StemCell Therapy

Summary Clinical 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.

The diagnosis of biotinidase deficiency is established in a proband whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on either detection of deficient biotinidase enzyme activity in serum/plasma OR identification of biallelic pathogenic variants in BTD on molecular genetic testing.

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 continuously lifelong.

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.

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 options if the pathogenic variants in the family are known.

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

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

Virtually 100% of infants with either profound biotinidase deficiency or partial biotinidase deficiency can be detected in the US by newborn screening (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:

Children or adults with untreated profound biotinidase deficiency usually exhibit one or more of the following non-specific features (which are also observed in 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

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 manifestations are mild and occur only when the person is stressed, such as with a prolonged infection.

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 in individuals with biotinidase deficiency who are symptomatic.

Hyperammonemia

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

Biotinidase enzyme activity in serum. 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] (full text).

Molecular genetic testing 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.

Molecular Genetic Testing Used in Biotinidase Deficiency

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Test characteristics. See Clinical Utility Gene Card [Kry et al 2012] for information on test characteristics including sensitivity and specificity.

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

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 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.

Many symptomatic children with biotinidase deficiency exhibit a variety of central nervous system abnormalities on brain MRI or CT [Wolf et al 1983b, Wastell et al 1988, Lott et al 1993, Salbert et al 1993b, Grnewald 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 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 2002].

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

Respiratory problems including 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].

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].

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 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.

Genotype/phenotype correlations are not well established. Deletions, insertions, or nonsense variants 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 variants, even if not treated for a period of time [Sivri et al 2007].

Certain genotypes correlate with complete biotinidase deficiency and others 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 develop symptoms if not treated with biotin.

Partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity)

Heterozygotes

Individuals with one profound or one partial biotinidase deficiency BTD variant are carriers of biotinidase deficiency and do not exhibit symptoms [B Wolf, personal observation]. Such individuals do not require biotin therapy.

Individuals who are homozygous for the p.Asp444His pathogenic variant are expected to have approximately 45%-50% of mean normal serum biotinidase enzyme activity (which is similar to the activity of heterozygotes for profound biotinidase deficiency) and do not require biotin therapy.

Almost 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.

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 (see Differential Diagnosis), previously refered to as early-onset or infantile multiple or combined carboxylase deficiency.

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.

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 (e.g., isolated carboxylase 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 deficiency, or essential fatty acid deficiency. See .

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, propionyl-CoA (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; however, it is important to know the method used for determining the biotin concentration 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 holocarboxylase synthetase deficiency:

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 (OMIM). 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 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:

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.

To establish the extent of disease and needs in a symptomatic 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 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 following newborn screening, the following evaluations are recommended:

Physical examination for neurologic findings (e.g., hypotonia, ataxia), eye findings (e.g., conjunctivitis), skin findings (eczematous rash, alopecia), breathing abnormalities (e.g., stridor) and fungal infections caused by immunologic dysfunction (thrush and/or candidiasis).

Evaluation for psychomotor deficits

Evaluation for sensorineural hearing loss

Ophthalmologic examination (for finding such as optic atrophy)

Consultation with a metabolic specialist or clinical geneticist

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Biotinidase Deficiency - GeneReviews - NCBI Bookshelf

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