Fabry disease is an X-linked lysosomal storage disorder that causes accumulation of glycosphingolipids in body tissues and fluids, leading to progressive organ damage and life-threatening complications. It can affect both males and females and can be classified into classic or later-onset phenotypes. The disease severity in females ranges from asymptomatic to the more severe, classic phenotype. Most females are hemizygous and the X-linked inheritance is associated with variable X-activation pattern and residual enzymatic activity. The heterogeneity of clinical presentation in females requires different approaches to diagnosis and management than males. A European group of 7 physicians, experienced in the management of Fabry disease, convened to discuss patient perspectives and published guidelines. The experts discussed the need to focus on psychological treatment in relation to individual coping styles when monitoring targets, and the lack of data supporting the use of plasma globotriaosylsphingosine over enzyme activity in the diagnosis of these patients. It was suggested that the high phenotypic variability in female patients may be related to the dynamic nature of the X-chromosome inactivation process and further understanding of this process could help predict the progression of Fabry disease in females and facilitate timely intervention. Due to the range of disease severity they exhibit, female patients with Fabry disease may require a more individualized treatment approach than males. Despite current recommendations, the experts agreed that early disease-specific treatment initiation in high-risk females could improve clinical outcome.

• Klíčová slova
• Early diagnosis, Enzyme replacement therapy, Fabry disease, Female, Patient-reported outcome measures,
• MeSH
• Fabryho nemoc * terapie   genetika   diagnóza   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was -0.36 mL/min/1.73 m2/year [-2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of -3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

• Klíčová slova
• Fabry disease, PEGylation, agalsidase, non-inferiority trial, renal function,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

AIMS: Fabry disease (FD) is a multisystemic lysosomal storage disorder caused by a defect in the alpha-galactosidase A gene that manifests as a phenocopy of hypertrophic cardiomyopathy. We assessed the echocardiographic 3D left ventricular (LV) strain of patients with FD in relation to heart failure severity using natriuretic peptides, the presence of a cardiovascular magnetic resonance (CMR) late gadolinium enhancement scar, and long-term prognosis. METHODS AND RESULTS: 3D echocardiography was feasible in 75/99 patients with FD [aged 47 ± 14 years, 44% males, LV ejection fraction (EF) 65 ± 6% and 51% with hypertrophy or concentric remodelling of the LV]. Long-term prognosis (death, heart failure decompensation, or cardiovascular hospitalization) was assessed over a median follow-up of 3.1 years. A stronger correlation was observed for N-terminal pro-brain natriuretic peptide levels with 3D LV global longitudinal strain (GLS, r = -0.49, P < 0.0001) than with 3D LV global circumferential strain (GCS, r = -0.38, P < 0.001) or 3D LVEF (r = -0.25, P = 0.036). Individuals with posterolateral scar on CMR had lower posterolateral 3D circumferential strain (CS; P = 0.009). 3D LV-GLS was associated with long-term prognosis [adjusted hazard ratio 0.85 (confidence interval 0.75-0.95), P = 0.004], while 3D LV-GCS and 3D LVEF were not (P = 0.284 and P = 0.324). CONCLUSION: 3D LV-GLS is associated with both heart failure severity measured by natriuretic peptide levels and long-term prognosis. Decreased posterolateral 3D CS reflects typical posterolateral scarring in FD. Where feasible, 3D-strain echocardiography can be used for a comprehensive mechanical assessment of the LV in patients with FD.

• Klíčová slova
• 3D echocardiography, Fabry disease, cardiovascular magnetic resonance, heart failure, myocardial strain,
• MeSH
• dysfunkce levé srdeční komory * diagnostické zobrazování   etiologie   MeSH
• echokardiografie trojrozměrná * metody   MeSH
• echokardiografie metody   MeSH
• Fabryho nemoc * komplikace   diagnostické zobrazování   MeSH
• funkce levé komory srdeční MeSH
• gadolinium MeSH
• jizva diagnostické zobrazování   MeSH
• kontrastní látky MeSH
• lidé MeSH
• prognóza MeSH
• reprodukovatelnost výsledků MeSH
• srdeční selhání * diagnostické zobrazování   etiologie   MeSH
• tepový objem MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• gadolinium MeSH
• kontrastní látky MeSH

AIMS: Fabry disease (FD) is often associated with heart failure (HF). However, data on HF prevalence, prognosis, and applicability of echocardiographic criteria for HF diagnosis in FD remain uncertain. METHODS AND RESULTS: We evaluated patients with genetically proven FD for symptoms and natriuretic peptides indicating HF. We then analysed the diagnostic utility of the currently recommended European Society of Cardiology (ESC) echocardiographic criteria for HF diagnosis and their relationship to natriuretic peptides. Finally, we examined the association between HF and echocardiographic criteria with mortality and cardiovascular events during follow-up. Of 116 patients with FD, 48 (41%) had symptomatic HF (mean age 58 ± 11 years, 62% male). HF with preserved ejection fraction (HF-pEF) was diagnosed in 43 (91%) patients, representing the dominant phenotype. Left ventricular mass index (LVMi) had the highest diagnostic utility (sensitivity 71% and specificity 83%) for HF diagnosis in FD, followed by E/e' > 9 (sensitivity 76% and specificity 78%) and global longitudinal strain (GLS) <16% (sensitivity 54% and specificity 88%). Log N-terminal pro-brain natriuretic peptide correlated significantly with LVMi (r = 0.60), E/e' (r = 0.54), and GLS (r = 0.52) (all Ps < 0.001) but not with left ventricular ejection fraction (r = -0.034, P = 0.72). During follow-up (mean 1208 ± 444 days), patients diagnosed with HF had a higher rate of all-cause mortality and worsening HF (33% vs. 1.5%, P < 0.001). Abnormal LVMi, E/e' > 9, and GLS < 16% were all associated with higher all-cause mortality and worsening HF. CONCLUSIONS: This study found a high prevalence of symptomatic HF in FD patients. HF-pEF was the dominant phenotype. LVMi, E/e', and GLS yielded the highest diagnostic utility for HF diagnosis and were significantly correlated with natriuretic peptides levels. Echocardiographic criteria proposed by current ESC HF guidelines apply to Fabry patients and predict cardiovascular events. At follow-up, Fabry patients with HF diagnosis had high event rates and significantly worse prognosis than patients without HF.

• Klíčová slova
• Echocardiography, Fabry disease, Global longitudinal strain, Heart failure, Left ventricular hypertrophy, Natriuretic peptides,
• MeSH
• Fabryho nemoc * komplikace   diagnóza   epidemiologie   MeSH
• funkce levé komory srdeční MeSH
• lidé středního věku MeSH
• lidé MeSH
• natriuretické peptidy MeSH
• senioři MeSH
• srdeční selhání * diagnóza   epidemiologie   etiologie   MeSH
• tepový objem MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• natriuretické peptidy MeSH

BACKGROUND: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body's cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy. PATIENTS AND METHODS: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members. RESULTS: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members. DISCUSSION: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment.

• Klíčová slova
• Fabry disease, cascade genotyping, early diagnosis, family screening, rare diseases,
• MeSH
• alfa-galaktosidasa genetika   MeSH
• chronická renální insuficience * diagnóza   genetika   MeSH
• Fabryho nemoc * diagnóza   genetika   metabolismus   MeSH
• genetické testování MeSH
• glykosfingolipidy MeSH
• kvalita života MeSH
• lidé MeSH
• mutace MeSH
• rodina MeSH
• vzácné nemoci genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-galaktosidasa MeSH
• glykosfingolipidy MeSH

BACKGROUND: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise. METHODS: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries. RESULTS: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists. CONCLUSION: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases.

• Klíčová slova
• Fabry disease, at-risk populations screening, cascade genotyping, early diagnosis, family genetic testing, pedigree drawing, rare disease,
• MeSH
• Fabryho nemoc diagnóza   genetika   MeSH
• genetické testování metody   normy   MeSH
• lidé MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH