubim R, Lewis E, DeMari J, Castilhos C, Brites A, Giugliani R, Jensen KP, Wolf B. Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. Braz J Med Biol Res. 2004;37:295–9. [PubMed: 15060693]
  28. Norrgard KJ, Pomponio RJ, Hymes J, Wolf B. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999;46:20–7. [PubMed: 10400129]
  29. Norrgard KJ, Pomponio RJ, Swango KL, Hymes J, Reynolds T, Buck GA, Wolf B. Double mutation [A171T and D444H] is a common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Hum Mutat. 1998;11:410. [PubMed: 10206677]
  30. Norrgard KJ, Pomponio RJ, Swango KL, Hymes J, Reynolds TR, Buck GA, Wolf B. Mutation (Q456H) is the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Biochem Mol Med. 1997;61:22–7. [PubMed: 9232193]
  31. Oizumi J, Hayakawa K, Hosoya M. Comparative study on human milk and serum biotinidase. Biochimie. 1989;71:1163–9. [PubMed: 2517477]
  32. Pindolia K, Jordan M, Wolf B. Analysis of mutations causing biotinidase deficiency. Hum Mutat. 2010;31:983–91. [PubMed: 20556795]
  33. Pispa J. Animal biotinidase. Ann Med Exp Biol Fenn. 1965;43 Suppl 5:1–39. [PubMed: 5867120]
  34. Pomponio RJ, Hymes J, Reynolds TR, Meyers GA, Fleischhauer K, Buck GA, Wolf B. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res. 1997a;42:840–8. [PubMed: 9396567]
  35. Pomponio RJ, Norrgard KJ, Hymes J, Reynolds TR, Buck GA, Baumgartner R, Suormala T, Wolf B. Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children. Hum Genet. 1997b;99:506–12. [PubMed: 9099842]
  36. Pomponio RJ, Reynolds TR, Cole H, Buck GA, Wolf B. Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency. Nat Genet. 1995;11:96–8. [PubMed: 7550325]
  37. Procter M, Wolf B, Crockett DK, Mao R. The Biotinidase Gene Variants Registry: A Paradigm Public Database. G3 (Bethesda). 2013 Mar 11. pii: g3.113.005835v1. [PMC free article: PMC3618359] [PubMed: 23550138]
  38. Ramaekers VT, Brab M, Rau G, Heimann G. Recovery from neurological deficits following biotin treatment in a biotinidase Km variant. Neuropediatrics. 1993;24:98–102. [PubMed: 8352834]
  39. Ramaekers VT, Suormala TM, Brab M, Duran R, Heimann G, Baumgartner ER. A biotinidase Km variant causing late onset bilateral optic neuropathy. Arch Dis Child. 1992;67:115–9. [PMC free article: PMC1793569] [PubMed: 1739323]
  40. Salbert BA, Astruc J, Wolf B. Ophthalmologic findings in biotinidase deficiency. Ophthalmologica. 1993a;206:177–81. [PubMed: 8278163]
  41. Salbert BA, Pellock JM, Wolf B. Characterization of seizures associated with biotinidase deficiency. Neurology. 1993b;43:1351–5. [PubMed: 8327137]
  42. Secor McVoy JR, Heard GS, Wolf B. Potential for prenatal diagnosis of biotinidase deficiency. Prenat Diagn. 1984;4:317–8. [PubMed: 6483793]
  43. Sivri HS, Genc GA, Tokatli A, Dursun A, Coskun T, Aydin HI, Sennaroglu L, Belgin E, Jensen K, Wolf B. hearing loss in biotinidase deficiency: genotype-phenotype correlation. J Pediatr. 2007;150:439–42. [PubMed: 17382128]
  44. Suormala T, Wick H, Bonjour JP, Baumgartner ER. Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample. Clin Chim Acta. 1985;145:151–62. [PubMed: 3918814]
  45. Suormala TM, Baumgartner ER, Wick H, Scheibenreiter S, Schweitzer S. Comparison of patients with complete and partial biotinidase deficiency: biochemical studies. J Inherit Metab Dis. 1990;13:76–92. [PubMed: 2109151]
  46. Swango KL, Demirkol M, Huner G, Pronicka E, Sykut-Cegielska J, Schulze A, Mayatepek E, Wolf B. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet. 1998;102:571–5. [PubMed: 9654207]
  47. Taitz LS, Leonard JV, Bartlett K. Long-term auditory and visual complications of biotinidase deficiency. Early Hum Dev. 1985;11:325–31. [PubMed: 4054050]
  48. Tokatli A, Coskun T, Ozalp I. Biotinidase deficiency with neurological features resembling multiple sclerosis. J Inherit Metab Dis. 1997;20:707–8. [PubMed: 9323568]
  49. Wastell H, Dale G, Bartlett K. A sensitive fluorimetirc rate for biotinidase using a new derivative of biotin, biotinyl-6-aminoquinoline. Anal Biochem. 1984;140:69–73. [PubMed: 6548338]
  50. Wastell HJ, Bartlett K, Dale G, Shein A. Biotinidase deficiency: a survey of 10 cases. Arch Dis Child. 1988;63:1244–9. [PMC free article: PMC1779020] [PubMed: 3196050]
  51. Weber P, Scholl S, Baumgartner ER. Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol. 2004;46:481–4. [PubMed: 15230462]
  52. Weissbecker KA, Nance WE, Eaves LJ, Piussan C, Wolf B. Statistical approaches for the detection of heterozygotes for biotinidase deficiency. Am J Med Genet. 1991;39:385–90. [PubMed: 1877614]
  53. Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis. 1991;14:923–7. [PubMed: 1779651]
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  55. Wolf B. Disorders of biotin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7 ed. New York, NY: McGraw-Hill; 1995:3151-77.
  56. Wolf B. Children with profound biotinidase deficiency should be treated with biotin regardless of their residual enzyme activity or genotype. Eur J Pediatr. 2002;161:167–8. [PubMed: 11998918]
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Suggested Reading

  1. Procter M, Mao R, Wolf B. ARUP Online Scientific Resource: Biotinidase Deficiency and BTD. Available online. Accessed 11-27-13.
  2. Wolf B. Disorders of biotin metabolism: treatable neurological syndromes. In: Rosenberg R, DiMauro S, Paulson HL, Ptacek L, Nestler EJ, eds. The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. Philadelphia, PA: Wolters Kluwer-Lippincott Williams and Wilkins; 2001:739-45.

Chapter Notes

Author Notes

The author's laboratory was the first to describe biotinidase deficiency in individuals with late-onset multiple carboxylase deficiency and has characterized the clinical, biochemical, and molecular features of the disorder. They developed the method used to screen newborns for biotinidase deficiency and piloted the first newborn screening for the disorder. They currently confirm the diagnosis of the enzyme deficiency in a majority of children in the United States and collaborate with laboratories in the US and around the world in determining the mutations that cause profound and partial biotinidase deficiency. Dr. Wolf's laboratory accepts DNA from children with biotinidase deficiency for molecular genetic testing on an experimental basis. He is also currently studying the outcomes of children with biotinidase deficiency identified by newborn screening.

Biotinidase Deficiency: A Booklet for Families and Professionals
by DL Thibodeau, MS, and B Wolf, MD, PhD
Available on request from Barry Wolf
Email: gro.shfh@1flowb

Revision History

  • 5 December 2013 (me) Comprehensive update posted live
  • 15 March 2011 Comprehensive update posted live
  • 25 September 2008 (me) Comprehensive update posted live
  • 2 March 2006 (me) Comprehensive update posted to live Web site
  • 10 February 2005 (bw,cd) Revision: targeted mutation analysis clinically available
  • 26 November 2003 (me) Comprehensive update posted to live Web site
  • 27 September 2001 (me) Comprehensive update posted to live Web site
  • 24 March 2000 (pb) Review posted to live Web site
  • December 1999 (bw) Original submission
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