α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease

Oder, Daniel; Liú, Dan; Hu, Kai; Üçeyler, Nurcan; Salinger, Tim; Müntze, Jonas; Lorenz, Kristina; Kandolf, Reinhard; Gröne, Hermann Josef; Sommer, Claudia; Ertl, Georg; Wanner, Christoph; Nordbeck, Peter

doi:10.1161/circgenetics.116.001691

Cited by 30 publications

(24 citation statements)

References 49 publications

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“…Residual enzyme activity can vary widely in FD, depending on the mutation and patient's sex . However, Fabry‐specific therapy could not achieve significant changes in residual enzyme activity for longer than several hours.…”

Section: Discussionmentioning

confidence: 99%

“…All subjects had a confirmed FD diagnosis via genetic testing. Mutations were classified as “classic” or “nonclassic” (also called “late‐onset,” with N215S and A143T mutations) based on current knowledge and an expert evaluation . The leading indication for initiation of Fabry‐specific therapy in all patients with the N215S mutation was cardiac involvement.…”

Section: Methodsmentioning

confidence: 99%

“…Residual enzyme activity can vary widely in FD, depending on the mutation and patient's sex. 4,[38][39][40][41][42] However, Fabry-specific therapy could not achieve significant changes in residual enzyme activity for longer than several hours. Therefore, it remains unknown whether residual enzyme activity was directly related to improvements in involved organs.…”

Section: Correlation Between Enzyme Activity and Organ Involvementmentioning

confidence: 99%

“…Progressive fibrosis in various organs causes neurological dysfunction, myocardial hypertrophy, progressive heart failure, and loss of renal function. Ultimately, patients with FD require dialysis and organ transplantation, and it often results in premature death …”

mentioning

confidence: 99%

“…Ultimately, patients with FD require dialysis and organ transplantation, and it often results in premature death. 3,4 In 2001, enzyme replacement therapy (ERT) was developed for treating this genetic disease. Long-term data have shown positive effects on disease progression.…”

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confidence: 99%

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Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

Müntze

Gensler

Maniuc

et al. 2019

Clin Pharma and Therapeutics

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Correlation Between Enzyme Activity and Organ Involvementmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

Müntze

Gensler

Maniuc

et al. 2019

Clin Pharma and Therapeutics

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Treatment of Fabry's Disease With Migalastat: Outcome From a Prospective Observational Multicenter Study (FAMOUS)

Lenders

Nordbeck

Kurschat

et al. 2020

Clin Pharma and Therapeutics

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Fabry's disease (FD) is an X‐linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α‐galactosidase A (α‐Gal A) leading to intracellular accumulation of globotriaosylceramide (Gb3). Patients with amenable mutations can be treated with migalastat, a recently approved oral pharmacologic chaperone to increase endogenous α‐Gal A activity. We assessed safety along with cardiovascular, renal, and patient‐reported outcomes and disease biomarkers in a prospective observational multicenter study after 12 months of migalastat treatment under “real‐world” conditions. Fifty‐nine (28 females) patients (34 (57.6%) pretreated with enzyme replacement therapy) with amenable mutations were recruited. Migalastat was generally safe and well tolerated. Females and males presented with a reduction of left ventricular mass index (primary end point) (−7.2 and −13.7 g/m2, P = 0.0050 and P = 0.0061). FD‐specific manifestations and symptoms remained stable (all P > 0.05). Both sexes presented with a reduction of estimated glomerular filtration rate (secondary end point) (−6.9 and −5.0 mL/minute/1.73 m2; P = 0.0020 and P = 0.0004, respectively), which was most prominent in patients with low blood pressure (P = 0.0271). α‐Gal A activity increased in male patients by 15% from 29% to 44% of the normal wild‐type activity (P = 0.0106) and plasma lyso‐Gb3 levels were stable in females and males (P = 0.3490 and P = 0.2009). Reevaluation of mutations with poor biochemical response revealed no marked activity increase in a zero activity background. We conclude that therapy with migalastat was generally safe and resulted in an amelioration of left ventricular mass. In terms of impaired renal function, blood pressure control seems to be an unattended important goal.

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Nationwide screening of Fabry disease in patients with hypertrophic cardiomyopathy in Czech Republic

et al. 2022

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Aims Fabry disease (FD) is a rare X‐linked genetic disorder caused by α‐galactosidase A (AGALA) deficiency. Whereas ‘classic’ variant has multisystemic manifestation, the more recently described ‘later‐onset’ variant is characterized by predominant cardiac involvement that often mimics hypertrophic cardiomyopathy (HCM). Methods and results Consecutive unrelated patients with HCM were screened for FD in 16 (out of 17) cardiac centres in the Czech Republic covering specialized cardiology care from June 2017 to December 2018. AGALA activity and globotriaosylsphingosine (lyso‐Gb3) levels were measured in all subjects using the dry blood spot method. FD was suspected in male patients with AGALA activity <1.2 μmol/h/L and in females with either low AGALA activity or lyso‐Gb3 > 3.5 ng/mL. Positive screening results were confirmed by genetic testing. We evaluated 589 patients (390 males, 66%) with HCM (mean maximal myocardial thickness 19.1 ± 4.3 mm). The average age was 58.4 ± 14.7 years. In total, 17 patients (11 males, 6 females) had a positive screening result, and subsequently, six of them (four males and two females) had a genetically confirmed pathogenic GLA mutation (total prevalence of 1.02%). Five of these patients were carrying the p.N215S mutation known to cause a typical later‐onset cardiac FD. Conclusions We confirmed the prevalence of FD repeatedly reported in previous screening programmes (approximately 1% irrespective of gender) in a non‐selected HCM population in Central Europe. Our findings advocate a routine screening for FD in all adult patients with HCM phenotype including both genders. The dry blood spot method used led to identification of clearly pathogenic variants.

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α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease

Cited by 30 publications

References 49 publications

Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

Treatment of Fabry's Disease With Migalastat: Outcome From a Prospective Observational Multicenter Study (FAMOUS)

Nationwide screening of Fabry disease in patients with hypertrophic cardiomyopathy in Czech Republic

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