Biotinidase deficiency

Profound biotinidase deficiency, the more severe form of the condition, can cause seizures, weak muscle tone (hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis. Affected children also have delayed development. Lifelong treatment can prevent these complications from occurring or improve them if they have already developed.


, skin rash, candid
asis).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/testingThe diagnosis of biotinidase deficiency is est

lished in
proband whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on either detection o

deficient biotinidas
enzyme activity in serum/plasma OR identification of biallelic pathogenic variants in BTD on molecular genetic testing.ManagementTreatment of manifestations: All symptomatic children with profound biotinidase defi

ency 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 p oblems may benefit from vision aids; those with hearing loss will usually benefit from hearing aids or cochlear implants, and th se 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 continuously

felong.

Surveilla
ce: 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 prote n 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 aff cted sibs can be instituted in a timely manner.


Genetic counseling

Biotinidase deficiency is inherited

n 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 atrisk family members and prenatal testing for preg ancies at increased risk are options if the pathogenic variants in the family are known.


Diagnosis

Clinical issues and frequently asked questions regarding biotinidase deficiency have been addressed in a review [Wolf 2010].

Suggestive Findings

Biotinidas
deficiency should be suspected in infants with positive newborn s reening results, untreated individuals with clinical findings, and persons with suggestive preliminary laboratory findings [Wolf 2012]:


Positive Newborn Screening Results

Virtually 100% of infants with either profound biotinidase deficiency or partial biotinidase deficiency can be detected in the US by ne

National Newborn Screening
tatus Report).

Newborn screening utilizes a small amount of blood obtained from a heel prick for a colorimetric test for biotinidase activity:

• False positive test results may occur in pre ature infants and in samples placed in plastic prior to sufficient drying.• Measurement of biotinidase enzyme activity in serum/plasma is warranted in infants whose initial screening tests are abnormal.


Clinical Findings

Children or adults with untreated profound biotinidase deficiency usually exhibit one or more of the following nonspecific features (which are also observed in many other inherited metabolic disorde s):

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

Features more specific to profound biotinidase deficiency include the following • Eczematous skin rash
• Alopecia • Conjunctivitis • Candidiasis • Ataxia
Older children and adolescents may exhibit limb weakness, paresis, and scotomata.Some have exhibited findings suggestive of a myelopathy and have been initially incorrectly diagnosed and treated as having another disorder before biotinidase deficiency is correctly diagnosed [Wolf 2015].

Children or adults with untreated partial biotinidase deficiency may exhibit any of the above signs and symptoms, but the manifestatio s are mild and occur only when the person is stressed, such as with a prolonged infection.


Preliminary Laboratory Findings

The following findings are sugggestive of biotinidase deficiency:

• Metabolic ketolactic acidosis • Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency; however, 3-hydroxyisovalerate may be the only metabolite present).Note: Urinary organic acids can be normal even

individuals with biotinidase deficiency who a
e symptomatic.


• Hyperammonemia


Establishing the Diagnosis

The diagnosis of biotinidase deficiency is established in a proband whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on EITHER of the following:

• Detection of deficient biotinidase enzyme activity in serum/plasma • Identification of biallelic pathogenic variants in BTD on molecular genetic testing (Table 1) when the results of

nzymatic testing are ambiguous (
.g., in differentiating profound biotinidase deficiency from partial biotinidase deficiency and in differentiating heterozygosity for profound biotinidase deficiency from partial biotinidase deficiency)

Biotinidase enzyme activit in serum.The working group of the American College of Medical Genetics Laboratory Quality Assurance Committee has established technical stan ards and guidelines for the diagnosis of biotinidase deficiency [Cowan et al 2010] (full text).

• Profound biotinidase deficiency: <10% mean normal serum biotinidase activity

• Partial biotinidase deficiency: 10%-30% of mean normal serum biotinidase activity Note: (1) 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 inte pretation of enzymatic results [Neto et al 2004].

(2) 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 test ng is performed by single-gene testing.Sequence analysis of BTD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.


Clinical Characteristics Clinical Description

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 developm nt [Möslinger et al 2001, Weber et al 2004] (see also Management, Prevention of Primary Manifestations).Neurologic problems occur nly in those individuals with biotinidase deficiency who have recurrent symptoms and meta olic compromise prior to biotin treatment.


Profound Biotinidase Deficiency

Early onset.Symptoms of untreated profound biotinidase deficiency (<10 mean normal serum biotinidase activity) usually appear between ages one week and ten years, with a mean age of three and one-half months [Wolf et al 1985b].

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

The most common neurologic features in individuals with untreated, profound biotinidase deficiency are seizures and hypotonia [Wolf et al 1983a, Wolf et al 1985b, Wastell et al 1988, Wolf 1995, Wolf 2011].The seiz

es are usually myoclonic but ma
be grand mal and focal; some children have infantile spasms [Salbert et al 1993b].Some untreated children have exhibited spinal cord involvement characterized by prog essive spastic paresis and myelopathy [Chedrawi et al 2008].Older affected children often have ataxia and developmental delay.

Many symptomatic children with biotinidase deficiency exhibit a variety of central nervous system abnormalities on

ain MRI or CT [Wolf et al 1983b,
Wastell et al 1988, Lott et al 1993, Salbert et al 1993b, Grünewald et al 2004].These findings may improve or become normal after biotin treatment.

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 child en with profound biotinidase deficiency have sensorineural hearing loss that usually does not resolve or improve but remains static with biotin treatment [Wolf et al 2002].

Cutaneous manifestations include skin rash, alopecia, and recurrent viral or fungal infections caused by immunologic dysf nction.

Respiratory problems including hyperventilation, laryngeal stridor, and apnea can occur.

One death init ally thought to be caused by sudden infant death syndrome was subsequently attr buted to biotinidase deficiency [Burton et al 1987].


Late onset.

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, Wolf 2015].


Partial Biotinidase Deficiency

Individuals with partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection.

One child with part al 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.


Genotype-Phenotype Correlations

Genotype/phenotype correlations are not well established.Deletions, insertion

or nonsense v
riants usually result in complete absence of biotinidase enzyme activity, whereas missense variants 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.

Although genotype-phenotype correlations are not well established, in one study, children with symptoms of profound biotinidase deficiency with null variants were more likely to develop hearing loss than those with missense v

iants, even
if not treated for a period of time [Sivri et al 2007].

Certain genotypes correlate with complete biotinidase deficiency and other with partial biotinidase deficiency.

Profound biotinidase deficiency (<10% mean normal serum biotinidase activity):

• Most BTD pathogenic variants 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 profound biotinidase deficiency.Affected individuals are likely to develo

symptoms if n
t treated with biotin.• Several adults with profound biotinidase deficiency have never had s mptoms and have never been treated [Wolf et al 1997] whereas some children with the same pathogenic variants have been symptomatic.Therefore, it has bee speculated that some children with profound biotinidase deficiency may exhibit mild or no symptoms if left untreated.Nonetheless, it is recommended that such children be treated [Möslinger et al 2003].

Partial bi

inidase def
ciency (10%-30% of mean normal serum biotinidase activity)

• Compound heterozygotes for the p.Asp444His pathogenic v riant and a pathogenic variant that results in profound biotinidase deficiency are expected to have approximately 20%-25% of mean normal serum biotinidase enzyme activity [Swango et al 1998].


Hete ozygotes

• Individuals with one profound or one partial biotinidase deficiency BTD variant are carriers of biotinidase deficiency and do n t exhibit symptoms [B Wolf, personal observation].Such individuals do not require biotin therapy.• Individuals who are homozygous for the p.
sp444His pathogenic variant are expected to have approximately 45%-50% of

ean normal serum biotinidase enzyme acti
ity (which is similar to the activity of heterozygotes for profound biotinidase deficiency) and do not require biotin th

apy.


Penetrance

Almo
t all children with profound biotinidase deficiency become symptomatic or are at risk of becoming symptomatic if not treated.

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].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 th s 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 holocarboxy ase synthetase deficiency (see Differential Diagnosis), previously refered to as 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, S udi 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.


Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in BTD.


Differential Diagnosis

Clinical features including vomiting, hypotonia, and seizures accompanied by metabolic ketolactic acidosis or mild hy erammonemia are often observed in inherited metabolic diseases.Individuals with biotinidase deficiency may exhibit clinical features that are misdiagnosed as other disorders (e.g., isolated arboxylase deficiency) before they are correctly identified [Suormala et al 1985, Wolf & Heard 1989].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 deficie cy, or essential fatty acid deficiency.See Figure 1.

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 bio inidase deficiencies from holocarboxylase synthetase deficiency; however, it is important to know the method used for determining the biotin co centration as 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 h locarboxylase synthetase deficiency:

• Beta-hydroxyisovalerate is the most commonly elevated urinary metabolite in biotinidase deficiency, holocarboxylase synthetase deficiency (OMIM 253270), isolated beta-methylcrotonyl-CoA carboxylase deficiency (OMIM PS210220), and acquired biotin deficiency.• In addition to beta-hydroxyisovalerate, elevated concentrations of urinary lactate, methylcitrate, and betahydroxypropionate are indicative of the multiple carboxylase deficiencies, including the above disorders and propionic acidemia and pyruvate carbox lase deficiency.

The multiple carboxylase deficiencies are biotin responsive, whereas t e 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 (OMIM 253270).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.

The symptoms of biotinidase deficiency and holocarboxylase synthe

d clinical differentiation is often difficult.

The
age of onset of symptoms may be useful for distinguishing between holocarboxylase synthetase deficiency and biotinidase deficiency.Holocarboxylase syntheta e 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 Defic ency

• Biotinidase enzyme 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.


Management Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a symptomatic individual diagnosed with biotinidase deficiency, the following eva

ations are recommended:

• H
story 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 psychomotor deficits • Evaluation for sensorineural hearing loss • Ophthalmologic examination • Identification of cellular immunologic abnormalities because of the increased risk of recurrent viral or fungal infections caused by immunologic dysfunction • Consultation with a metabolic specialist or clinical geneticist To establish the extent of disease and needs in infants or children diagnosed with biotinidase deficiency followi

tion for sensorineural hearing loss •
Ophthalmologic examination (for finding such as optic atrophy) • Consultation with a metabolic specialist or clinical geneticist


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 hyperam onemia.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 ma y 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 coc lear implants, and appropriate interventions for developmental deficits.


Prevention of Primary Manifestations

All individuals with profound biotinidase deficiency (<10% mean normal enzyme activity), even those who have some residual biotinidase enzyme activity, should be treated with biotin independent of their genotype [Wolf 2003].Note: Although Möslinger et al [2003] stated that children 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 deve op 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.

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

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 dispen ed as a tablet or a capsule (most of which is filler: the quantity of biotin 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 n pple, 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 rapid y resolve after biotin treatment, followed b

improvement o
the cutaneous abnormalities.Hair growth retur s 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 iotin, children with partial deficiency are usually treated with 1-10 mg oral biotin per day.

Biotin therapy is lifelong.The e are no known adverse side effects from pharmacologic doses of biotin.In fact, the major problem is the lack of treatme

or non-compliance with prescr
bed treatment.

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

necdotally, two girls with profo
nd 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.


Surveillance

For all children with biotin dase 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 clinical geneticist or metabol c 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 subspecialists:

• 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 o

urine is not useful e
cept 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 avid

, rendering it incapable of bi
ding biotin.)


Evaluation of Relatives at Risk

A newborn with an older sib with biotinidase deficiency should be treated at birth with biotin pending results of the definitive biotinidase enzyme activity assay and/or molecula

genetic testing (if
the BTD pathogenic variants in the family are known).

The genetic status of older sibs (even if asymptomatic) of a child with biotinidase deficiency should be clarified by assay of biotinidase enzyme activity or molecular genetic testing (if the BTD pathogenic variants in the family are known) so that biotin therapy can be instituted in a timely manner.

The genetic status of any relative with symptoms consistent with biotinidase deficiency should be clarified by assay of biotinidase enzyme activity or molecular genetic testing (if th

BTD pathogenic varia
ts in the family are known) so that biotin therapy can be instituted i

etic Counseling for i
sues 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 de

ciency or is at ri
k 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 in the US and EU Clinical Trials Register in Europe 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 Couns

ing

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

Bioti idase deficiency is inherited in an autosomal recessive manner.

Biotinidase Deficiency


Risk to Family M

bers

Parents of a proband

• The
parents of a child with biotinidase deficiency are obligate heterozygotes (i.e., carriers of one BTD pathogenic variant).• Heterozygotes are symptomatic and are not at risk of developing the disorder.


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

Heterozygotes (carriers) are asym
tomatic and are not at risk of developing the disorder.


Offspring of a proband

• All offspring of an individual with biotinidase deficiency are

bligate heterozy
otes (carriers) for a BTD pathogenic variant.• 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 a BTD pathogenic variant.• Based on a carrier frequency of approximately one in 120 in the general population [Wolf 1991], the empiric risk to an i dividual 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 (Heterozygote) Detection

Molecular genetic testing.Carrier testing for at-risk relatives requires prior id

tification of the BTD pathogenic variants in the fami
y.

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 BTD pathogenic variants in the family have been identified, molecular testing is preferred.


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.


Fa ily 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

f being ca
riers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.


Pren

al Testing and Prei
plantation Genetic Testing

Molecular genetic testing.Once the BTD pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for biotinidase deficiency are possible.

Enzyme activity.Prenatal testing for pregnancies at increased risk for biotinidase deficiency is possible through measurement of biotinidase enzyme activity in cultured amniotic fluid cells and in amniotic fluid obtained by amniocentesis [Secor McVoy et al 1984, Chalmers et al 1994].In the United States, molecular prenatal testing is available and preferred.

Diffe ences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the esting is being considered for the purpose of pregnancy termination rather than early diagnosis.While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


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.

• Biotinidase Deficiency Family Support Group Email: volk4olks@aol.com


• Medical Home Portal

The Parents & Families section of the Medical Home Portal provides information and resources to help families learn how to better care for a child with chronic and complex conditions and to become more effective partners in their child's care.GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org).See Quic Reference for an explanation of nomenclature.

1. Variant designation that does not conform to curre

ons.

Normal
ene 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 BTD cDNA 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.BTD is expressed in human lung, liver, skeletal muscle, kidney, pancreas, heart, brain, and placenta.The enzyme is a monomeric sialylated glycoprotein with multiple isoforms resulting from differences in the degree of sialylation [Hart et al 1

1].

Abn
rmal gene product.Loss of biotinidase activity is associated with disease [Hymes & Wolf 1996].

Figure 1 .
1
Figure 1.The biotin cycleFree 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, propionyl-CoA carboxylase (PCC), beta-methylcrotonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), and acetyl-CoA carboxylase (ACC) by the action of biotin holocarboxylase synthetase, thereby forming active holocarboxylases.The holocarboxylases are subsequently proteolyzed to biocytin and/or biotinyl-peptides which are then further cleaved by biotinidase, thus recycling the bio in.The liberated biotin can then enter the free biotin pool.Isolated deficiencies f each of the carboxylases and deficiencies of both holocarboxylase synthetase and biotinidase can o