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/m 2 ; 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 m 2 ; 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.

Fabry disease is a rare inborn error of the enzyme α-galactosidase (α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years, in particular since enzyme replacement therapy (ERT) has become widely available in 2001. With rising awareness and rising numbers of (diagnosed) patients, physicians encounter new challenges. Over 900 α-Gal gene mutations are currently known, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician and a lot of uncertainty for patients. Another challenge are patients who develop neutralising antibodies to ERT, which possibly leads to reduced therapy effectiveness. In this article, we summarise the latest developments in the science community regarding diagnostics and management of this rare lysosomal storage disorder and offer an outlook to future treatments.

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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.

Despite several attempts at setting up a standardized disease severity score for Fabry disease in the past, none have been established in routine clinical practice due to the multisystem nature and complexity of this inherited enzyme deficiency disorder. In this issue, Mignani et al. report a large multicentre application of the FASTEX, an online tool to assess disease progress over time that offers simple data inputting and graphic illustration of disease progression or stabilization. Mignani et al. succeeded in validating the tool in a large cohort of Fabry patients, including females and non-classical phenotypes, building on the first FASTEX introduction in 2016. We report on our own practical experience with the tool and comment on some limiting factors in its use as well as possible future prospects.

Background Fabry disease is a lysosomal storage disorder with multiple organ involvement. Renal and cardiac symptoms can lead to dialysis and myocardial hypertrophy with fibrosis, responsible for heart failure with preserved ejection fraction (HFpEF). Enzyme replacement therapy (ERT) is available for all patients with Fabry disease since 2001, requiring infusions every other week. Since May 2016, the chaperone migalastat represents a novel form of specific therapy as the first oral therapy available for certain Fabry patients. Through this molecule the function of the mutated enzyme α-galactosidase A can be restored. Recent trials have shown positive cardiac effects of chaperone therapy using echocardiography; however, MRI investigations further evaluating these findings are not available yet. Objective To evaluate cardiac effects of migalastat therapy in patients with amenable α-galactosidase A mutations in the prospective monocentric HEAL-FABRY registry (NCT03362164). Methods and results Comprehensive clinical investigations including serial MRI were conducted at baseline before initiation of migalastat therapy and at least one year thereafter in all patients without contraindications such as pacemakers or ICDs. Out of 29 patients included in the study (mean age at start of therapy 52.8±14 years, total range 20–74 years), until then 12 patients with MRI data completed the 1-year follow-up. At 1 year, enzyme activity in leucocytes increased from 0.06 to 0.21 nmol/min/mg protein (p=0.001). Distinctive changes over time were observed not only in diastolic but also systolic parameters. The systolic myocardial mass index was reduced by 2.39% (p=0.10). In the AHA segment number 5, most important for classification of severe myocardial damage in Fabry patients, late gadolinium enhancement was reduced by 8.58% in all 5 patients with verified progressive fibrosis (p=0.14). One patient stopped migalastat therapy due to personal reasons. No significant side effects were observed. Analysis of LGE (systolic phase) Conclusion These preliminary MRI data show positive effects of migalastat therapy in patients with Fabry disease and cardiac involvement. Compared to echocardiography, MRI has the potential to allow for comprehensive additional analyses regarding both cardiac morphology and function.

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