Table 1.
Molecular basis of biotinidase deficiency (BD)
|
BD |
Unaffected individuals |
||||
|---|---|---|---|---|---|
| Profound BD | Partial BD | ≈ Hz | Hz | ≈ N | N |
| Profound deficiency allele |
Profound deficiency allele |
p.D444H |
Profound deficiency allele |
p.D444H |
Wild-type allele |
| + |
+ |
+ |
+ |
+ |
+ |
| Profound deficiency allele | p.D444H | p.D444H | Wild-type allele | Wild-type allele | Wild-type allele |
Most variants in the BTD gene cause complete or almost complete loss of the biotinidase enzyme activity; they are called profound deficiency alleles (e.g., c.98_104del7ins3, c.1612C > T (p.R538C), c.1368A > C (p.Q456H), c.[511G > A;1330G > C] (p.[A171T;D444H]). The presence of two such alleles, in homozygous or compound heterozygous form, results in profound BD. Individuals who are compound heterozygotes for the c.1330G > C (p.D444H) variant and a profound deficiency allele are expected to have ~ 20-25% of the normal biotinidase activity. It is expected that individuals homozygous for the p.D444H variant have similar activity to individuals heterozygous (Hz) for profound deficiency alleles. Hz for p.D444H variant show similar activity to individuals homozygous for the wild-type allele (normal activity, N). The p.D444H variant in cis with a mutation that causes profound deficiency results in a profound deficiency allele [11]–[13].