Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to GLA variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat-amenable GLA variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient-focused registry evaluating outcomes for current Fabry disease treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry-associated clinical events (FACEs) in a cohort of patients who had received ≥3 years of migalastat treatment in a real-world setting. As of August 2022, 125 patients (60% male) had a mean migalastat exposure of 3.9 years. At enrolment, median age was 58 years (males, 57; females, 60) with a mean eGFR of 83.7 mL/min/1.73 m2 (n = 122; males, 83.7; females, 83.8) and a median left ventricular mass index of 115.1 g/m2 (n = 61; males, 131.2; females, 98.0). Mean (95% confidence interval) eGFR annualised rate of change in the overall cohort (n = 116) was -0.9 (-10.8, 9.9) mL/min/1.73 m2/year with a similar rate of change observed across patients with varying levels of kidney function at enrolment. Despite population age and baseline morbidity, 80% of patients did not experience a FACE during the mean 3.9 years of migalastat exposure. The incidence of renal, cardiac, and cerebrovascular events was 2.0, 83.2, and 4.1 events per 1000 patient-years, respectively. These data support a role of migalastat in preserving renal function and multisystem effectiveness during ≥3 years of migalastat treatment in this real-world Fabry population.

• Klíčová slova
• Fabry disease, migalastat, real world evidence,
• MeSH
• 1-deoxynojirimycin * analogy a deriváty   terapeutické užití   MeSH
• alfa-galaktosidasa genetika   MeSH
• dospělí MeSH
• Fabryho nemoc * farmakoterapie   komplikace   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• kohortové studie MeSH
• ledviny účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• registrace MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• 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
• 1-deoxynojirimycin * MeSH
• alfa-galaktosidasa MeSH
• migalastat MeSH Prohlížeč

Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by restrictive left ventricular pathophysiology, i.e. a rapid rise in ventricular pressure with only small increases in filling volume due to increased myocardial stiffness. More precisely, the defining feature of RCM is the coexistence of persistent restrictive pathophysiology, diastolic dysfunction, non-dilated ventricles, and atrial dilatation, regardless of ventricular wall thickness and systolic function. Beyond this shared haemodynamic hallmark, the phenotypic spectrum of RCM is wide. The disorders manifesting as RCM may be classified according to four main disease mechanisms: (i) interstitial fibrosis and intrinsic myocardial dysfunction, (ii) infiltration of extracellular spaces, (iii) accumulation of storage material within cardiomyocytes, or (iv) endomyocardial fibrosis. Many disorders do not show restrictive pathophysiology throughout their natural history, but only at an initial stage (with an evolution towards a hypokinetic and dilated phenotype) or at a terminal stage (often progressing from a hypertrophic phenotype). Furthermore, elements of both hypertrophic and restrictive phenotypes may coexist in some patients, making the classification challenge. Restrictive pathophysiology can be demonstrated by cardiac catheterization or Doppler echocardiography. The specific conditions may usually be diagnosed based on clinical data, 12-lead electrocardiogram, echocardiography, nuclear medicine, or cardiovascular magnetic resonance, but further investigations may be needed, up to endomyocardial biopsy and genetic evaluation. The spectrum of therapies is also wide and heterogeneous, but disease-modifying treatments are available only for cardiac amyloidosis and, partially, for iron overload cardiomyopathy.

• Klíčová slova
• Amyloidosis, Classification, Myocardial disease, RCM, Restrictive cardiomyopathy,
• MeSH
• dopplerovská echokardiografie MeSH
• dysfunkce levé srdeční komory * patologie   MeSH
• echokardiografie MeSH
• lidé MeSH
• myokard patologie   MeSH
• restriktivní kardiomyopatie * diagnóza   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease. METHODS: Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. "Prompt" was defined as treatment initiation <24 months from symptom onset (analysis A) or diagnosis (analysis B), and "delayed" was defined as ≥24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan-Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs). RESULTS: Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P<0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis. CONCLUSION: This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease.

• Klíčová slova
• cardiomyopathies, early diagnosis, mutation, nephrology, therapeutics,
• MeSH
• alfa-galaktosidasa aplikace a dávkování   MeSH
• časové faktory MeSH
• dospělí MeSH
• enzymová substituční terapie metody   MeSH
• Fabryho nemoc diagnóza   farmakoterapie   patofyziologie   MeSH
• izoenzymy aplikace a dávkování   MeSH
• kardiovaskulární nemoci epidemiologie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci ledvin epidemiologie   etiologie   MeSH
• průzkumy a dotazníky MeSH
• rekombinantní proteiny aplikace a dávkování   MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agalsidase alfa MeSH Prohlížeč
• alfa-galaktosidasa MeSH
• izoenzymy MeSH
• rekombinantní proteiny 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

Fabry disease (FD) is an X-linked lysosomal storage disorder due to reduced or undetectable α-galactosidase A (AGAL-A) enzyme activity caused by pathogenic variants in the AGAL-A gene (GLA). Tissue and organ changes are caused by widespread progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). The classical form of FD is multisystemic with cutaneous (angiokeratomas), neurological (peripheral neuropathy, premature stroke), renal (proteinuria and renal insufficiency), and cardiac involvement. Later onset variants may be limited to the heart. The objective of this review is to summarize the current knowledge on cardiac manifestations of FD and effects of targeted therapy. Cardiac involvement is characterized by progressive hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death (SCD). Targeted therapy is based on enzyme replacement therapy (ERT). Recently, small molecular chaperone, migalastat, became available for patients carrying amenable pathogenic GLA variants. The management of cardiac complications requires a complex approach. Several measures differ from standard clinical guidelines. Betablockers should be used with caution due to bradycardia risk, amiodarone avoided if possible, and anticoagulation used from the first appearance of atrial fibrillation. In Fabry cardiomyopathy SCD calculators are inappropriate. The awareness of FD manifestations is essential for early identification of patients and timely treatment initiation.

• Klíčová slova
• Fabry disease (FD), enzyme replacement therapy (ERT), hypertrophic cardiomyopathy (HCM), molecular chaperones,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. METHODS: We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. RESULTS: Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. CONCLUSIONS: ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.

• Klíčová slova
• ACEi, angiotensin-converting enzyme inhibitor, ANS, autonomic nervous system, ARB, angiotensin receptor blocker, BPI, Brief Pain Inventory, CES-D, Center for Epidemiologic Studies Depression Scale, CNS, central nervous system, CR, case report, CT, clinical trial, ECG, electrocardiogram/electrocardiography, EOW, every other week, ERT, enzyme replacement therapy, Fabry disease, GFR, glomerular filtration rate, GI, gastrointestinal, GL-3, globotriaosylceramide, IENFD, intra-epidermal nerve fibre density, IVST, intraventricular septum thickness, LPWT, left posterior wall thickness, LVEDD, left ventricular end-diastolic diameter, LVEF, left ventricular ejection fraction, LVH, left ventricular hypertrophy, LVM, left ventricular mass, LVMi, left ventricular mass index, LVWT, left ventricular wall thickness, MG, mixed gender, MRI, magnetic resonance imaging, MWT, maximal wall thickness, NYHA, New York Heart Association, OS, observational study, PNS, peripheral nervous system, QoL, quality of life, RCT, randomized controlled trial, SF-36, 36-item Short Form Health Survey, TIA, transient ischaemic attack, WMH, white matter hyperintensities., adult male patients, agalsidase alfa, agalsidase beta, eGFR, estimated glomerular filtration rate, enzyme replacement therapy, lyso-GL-3, globotriaosylsphingosine, systematic literature review,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH