Knowledge on rare diseases and orphan drugs

Prevalence of clinical biotinidase deficiency (BD) is estimated to be 1/61,000. Carrier frequency in the general population is approximately 1/120.

Symptoms of BD deficiency typically appear within the first few months of life, but later onset has also been reported. Individuals with untreated profound deficiency (less than 10 % of mean normal serum biotinidase activity) have variable clinical findings including seizures, hypotonia, eczematoid rash, alopecia, ataxia, hearing loss, fungal infections, and developmental delay. Metabolically, untreated children can exhibit ketolactic acidosis, organic acidemia (-uria) and mild hyperammonemia. Individuals with untreated partial BD (10% to 30% of mean normal biotinidase activity) may be asymptomatic, but during periods of stress, such as illness, fever or fasting, may develop symptoms similar to those of individuals with profound BD. Multiple adults with optic neuropathy and/or peripheral neuropathy, that is often mistakenly diagnosed as multiple sclerosis, have been shown to have profound biotinidase deficiency.

BD deficiency is caused by mutations in the BTD gene (3p25) resulting in reduced or absent biotinidase activity. This enzyme recycles free, non-protein bound, biotin which is required for multiple biotin-dependent metabolic processes. There are more than 150 known mutations of the BTD gene that cause BD.

The disorder is detected through newborn screening when available. Other cases are diagnosed by clinical signs and symptoms and confirmed by demonstration of deficient serum biotinidase activity. Molecular mutation analysis of the BTD gene is also possible.

The symptoms of BD overlap with those of other metabolic diseases, including holocarboxylase synthetase deficiency, isolated carboxylase deficiency, nutritional biotin deficiency, zinc deficiency and essential fatty acid deficiency. Testing for biotinidase deficiency should be considered in all individuals thought to have multiple sclerosis.

Prenatal diagnosis for at-risk pregnancies is possible and can be performed by enzymatic analysis or by mutation analysis when the mutation is known. However, because of the treatability of the disorder, prenatal testing is not considered by most families.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child for each pregnancy. Siblings of patients with BD should be tested for the deficiency even if they do not exhibit symptoms.

Supplementation with oral biotin in the free, non-protein bound, form is the primary treatment and improves symptoms in symptomatic patients, and prevents symptoms in those identified by newborn screening or before symptoms have developed. Once some features, such as optic atrophy, hearing loss, or developmental delay develop, they may not be reversible with biotin treatment. Treatment with biotin should be maintained lifelong. There are no known, serious adverse effects of biotin therapy. Patients and their families should be warned about the importance of treatment compliance. Periodic ophthalmological, neurological and metabolic evaluations are recommended. Raw eggs should be avoided because of their avidin content (biotin-binding substance), but cooking inactivates the binding effect of avidin.

The prognosis for individuals diagnosed with BD is very good, provided they are treated before symptoms occur and are compliant with biotin therapy. In adult patients presenting with optic neuropathy and/or peripheral neuropathy, improvement in symptoms is likely with early intervention. However, if such individuals remain symptomatic for too long a period, their symptoms may be irreversible.

Last update: September 2020 - Expert reviewer(s): Dr Barry WOLF