Biotinidase Deficiency Health Article

Definition

Biotinidase deficiency is a rare inherited defect in the body's ability to use dietary biotin, one of the B vitamins. The disease is also known as juvenile or late-onset multiple carboxylase deficiency.

Description

Biotin is essential as a co-factor (co-enzyme) for the reactions of four enzymes called carboxylases. These enzymes, in turn, play important roles in the metabolism of sugars, fats, and proteins within the human body. Another key enzyme, biotinidase, recycles biotin from these reactions so it can be used again. A defect in the biotinidase gene results in decreased amounts of normal enzyme, thus preventing the reuse of biotin. In turn, this leads to a disruption of the function of the four carboxylases that depend on biotin, and results in a variety of abnormalities of the nervous system and skin. Since symptoms usually do not appear immediately at birth, biotinidase deficiency is also referred to as late-onset or juvenile multiple carboxylase deficiency. A related disorder, early-onset or neonatal multiple carboxylase deficiency, is caused by the lack of a different enzyme, holocarboxylase synthetase, and, as the name suggests, results in symptoms in the newborn period.

Inheritance pattern

Biotinidase deficiency is an autosomal recessive disorder affecting both males and females. In individuals with this disorder, both copies of the biotinidase gene are defective. Both parents of an affected child have one abnormal copy of the gene, but usually do not show symptoms because they also have one normal copy. The normal copy provides approximately 50% of the usual enzyme activity, a level adequate for the body's needs. Individuals with one abnormal copy of the gene and 50% enzyme activity are said to be carriers or heterozygotes. As is typical of autosomal recessive inheritance, their risk for having another

child with the disorder is 25% in each subsequent pregnancy.

Gene location

The gene for biotinidase is located on the short arm of chromosome 3 (3p25). At least 40 different mutations in this gene have been identified in individuals with biotinidase deficiency. The fact that there are a number of different types of mutations helps explain why symptoms are variable from one individual to another. However, the presence of variability even within a family suggests there may be other, as yet unknown, factors that affect the severity of the disease.

Demographics

Individuals with biotinidase deficiency have been described in various ethnic groups worldwide. In the general population, the incidence of the disease is estimated at about one in 60,000 individuals and one in every 123 individuals is a carrier.

Signs and symptoms

The onset of symptoms is typically between three and six months of age but varies widely from one week to several years. The most common clinical features are hair loss (alopecia), skin rash (dermatitis), seizures (convulsions), decreased muscle tone (hypotonia), difficulty walking (ataxia), breathing problems, redness of the eyes (conjunctivitis), hearing and vision loss, and developmental delay. Children with biotinidase deficiency are prone to fungal and bacterial infections, suggesting that the immune system is also affected. Symptoms are highly variable among affected individuals, even within a single family.

Biotinidase deficiency is classified as either partial or profound. If there is at least 10% enzyme activity, the deficiency is considered partial and is usually associated with minimal to mild symptoms. Profound biotinidase deficiency, defined as less than 10% of normal activity, is characterized by many of the symptoms mentioned above, and can, if left untreated, result in coma and death.

Diagnosis

Children with profound biotinidase deficiency may show general signs such as vomiting, seizures, and low muscle tone, all of which can be associated with a number of different disorders. Diagnosis can be difficult because of the many different enzyme deficiencies (inborn errors of metabolism) with similar symptoms and test results. For example, abnormally high amounts of certain acidic products in the blood and urine can be typical of a number of different metabolic disorders including biotinidase deficiency. Accurate diagnosis is made by measuring the activity of the enzyme in blood or skin cells. A number of states and countries test for this disorder at birth as part of a comprehensive newborn screening program. Infants whose tests indicate they have biotinidase deficiency can be started on treatment before symptoms appear. With regular treatment these infants usually remain symptom-free.

Carrier testing

Most carriers can be detected by measuring biotinidase activity in their blood. Fifty percent of normal enzyme activity is characteristic of carriers. Specific DNA tests can usually detect the particular gene mutation in any affected individual or carrier.