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 development. Symptoms including seizures, developmental delay, cutaneous manifestations (skin rash, alopecia), optic atrophy, hearing loss, and respiratory problems occur only in those individuals with biotinidase deficiency prior to biotin treatment. Symptoms of untreated profound biotinidase deficiency (<10% mean normal serum biotinidase activity) usually appear between ages one week and ten years, typically with optic atrophy, hypotonia, seizures, hair loss, and skin rash. Affected children often have ataxia and developmental delay. Individuals with partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection. Some symptoms, such as feeding issues, cutaneous manifestations, and respiratory issues, usually resolve with biotin therapy, whereas other manifestations presenting prior to biotin treatment, such as optic atrophy, hearing loss, and developmental delay, may improve but are usually not completely reversible with the initiation of biotin therapy. Untreated adolescents and adults usually exhibit myelopathy and optic neuropathy and are often initially diagnosed with multiple sclerosis. Most of these individuals experience improvement in their symptoms with biotin supplementation.

Diagnosis/testing.

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 when the results of enzymatic testing are ambiguous

Management.

Treatment of manifestations: All individuals with profound biotinidase deficiency (<10% mean normal serum enzyme activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated with oral biotin in the free form as opposed to the protein-bound form; biotin therapy is lifelong.

Targeted therapy: Oral biotin of 5-10 mg/day for those who have <10% mean normal serum enzyme activity and 2.5-10 mg/day in those who have 10%-30% of mean normal serum enzyme activity.

Supportive care in symptomatic individuals: Hydration and bicarbonate in those with metabolic decompensation and acidosis, although biotin therapy can rapidly resolve the metabolic derangements within hours to days; supportive developmental therapies and educational resources for those with developmental delay; subspecialist ophthalmologic care for those with optic atrophy; hearing aids and, if severe, consideration of cochlear implants for those with hearing loss.

Prevention of primary manifestations: Adherence to biotin therapy can prevent symptom development, and also improves symptoms in symptomatic individuals.

Surveillance: Evaluation by a clinical geneticist or metabolic specialist annually for those with profound biotinidase deficiency and every two years for those with partial biotinidase deficiency. If symptoms return with biotin therapy, consider obtaining urine organic acids analysis to evaluate for non-adherence to biotin therapy. Measurement of growth parameters, assessment for new manifestations (seizures, changes in tone, movement disorders), monitoring of developmental progress and educational needs, and assessment for cutaneous manifestations (eczematous rash, alopecia, thrush, and/or candidiasis) at each visit. Ophthalmology and audiology evaluations annually for those with profound biotinidase deficiency and every two years for those with partial biotinidase deficiency.

Agents/circumstances to avoid: Raw eggs should be avoided because they contain avidin, an egg white protein that binds biotin, thus decreasing its bioavailability. However, thoroughly cooked eggs present no problem because heating inactivates avidin, rendering it incapable of binding biotin.

Evaluation of relatives at risk: If prenatal testing has not been performed, 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 molecular 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.

Pregnancy management: There have been females with profound biotinidase deficiency who are taking biotin therapy who have had normal pregnancies and offspring.

Genetic counseling.

Biotinidase deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a BTD pathogenic variant, each sib of an affected individual has at conception 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. Molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Suggestive Findings

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 (or likely pathogenic) variants in BTD on molecular genetic testing (see Table 1) when the results of enzymatic testing are ambiguous (e.g., in differentiating profound biotinidase deficiency from partial biotinidase deficiency and in differentiating heterozygosity for profound biotinidase deficiency from partial biotinidase deficiency)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.

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 [Strovel et al 2017] (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 interpretation 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 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.

Note: Targeted analysis for the pathogenic c.1330G>C (p.Asp444His) and c.1368A>C (p.Gln456His) variants can be performed first in individuals of Amish ancestry (see Table 8).

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 development [Möslinger et al 2001, Weber et al 2004, Wolf 2017, Tankeu et al 2023] (see also Management, Targeted Therapy and Table 5). Neurologic problems, including seizures, optic atrophy, and hearing loss, occur only in those individuals with biotinidase deficiency who have recurrent symptoms and metabolic compromise prior to biotin treatment.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not well established. However, certain genotypes correlate with profound biotinidase deficiency and others with partial biotinidase deficiency. There is a single report from Turkey in which symptomatic individuals with pathogenic null variants predicted to lead to profound enzyme deficiency had hearing loss, whereas those who had some residual enzyme activity did not [Sivri et al 2007].

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 and are more likely to be deletions, insertions, or nonsense pathogenic variants. The 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.
• Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms.
• In one study, children with symptoms of profound biotinidase deficiency with null pathogenic variants were more likely to develop hearing loss than those with pathogenic missense variants, even if those with pathogenic missense variants were not treated for a period of time [Sivri et al 2007].

Partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity). Compound heterozygotes for the p.Asp444His pathogenic variant 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].

Homozygotes 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.

Penetrance

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 NBS but who have never had symptoms [Wolf et al 1997, Baykal et al 2005]. In addition, several enzyme-deficient sibs of symptomatic individuals 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 (see Differential Diagnosis), previously referred 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, 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.

Inherited Metabolic Disorders

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 (see Table 2).

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.

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 biotinidase deficiency and holocarboxylase synthetase deficiency (see Table 2).

Sensorineural Hearing Loss

Sensorineural hearing loss (see Hereditary Hearing Loss and Deafness Overview) 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.

Late-Onset Biotinidase Deficiency

Older children, adolescents, and adults ultimately found to have biotinidase deficiency often exhibit symptoms different from those of younger children with the disorder [Ferreira et al 2017, Wolf 2018, Wolf 2019a, Van-Winckel et al 2020]. They usually present with ophthalmologic issues such as optic neuropathy and varying degrees of myelopathy [Wolf 2018]. Biotin therapy can reverse many of the optic findings and some or all of the myelopathy, if diagnosed in a reasonable time period. These individuals often are initially diagnosed with neuromyelitis optica spectrum disorder or multiple sclerosis. It has been recommended that any person diagnosed with these disorders be tested for biotinidase deficiency because of its treatability.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an asymptomatic infant diagnosed with biotinidase deficiency following newborn screening, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

To establish the extent of disease and needs in a symptomatic individual diagnosed with biotinidase deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for biotinidase deficiency. Biotin therapy is lifelong.

Prevention of Primary Manifestations

Adherence to biotin therapy (see Table 5) can prevent symptom development and also improves symptoms in symptomatic individuals.

Surveillance

To monitor existing manifestations, the individual's response to targeted and supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. When the pathogenic variants causing biotinidase deficiency in the family are known, prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to facilitate institution of treatment at birth.

Newborn sib. If prenatal testing has not been performed, 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 molecular genetic testing (if the BTD pathogenic variants in the family are known).

Older sibs. 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.

Symptomatic and non-symptomatic family members. The genetic status of any relative with symptoms consistent with biotinidase deficiency or individuals with symptoms of late-onset 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.

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

Pregnancy Management

There have been females with profound biotinidase deficiency who are taking biotin therapy who have had normal pregnancies and offspring [Wolf 2017].

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 for the mother. An optimal prenatal dose has not been determined.

See MotherToBaby for further information on medication use during pregnancy.

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.

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 presumed to be heterozygous for a BTD pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a BTD pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a BTD pathogenic variant, each sib of an affected individual has at conception 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 (see Penetrance).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has biotinidase deficiency or is a carrier (see Family planning), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in BTD.
• Based on a carrier frequency of approximately one in 120 in the general population [Wolf 1991], the empiric risk to an individual with biotinidase deficiency of having a child with the disorder is about one in 240.

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

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the BTD pathogenic variants in the family.

Biochemical genetic testing. Carriers (heterozygotes) usually have serum enzyme activity levels intermediate between those of affected and 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.

Note: Individuals with one profound or one partial biotinidase deficiency BTD pathogenic variant are carriers of biotinidase deficiency and do not exhibit symptoms. Such individuals do not require biotin therapy.

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 and discussion of the availability of prenatal/preimplantation genetic 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.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Two BTD founder variants have been identified in individuals of Amish ancestry (see Table 8).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the BTD pathogenic variants have been identified in an affected family member, prenatal 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 preferred.

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Biotinidase is a ubiquitously expressed enzyme essential for recycling the vitamin biotin, a water-soluble cofactor necessary for the function of several carboxylases. Biotinidase has been shown to have biotinyl-hydrolase and biotinyl-transferase activities. The enzyme is a monomeric sialylated glycoprotein with multiple isoforms resulting from differences in the degree of sialylation [Hart et al 1991]. Deficiency of biotinidase with secondary disruption of relevant carboxylases causes disruption of several pathways involved in amino acid, carbohydrate, and lipid metabolism, which leads to clinical manifestations of biotinidase deficiency.

Mechanism of disease causation. Loss of function

BTD-specific laboratory technical considerations. BTD consists of four exons and three introns [Knight et al 1998]. 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. These transcripts may have tissue-specific expression [Strovel et al 2017].

Author Notes

Dr Barry Wolf'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.

Biotinidase Deficiency: A Booklet for Families and Professionals by DL Thibodeau, MS, and B Wolf, MD, PhD

Acknowledgments

Safra Research Foundation at Henry Ford Hospital, Detroit, MI

Revision History

• 25 May 2023 (ma) Comprehensive update posted live
• 9 June 2016 (bp) Comprehensive update posted live
• 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 live
• 10 February 2005 (bw,cd) Revision: targeted mutation analysis clinically available
• 26 November 2003 (me) Comprehensive update posted live
• 27 September 2001 (me) Comprehensive update posted live
• 24 March 2000 (pb) Review posted live
• December 1999 (bw) Original submission

Published Guidelines / Consensus Statements

• Strovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19. Available online. Accessed 7-12-23. [PubMed]

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