Newly ID’d GLA mutations may be amenable to Galafold: Study
Discovery 'deepens our understanding' of Gal A protein structure, function
Researchers discovered new mutations in the GLA gene, the underlying cause of Fabry disease, but noted that all of them may be amenable to Galafold (migalastat) chaperone therapy, an approved treatment to slow or prevent organ function decline in Fabry patients, a new study reports.
Clinical manifestations of these novel Fabry-causing mutations were detailed in the study. The researchers reported that each patient experienced involvement in multiple organs.
“This study further enriches the Fabry disease GLA mutation database and deepens our understanding of GLA mutations and the structure and function of the [Gal A] protein,” the team wrote.
Additionally, a model developed by the scientists may predict patients’ responses to Galafold treatment, per the study.
The study, “Pathogenicity of novel GLA gene missense mutations in Fabry disease and the therapeutic impact of migalastat,” was published in the Journal of Advanced Research.
Researchers screened data from more than 150 Fabry patients
In Fabry, mutations in the GLA gene affect alpha-galactosidase A, or alpha-Gal A, an enzyme needed to break down certain fatty molecules, including globotriaosylceramide, known as Gb3. Because people with Fabry produce very little or an abnormal version of alpha-Gal A, these fatty molecules build up to toxic levels in various tissues and organs, causing disease symptoms.
There are two types of Fabry, dependent on the impact of the GLA mutation and its effect on alpha-Gal A activity. The classic form of the condition, which is more severe, is marked by less than 1% of alpha-Gal A activity, with symptoms arising in childhood. In comparison, the late-onset form is characterized by more than 1% of alpha-Gal A activity, with symptoms usually emerging in adulthood.
When new GLA mutations are discovered, it’s essential to understand their impact on alpha-Gal A function and, in turn, on Fabry patients.
Here, a research team in China retrospectively screened the clinical data of 163 Fabry patients, looking for new GLA mutations and examining their effect on disease development.
Of the 95 different GLA mutations detected, 12 had not been previously reported. Nine of these were considered to definitely cause Fabry because they led to a shortened version of alpha-Gal A, which would be rapidly degraded. The remaining three were missense mutations, meaning they caused a change in a single amino acid — which serve as the building blocks of proteins — within an intact alpha-Gal A enzyme.
The researchers then focused on the Fabry patients with missense mutations, as these specific genetic changes may still allow for the production of a partially functional enzyme. That makes these individuals suitable candidates for treatment with Galafold, an oral chaperone therapy approved for adults with Fabry carrying certain GLA mutations.
Galafold works by stabilizing the abnormal alpha-Gal A enzyme, allowing it to reach lysosomes, the cell’s recycling centers, where it boosts Gb3 clearance. The therapy has been shown to help manage symptoms in people with Fabry.
All patients found to have new GLA mutations were men
All of the patients with this type of mutation were men, with an average age of 14.75 years at onset and 29.5 at diagnosis.
The man in the first case, found to have a p.W44G mutation, experienced hand and foot pain, a lack of sweat, and benign skin lesions during childhood. He also had symptoms of dizziness, heart palpitations, left heart enlargement, episodic ankle swelling, and diarrhea. The patient was given pain medications but not enzyme replacement therapy (ERT). Prediction analysis also suggested that this mutation was highly pathogenic, or disease-causing.
The second patient, carrying a p.S65N mutation, also experienced hand and foot pain and a lack of sweat since childhood. As he aged, other symptoms emerged, including benign skin lesions, high blood pressure, and mild tinnitus, or ringing in the ears. At 31, he underwent a kidney biopsy due to unexplained proteinuria, or high levels of protein in the urine, that revealed scarring. Genetic tests confirmed Fabry, and he was treated with ERT. His mutation was deemed low pathogenic, indicating a mild impact on the enzyme.
In the third case, the patient had a p.G260W mutation. Unexplained proteinuria was discovered during a routine medical examination at age 32, with a subsequent kidney biopsy revealing damage. After being diagnosed with Fabry via genetic and alpha-Gal A enzyme testing, he was started on ERT, which significantly reduced his lyso-Gb3 levels. His mutation was considered highly pathogenic.
[Galafold] intervention increased the enzymatic activity in the disease models with the novel missense mutations.
The team then created human kidney cell lines (HEK-293) harboring each mutation to investigate their impact on GLA gene expression (activity), alpha-Gal A protein expression (production), and enzyme activity. The model was designed to work at different mutation sites.
The GLA gene expression levels of all of the mutations were significantly lower than those of unmutated control cells, the researchers found. The low pathogenic p.S65N mutation showed the highest expression across all of the mutations. Likewise, alpha-Gal A expression and its activity were significantly lower in all, with the p.S65N mutation showing the most residual enzyme activity at 43.75% of normal.
All cell lines were exposed to Galafold, with treatment significantly increasing the expression and activity of all the mutant alpha-Gal A enzymes, particularly in the p.S65N mutant, which reached as high as 80.7% of normal, according to the scientists.
“[Galafold] intervention increased the enzymatic activity in the disease models with the novel missense mutations, as well as [meeting] the amenable mutation criteria for GLA gene mutations applicable to [Galafold],” the research team concluded.
About the Author
