Biotinidase Deficiency - Genetics

Genetics

Mutations in the BTD gene cause biotinidase deficiency. Biotinidase is the enzyme that is made by the BTD gene. Many mutations that cause the enzyme to be nonfunctional or to be produced at extremely low levels have been identified. Biotin is a vitamin that is chemically bound to proteins. (Most vitamins are only loosely associated with proteins.) Without biotinidase activity, the vitamin biotin cannot be separated from foods and therefore cannot be used by the body. Another function of the biotinidase enzyme is to recycle biotin from enzymes that are important in metabolism (processing of substances in cells). When biotin is lacking, specific enzymes called carboxylases cannot process certain proteins, fats, or carbohydrates. Specifically, two essential branched-chain amino acids (leucine and isoleucine) cannot be completely broken down, and are instead diverted into harmful by-products such as hydroxyisovalerate (also referred to as hydroxyisovaleric acid).

Individuals lacking functional biotinidase enzymes can still have normal carboxylase activity if they ingest adequate amounts of biotin. The standard treatment regimen calls for 5–10 mg of biotin per day.

Biotinidase deficiency is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - must be inherited for a person to be affected by the disorder. The parents of a child with an autosomal recessive disorder are usually not affected by the disorder, but are carriers of one copy of the defective gene. If both parents are carriers for the biotinidase deficiency, there is a 25% chance that their child will be born with it and a 75% chance that they will be carriers.

The chromosomal locus is at 3p25. The BTD gene has 4 exons of lengths 79 bp, 265 bp, 150 bp and 1502 bp, respectively. There are at least 21 different mutations that have been found to lead to biotinidase deficiency. The most common mutatations in severe biotinidase deficiency (<10% normal enzyme activity) are: p.Cys33PhefsX36, p.Gln456His, p.Arg538Cys, p.Asp444His, and p.. Almost all individuals with partial biotinidase deficiency (10-30% enzyme activity) have the mutation p.Asp444His in one allele of the BTD gene in combination with a second allele.