Definition of disease
Biotinidase deficiency is a late onset form of multiple carboxylase deficiency (see this term), a congenital biotin metabolism disorder which, if untreated, is characterized by convulsions, respiratory problems, hypotonia, rash, alopecia, deafness and developmental delay.
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Epidemiology
The prevalence of clinical biotinidase deficiency (BTD) is estimated at 1 / 61,000. The frequency of carriers in the general population is approximately 1/120.
Clinical description
The symptoms of BTD deficiency usually appear within the first few months of life, but the later onset was also described. Individuals with profound untreated deficiency (less than 10% of normal mean serum biotinidase activity) have variable clinical findings, including seizures, hypotonia, eczematous erythema, alopecia, ataxia, deafness, fungal infections, and developmental delay. Metabolically, untreated children may present with ketolac acidosis, organic acidemia (-uria) and mild hyperammonemia. Individuals with partial disability (10% to 30% of average normal BTD activity) without treatment may be asymptomatic, but during periods of stress, such as fever, illness or fasting, they may develop symptoms similar to those of individuals with profound BTD deficiency.
Etiology
BTD deficiency is caused by mutations in the BTD gene (3p25), resulting in the reduction or absence of BTD activity. This enzyme recycles free, non-protein bound biotin, which is required for various biotin-dependent metabolic processes. There are more than 150 mutations of the BTD gene known causes of BTD deficiency.
Diagnostic Methods
The disease is detected through neonatal screening when available. The other cases are diagnosed by clinical signs and symptoms and confirmed by the demonstration of serum-deficient BTD activity. Molecular analysis of mutations in the BTD gene is also possible. The symptoms of BTD deficiency overlap with those of other metabolic diseases, including holocarboxylase synthetase deficiency (see this term), isolated carboxylase deficiency, nutritional deficiency of biotin, zinc deficiency, and essential fatty acid deficiency.
Prenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible and can be performed by enzyme analysis or by mutation analysis when the mutation is known. However, because it is a treatable disease, prenatal testing is not considered by most families.
Genetic counseling
BTD deficiency is transmitted in an autosomal recessive manner. For parents of affected children, genetic counseling is recommended. Parents are required asymptomatic heterozygous carriers. Siblings of patients with BTD deficiency should be tested for the deficiency even if they do not present symptoms.
Disease control and treatment
Oral, non-protein-bound oral biotin supplementation is the main treatment and improves symptoms in symptomatic patients, and avoids symptoms in those identified by neonatal screening or before symptoms develop. After the installation of some features, such as optic atrophy, deafness, or developmental delay, they may not be reversible with biotin treatment. Biotin treatment should be continued throughout life. Serious adverse effects of biotin therapy are not known. Patients and their families should be made aware of the importance of adherence to treatment. Ophthalmologic, neurological and metabolic periodic evaluations are recommended. Raw eggs should be avoided because of their avidin content (biotin-binding substance), but cooking inactivates the avidin binding effect.
Prognosis
The prognosis for individuals with BTD deficiency is very good as long as they are treated before symptoms occur and are compliant with biotin therapy.