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Background
Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future.
Methods
This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years.
Results
Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy.
Conclusion
These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.
Long-term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single-center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open-label migalastat therapy, patients showed significant changes in alpha-galactosidase-A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m2; P = 0.037), and serum creatinine (0.94–1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = −0.546; P = 0.044) but not with renal function (r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy-naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme-replacement therapy. These first real-world data show that migalastat substantially increases alpha-galactosidase-A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.