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 gm/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: Compliance with 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-compliance with 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.
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