BACKGROUND: Use of artificial intelligence (AI) in rare diseases has grown rapidly in recent years. In this review we have outlined the most common machine-learning and deep-learning methods currently being used to classify and analyse large amounts of data, such as standardized images or specific text in electronic health records. To illustrate how these methods have been adapted or developed for use with rare diseases, we have focused on Fabry disease, an X-linked genetic disorder caused by lysosomal α-galactosidase. A deficiency that can result in multiple organ damage. METHODS: We searched PubMed for articles focusing on AI, rare diseases, and Fabry disease published anytime up to 08 January 2025. Further searches, limited to articles published between 01 January 2021 and 31 December 2023, were also performed using double combinations of keywords related to AI and each organ affected in Fabry disease, and AI and rare diseases. RESULTS: In total, 20 articles on AI and Fabry disease were included. In the rare disease field, AI methods may be applied prospectively to large populations to identify specific patients, or retrospectively to large data sets to diagnose a previously overlooked rare disease. Different AI methods may facilitate Fabry disease diagnosis, help monitor progression in affected organs, and potentially contribute to personalized therapy development. The implementation of AI methods in general healthcare and medical imaging centres may help raise awareness of rare diseases and prompt general practitioners to consider these conditions earlier in the diagnostic pathway, while chatbots and telemedicine may accelerate patient referral to rare disease experts. The use of AI technologies in healthcare may generate specific ethical risks, prompting new AI regulatory frameworks aimed at addressing these issues to be established in Europe and the United States. CONCLUSION: AI-based methods will lead to substantial improvements in the diagnosis and management of rare diseases. The need for a human guarantee of AI is a key issue in pursuing innovation while ensuring that human involvement remains at the centre of patient care during this technological revolution.

• Klíčová slova
• Artificial intelligence, Deep learning, Fabry disease, Machine learning, Rare diseases,
• MeSH
• Fabryho nemoc * diagnóza   MeSH
• lidé MeSH
• umělá inteligence * MeSH
• vzácné nemoci * diagnóza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disease resulting from pathogenic variants in the GLA gene coding α-galactosidase A (AGAL) and cleaving terminal alpha-linked galactose. Globotriaosylceramide (Gb3) is the predominantly accumulated sphingolipid. Gb3, deacylated-Gb3 (lysoGb3), and methylated-Gb3 (metGb3) have been suggested as FD biomarkers. MATERIALS AND METHODS: We developed a novel LC-MS/MS method for assessing lysoGb3 levels in plasma and Gb3 and metGb3 in urine and tested 62 FD patients, 34 patients with GLA variants of unknown significance (VUS) and 59 healthy controls. AGAL activity in white blood cells (WBCs) and plasma was evaluated in parallel. RESULTS: In males, lysoGb3 concentrations in plasma separated classic and late-onset FD patients from each other and from individuals carrying GLA VUS and healthy controls. Calculating AGAL activity/plasmatic lysoGb3 ratio allowed to correctly categorize all females with classic and majority of patients with late-onset FD phenotypes. Correlation of AGAL activity in WBCS with lipid biomarkers identified threshold activity values under which the biomarkers' concentrations increase. CONCLUSION: We developed a novel simplified LC-MS/MS method for quantitation of plasma lysoGb3. AGAL activity/plasma lysoGb3 ratio was identified as the best predictor for FD. AGAL activity correlated with plasma lysoGb3 and corresponded to individual FD phenotypes.

• Klíčová slova
• Diagnostics, Fabry disease, Globotriaosylsphingosine, Lysosomal storage, Mass spectrometry, Phenotype,
• MeSH
• alfa-galaktosidasa genetika   metabolismus   MeSH
• biologické markery krev   MeSH
• chromatografie kapalinová MeSH
• dospělí MeSH
• Fabryho nemoc * krev   diagnóza   moč   MeSH
• fenotyp MeSH
• glykolipidy krev   moč   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři MeSH
• sfingolipidy * krev   MeSH
• tandemová hmotnostní spektrometrie * MeSH
• trihexosylceramidy metabolismus   krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-galaktosidasa MeSH
• biologické markery MeSH
• globotriaosyl lysosphingolipid MeSH Prohlížeč
• globotriaosylceramide MeSH Prohlížeč
• glykolipidy MeSH
• sfingolipidy * MeSH
• trihexosylceramidy MeSH

INTRODUCTION: Fabry disease (FD) can be undiagnosed in the context of multiple sclerosis (MS) due to similar clinical and paraclinical features. Our study aimed to determine the prevalence (and the necessity of screening) of FD among patients with possible or definite MS. METHODS: In this prospective monocentric observational study, we included consecutive patients enrolled between May 2017 and May 2019 after the first clinical event suggestive of MS. All patients underwent FD screening using dried blood spots in a stepwise manner combining genetic and enzyme testing. Patients were followed until May 2022. RESULTS: We included 160 patients (73.1% female, mean age 33.9 years). The 2017 revised McDonald's criteria for definite MS were fulfilled by 74 (46.3%) patients at the time of study recruitment and 89 (55.6%) patients after 3-5 years of follow-up. None of the patients had a pathogenic GLA variant, and four (2.5%) had a variant of unknown significance (p.A143T, p.S126G, 2 × p.D313Y). In two of these patients, the intrathecal synthesis of oligoclonal bands was absent, and none had hyperproteinorachia or pleocytosis in cerebrospinal fluid. Detailed examination of FD organ manifestations revealed only discrete ocular and kidney involvement in two patients. CONCLUSION: The prevalence of FD in the population of suspected or definite MS patients does not appear to be high. Our results do not support routine FD screening in all patients with a possible diagnosis of MS, but there is an urgent need to search for red flags and include FD in the differential diagnosis of MS.

• Klíčová slova
• A variant of unknown significance, Differential diagnosis, Fabry disease, Misdiagnosis, Multiple sclerosis, Screening,
• MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• Fabryho nemoc * diagnóza   epidemiologie   MeSH
• lidé MeSH
• nepoznaná diagnóza MeSH
• prospektivní studie MeSH
• roztroušená skleróza * diagnóza   epidemiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

BACKGROUND: The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD. METHODS: We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q. CONCLUSIONS: This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data. REGISTRATION: URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663.

• Klíčová slova
• Fabry disease, galactosidases, globotriaosylceramide, humans, prevalence,
• MeSH
• alfa-galaktosidasa genetika   MeSH
• cévní mozková příhoda * MeSH
• Fabryho nemoc * diagnóza   epidemiologie   genetika   MeSH
• hypertrofie levé komory srdeční MeSH
• lidé MeSH
• novorozenec MeSH
• prevalence MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• alfa-galaktosidasa MeSH

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked inherited lysosomal disease caused by a defect in the gene encoding lysosomal enzyme α-galactosidase A (GLA). Atrio-ventricular (AV) nodal conduction defects and sinus node dysfunction are common complications of the disease. It is not fully elucidated how frequently AFD is responsible for acquired AV block or sinus node dysfunction and if some AFD patients could manifest primarily with spontaneous bradycardia in general population. The purpose of study was to evaluate the prevalence of AFD in male patients with implanted permanent pacemaker (PM). METHODS: The prospective multicentric screening in consecutive male patients between 35 and 65 years with implanted PM for acquired third- or second- degree type 2 AV block or symptomatic second- degree type 1 AV block or sinus node dysfunction was performed. RESULTS: A total of 484 patients (mean age 54 ± 12 years at time of PM implantation) were enrolled to the screening in 12 local sites in Czech Republic. Out of all patients, negative result was found in 481 (99%) subjects. In 3 cases, a GLA variant was found, classified as benign: p.Asp313Tyr, p.D313Y). Pathogenic GLA variants (classical or non-classical form) or variants of unclear significance were not detected. CONCLUSION: The prevalence of pathogenic variants causing AFD in a general population sample with implanted permanent PM for AV conduction defects or sinus node dysfunction seems to be low. Our findings do not advocate a routine screening for AFD in all adult males with clinically significant bradycardia.

• Klíčová slova
• Bradycardia, Fabry disease, Permanent pacing, Screening,
• MeSH
• atrioventrikulární blokáda * diagnóza   epidemiologie   terapie   MeSH
• bradykardie komplikace   terapie   MeSH
• dospělí MeSH
• Fabryho nemoc * diagnóza   epidemiologie   genetika   MeSH
• kardiostimulátor * škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• senioři MeSH
• syndrom chorého sinu diagnóza   epidemiologie   terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• Alpha-galactosidase, Fabry disease, Genetic testing, Hypertrophic cardiomyopathy, Lyso-Gb3, Screening,
• MeSH
• alfa-galaktosidasa genetika   MeSH
• dospělí MeSH
• Fabryho nemoc * diagnóza   epidemiologie   genetika   MeSH
• genetické testování MeSH
• hypertrofická kardiomyopatie * diagnóza   epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři 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
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• alfa-galaktosidasa 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

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding alpha-galactosidase A (AGAL). The impact of X-chromosome inactivation (XCI) on the phenotype of female FD patients remains unclear. In this study we aimed to determine pitfalls of XCI testing in a cohort of 35 female FD patients. XCI was assessed by two methylation-based and two allele-specific expression assays. The results correlated, although some variance among the four assays was observed. GLA transcript analyses identified crossing-over in three patients and detected mRNA instability in three out of four analyzed null alleles. AGAL activity correlated with XCI pattern and was not influenced by the mutation type or by reduced mRNA stability. Therefore, AGAL activity may help to detect crossing-over in patients with unstable GLA alleles. Tissue-specific XCI patterns in six patients, and age-related changes in two patients were observed. To avoid misinterpretation of XCI results in female FD patients we show that (i) a combination of several XCI assays generates more reliable results and minimizes possible biases; (ii) correlating XCI to GLA expression and AGAL activity facilitates identification of cross-over events; (iii) age- and tissue-related XCI specificities of XCI patterning should be considered.

• Klíčová slova
• Fabry disease heterozygotes, GLA transcript expression, X chromosome inactivation assay, alpha-galactosidase A activity,
• MeSH
• alfa-galaktosidasa genetika   MeSH
• chromozomy MeSH
• Fabryho nemoc * diagnóza   genetika   MeSH
• fenotyp MeSH
• inaktivace chromozomu X genetika   MeSH
• lidé MeSH
• mutace MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa-galaktosidasa MeSH