What is an amenable mutation?

An amenable mutation is a genetic change or variant that a person may have that is responsive - amenable - to treatment.

The term ‘amenable mutation’ is used to describe certain mutations of the galactosidase alpha gene (GLA), found in people with Fabry disease, which respond to treatment with Galafold (migalastat).

Fabry disease is a rare genetic lysosomal storage disorder that predominantly affects the nervous system, heart and kidneys. It is caused by mutations in the GLA gene, which is needed to make an enzyme that works in lysosomes called alpha-galactosidase A. Alpha-galactosidase A helps to break down and recycle a molecule called globotriaosylceramide, as part of the process to recycle old red blood cells and other cells. If globotriaosylceramide isn’t broken down it accumulates and can damage cells.

Mutations in GLA produce abnormal versions of the alpha-galactosidase A enzyme. Mutations can result in an enzyme with reduced activity, which results in a milder version of Fabry disease, or a complete loss of enzyme activity, which results in a more severe version of the disease.

The most common type of mutation found in people with Fabry disease results in a single amino acid being changed, but mutations that delete part of the GLA gene, insert extra genetic material into the gene, or signal the gene to prematurely stop before alpha-galactosidase is produced are also found.

Galafold works by binding to sites on amenable mutant forms of alpha-galactosidase A, stabilizing it and chaperoning it into lysosomes where it can work. Mutant forms that aren’t responsive to treatment with Galafold are known as nonamenable mutations.