Each gene in the body is made of one allele (a grouping of instructions) which originated from the mother and another allele which originated from the father. Picture the alleles as two railroad trains having cars loaded with various kinds of information and instructions.
The glycogen branching enzyme gene GBE1 is responsible for making glycogen branching enzyme (GBE). When that enzyme is mainly missing or is seriously flawed, APBD can occur.
Looking at the Glycogen Branching Enzyme gene (GBE1) in light of our train analogy, each of the two alleles has 16 railroad cars of information, called exons. There are 15 buffer spaces between the cars. The buffer spaces are called introns.
Our scientists have identified two common allele mutations associated with APBD. A mutation on the railroad car named Exon 7, at location p.Y239S has been identified with greater frequency. A mutation associated with the buffer space named Intron 15, between exons 15 and 16, is the other common mutation.
“Heterozygous” carriers for APBD don’t have disease symptoms; they simply carry a mutation on one of the two alleles composing their GBE1 gene.
In order to present with APBD, a patient must have a mutation on the allele s/he inherited from their father and also on the allele s/he inherited from their mother. Two mutated alleles.
In “homozygous” APBD patients, the same mutation is found on each of the two alleles of the GBE1 gene. Universally to date, our homozygous APBD patients have the Exon 7 flaw at p.Y329S on both alleles of their GBE1 gene. The flaw does not completely stop enzyme production. Scientists say that a small amount of active enzyme “leaks” from each affected allele. This explains why homozygous APBD patients have 18-22 percent of the normal GBE activity. About 70 percent of known APBD patients are homozygous for the p.Y329S mutation.
In “compound heterozygous” APBD patients, the mutation found on the allele from the mother differs from that found on the allele from the father. Most often in this group, one allele has the exon 7 flaw at p.Y329S and the other has the Intron 15 flaw. In these cases, a small amount of active enzyme “leaks” from the allele with the exon 7 mutation, but enzyme production from the other allele is entirely shut down due to the nature of the Intron 15 mutation. Compound heterozygous patients who have the combination of a p.Y329S exonic mutation and an intron 15 mutation have about 8 percent of the normal GBE activity, and all of it comes from the allele which has the exon 7 mutation.