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). As of 1999, at least 40 different mutations in this gene had 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.
Prenatal diagnosis
If a couple has had one child with biotinidase deficiency, they can be offered prenatal testing in future pregnancies. Prenatal testing is accomplished by measuring biotinidase activity in amniotic fluid cells obtained by amniocentesis around the sixteenth week of pregnancy. Alternatively, if specific gene mutations have been identified in the parents, fetal DNA from amniotic fluid cells can be studied to test for these same mutations in the fetus. Carrier couples who are considering prenatal diagnosis should discuss the risks and benefits of this type of testing with a geneticist or genetic counselor.
Treatment and management
Treatment of the profound form of biotinidase deficiency consists of giving large doses of biotin orally. Partial deficiencies are usually treated with lower doses. The biotin must be in a free form; that is, not attached to other molecules as would be the case with the biotin found in food. Properly treated, biotinidase deficiency is not a life-threatening condition, but biotin treatment must continue throughout life. No treatment is needed before birth because the developing fetus is provided with sufficient free biotin from the mother.
Prognosis
Daily treatment with free biotin usually results in rapid improvement of the skin condition, hair regrowth, and a lessening or cessation of seizure activity. Many children whose development has been affected by biotinidase deficiency have shown some improvement after treatment. Hearing and vision losses are less reversible. Children who are diagnosed at birth through newborn screening programs rarely develop symptoms if they are started on biotin replacement therapy immediately.
BOOKS
Wolf, Barry. "Disorders of Biotin Metabolism." In Metabolic and Molecular Bases of Inherited Disease, edited by C.R. Scriver, et al. New York: McGraw-Hill, 2001.
PERIODICALS
Blanton, S. H., et al. "Fine Mapping of the Human Biotinidase Gene and Haplotype Analysis of Five Common Mutations." Human Heredity 50 (March-April 2000): 102-11.
Norrgard, K. J., et al. "Mutations Causing Profound Biotinidase Deficiency in Children Ascertained by Newborn Screening in the United States Occur at Different Frequencies Than in Symptomatic Children." Pediatric Research 46 (July 1999): 20-27.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
