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We describe a patient with Fabry disease (FD) who initially presented with atrial fibrillation without left ventricular hypertrophy (LVH) 14 years before being correctly diagnosed with FD. In the interim, he survived a myocardial infarction complicated by ventricular fibrillation, and his severe LVH was misdiagnosed as sarcomeric hypertrophic cardiomyopathy. In the following 4 years, he developed proteinuric kidney disease, neuropathy, sensorineural hearing loss and gastrointestinal symptoms. The patient was eventually readmitted for an overt heart failure (HF) exacerbation and was seen by an HF cardiologist. The constellation of systemic findings led to further diagnostic testing, including an endomyocardial biopsy, tests to determine alpha-galactosidase A enzyme activity and α-galactosidase A gene (GLA) analysis. The results of the patient’s tests were consistent with FD and he was started on enzyme replacement therapy. To our knowledge, this is the first detailed description of a late-onset phenotype of FD with c.146 G>C GLA variant. In addition, this case serves as a potent reminder to pay meticulous attention to ‘red flags’ accompanying LVH.

Fabry disease is an X-linked lysosomal storage disorder caused by reduced activity or absence of the alpha-galactosidase A enzyme resulting in systemic accumulation of glycosphingolipids. End-stage renal disease (ESRD) is a late-stage manifestation of Fabry disease, typically presenting in the fifth decade of life, but is very rare in childhood. Here we present a case of an 11-year-old boy with classical Fabry disease presenting with ESRD requiring haemodialysis and transplant. Diagnosis was confirmed by renal biopsy, GLA mutation and low alpha-galactosidase A levels. He has an unusual genotype, hemizygous for the c.1000–11T>A intronic variant and positive for the pseudodeficiency allele D313Y. Due to the possibility of very early and accelerated disease progression, Fabry disease should be considered as a possible diagnosis in unexplained renal failure in males from a younger age.

Introduction: Left ventricular (LV) hypertrophy is the main feature of cardiac involvement in Anderson-Fabry disease (FD), but the right ventricle (RV) is also frequently affected. Previous studies failed to demonstrate an independent association between conventional parameters of RV performance and outcomes in FD. Nevertheless, if RV free wall strain (RV-FWS), assessed by 2D speckle tracking analysis, may provide a better prognostication is currently unknown. Methods: We retrospectively evaluated the association between RV-FWS and the occurrence of cardiovascular events in a cohort of 56 patients with FD. The study endpoint comprises cardiovascular mortality, severe heart failure symptoms, new-onset atrial fibrillation and major arrhythmias requiring device implantation. Results: Reduced RV-FWS, defined by values lower than 23%, was found in 25 (45%) patients. During a median follow-up of 47 months, 16 (29%) patients met the study endpoint. A ROC-curve analysis confirmed the threshold of reduced RV-FWS (

Little is known about prevalence and predictors of myocardial infarction with non-obstructive coronary arteries (MINOCA) in Fabry disease (FD) and hypertrophic cardiomyopathy (HCM). We assessed and compared the prevalence and predictors of MINOCA in a large cohort of HCM and FD patients.In this multicenter, retrospective study we enrolled 2870 adult patients with HCM and 267 with FD. The only exclusion criterion was documented obstructive coronary artery disease. MINOCA was defined according to guidelines. For each patient we collected clinical, ECG and echocardiographic data recorded at initial evaluation.Overall, 36 patients had MINOCA during a follow-up period of 4.5 ± 11.2 years. MINOCA occurred in 16 patients with HCM (0.5%) and 20 patients with FD (7.5%; p lt; 0.001). The difference between the 2 groups was highly significant, also after adjustment for the main clinical, ECG and echocardiographic variables (OR 6.12; 95%CI 2.80-13.3; p lt; 0.001). In the FD population MINOCA occurred in 17 out of 96 patients with left ventricle hypertrophy (LVH, 17.7%) and in 3 out of 171 patients without LVH (1.7%; OR 12.0; 95%CI 3.43-42.3; p lt; 0.001). At multivariable analysis, voltage criteria for LVH at ECG (OR 7.3; 95%CI 1.93-27.7; p = 0.003) and maximal LV wall thickness at echocardiography (OR 1.15; 95%CI 1.05-1.27; p = 0.002) maintained an independent association with MINOCA. No major significant differences were found in clinical, ECG and echocardiographic findings between HCM patients with or without MINOCA.MINOCA was rare in HCM patients, and 6-fold more frequent in FD patients. MINOCA may be considered a red flag for FD and aid in the differential diagnosis from HCM.

The prevalence of Fabry disease (FD) in male patients with left ventricular hypertrophy (LVH) is about 1%. From the perspective of performing more efficient screening with measurement of α-galactosidase (α-Gal) activity, it is important to raise the pretest probability.We retrospectively investigated the prevalence of FD in 701 male patients with LVH who already had been screened by measurement of α-Gal activity in eight hospitals. From the viewpoint of enzymatic screening, we validated previously reported clinical features of FD including the electrocardiographic and echocardiographic characteristics with comparing each clinical determinant between patients with FD and non-FD patients. We finally aimed to establish a new screening approach for the detection of patients at high risk of FD.There were five FD patients (0.7%) in the 701 male patients with LVH. Those five patients with FD all had the cardiac variant type and age at detection of LVH was ≥35 years in all patients. In LVH patients with LV ejection fraction (EF) ≥ 50%, Pend-Q interval 40 msec, SV1 + RV5 4.0 mV, and diffuse LVH were important determinants of FD. In LVH patients with LVEF 50%, asymmetric septal hypertrophy and posterior wall motion abnormality seemed to be associated with FD.In our retrospective study, the prevalence of FD in male patients with LVH was found to be 0.7%. We established the efficient combinations of clinical determinants using age at detection of LVH, Pend-Q interval, high voltage, and LVH pattern in an echocardiogram.

What is Fabry disease & what is this study about? Fabry disease is a rare genetic condition that affects many different cells and organs in the body. People have Fabry disease when they inherit a GLA gene containing an error from one or both of their parents. This causes an enzyme in their body called alpha-galactosidase (also called α-Gal) to not work properly. In people without Fabry disease, a-Gal breaks down fats called glycolipids. In people with Fabry disease, as a-Gal does not work properly, glycolipids build up in the body, particularly in the cells of the kidney, heart, nerves, and the cells that line blood vessels. People who have Fabry disease can receive an enzyme replacement therapy (ERT for short) called agalsidase beta, which acts as a substitute for a-Gal. Although both males and females can have Fabry disease, it generally affects males more severely than females, and symptoms in females can vary significantly. Several researchers have studied the long-term effects of agalsidase beta ERT in males, but there have been fewer studies in females. This study looked at women with Fabry disease who started receiving agalsidase beta treatment when they were at least 18 years old, using information from the Fabry Registry (the largest worldwide database that collects and stores information about people with Fabry disease). The researchers evaluated heart muscle thickness (thickening can be a sign of poor heart health) and kidney function from 5 years before women with Fabry disease started agalsidase beta treatment to 5 years after they started treatment. What were the study results? Before women with Fabry disease started treatment, their heart muscle tended to thicken over time. After starting treatment, their heart muscle thickening slowed. Kidney function was similar to that of unaffected people both before and after treatment. What do the results of the study mean? This study provides a unique insight into the effects of agalsidase beta in women with Fabry disease. The findings suggest that agalsidase beta may slow heart muscle thickening and maintain normal kidney function in women with Fabry disease. Clinical Trial Registration: NCT00196742 ( ClinicalTrials.gov )

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by reduced or absent activity of the enzyme α-galactosidase A. Due to systemic accumulation of glycolipids, FD phenotype is diverse, and diagnosis may be challenging. Clinical manifestations include small fiber neuropathy, renal dysfunction, cardiac involvement, cerebrovascular disease, among others. In the present study, we describe biopsy proven small fiber neuropathy and subclinical cardiac involvement in two cousins diagnosed with FD secondary to a recently described pathogenic variant, highlighting the importance of diagnostic tools to document organ damage and allow early treatment.

Dried blood spots (DBSs) biomarkers are convenient for monitoring for specific lysosomal storage diseases (LSDs), but they could have relevance for other LSDs. To determine the specificity and utility of glycosphingolipidoses biomarkers against other LSDs, we applied a multiplexed lipid liquid chromatography tandem mass spectrometry assay to a DBS cohort of healthy controls (n = 10) and Gaucher (n = 4), Fabry (n = 10), Pompe (n = 2), mucopolysaccharidosis types I–VI (n = 52), and Niemann–Pick disease type C (NPC) (n = 5) patients. We observed no complete disease specificity for any of the markers tested. However, comparison among the different LSDs highlighted new applications and perspectives of the existing biomarkers. We observed elevations in glucosylceramide isoforms in the NPC and Gaucher patients relative to the controls. In NPC, there was a greater proportion of C24 isoforms, giving a specificity of 96–97% for NPC, higher than 92% for the NPC biomarker N-palmitoyl-O-phosphocholineserine ratio to lyso-sphingomyelin. We also observed significantly elevated levels of lyso-dihexosylceramide in Gaucher and Fabry disease as well as elevated lyso-globotriaosylceramide (Lyso-Gb3) in Gaucher disease and the neuronopathic forms of Mucopolysaccharidoses. In conclusion, DBS glucosylceramide isoform profiling has increased the specificity for the detection of NPC, thereby improving diagnostic accuracy. Low levels of lyso-lipids can be observed in other LSDs, which may have implications in their disease pathogenesis.

Background: Fabry disease cardiomyopathy (FDCM) has manifested some resistance to enzyme replacement therapy (ERT), particularly in its advanced phase. Recently, myocardial inflammation of autoimmune origin has been demonstrated in FDCM. Aims: The objective of this study was the assessment of circulating anti-globotriaosylceramide (GB3) antibodies as potential biomarkers of myocardial inflammation in FDCM, defined by the additional presence of ≥CD3+ 7 T lymphocytes/low-power field associated with focal necrosis of adjacent myocytes. Its sensitivity was based on the evidence of overlapping myocarditis at left ventricular endomyocardial biopsy. Methods and Results: From January 1996 to December 2021, 85 patients received a histological diagnosis of FDCM in our department and 48 (56.5%) of them had an overlapping myocardial inflammation with negative PCR for common cardiotropic viruses, positive antiheart, and antimyosin abs. The presence of anti-GB3 antibodies was evaluated with an in-house ELISA assay (BioGeM scarl Medical Investigational Research, MIR—Ariano Irpino, Italy), along with antiheart and antimyosin abs, in the FDCM patients and compared with control healthy individuals. The correlation between levels of circulating anti-GB3 autoantibody myocardial inflammation and FDCM severity was assessed. Anti-Gb3 antibodies were above the positivity cut-off in 87.5% of FDCM subjects with myocarditis (42 out of 48), while 81.1% of FDCM patients without myocarditis were identified as negative for Gb3 antibodies. Positive anti-Gb3 abs correlated with positive antiheart and antimyosin abs. Conclusions: The present study suggests a potential positive role of anti-GB3 antibodies as a marker of overlapping cardiac inflammation in patients with FDCM.

In clinical practice, the consideration of non-specific symptoms of rare diseases in order to make a correct and timely diagnosis is often challenging. To support physicians, we developed a decision-support scoring system on the basis of retrospective research. Based on the literature and expert knowledge, we identified clinical features typical for Fabry disease (FD). Natural language processing (NLP) was used to evaluate patients’ electronic health records (EHRs) to obtain detailed information about FD-specific patient characteristics. The NLP-determined elements, laboratory test results, and ICD-10 codes were transformed and grouped into pre-defined FD-specific clinical features that were scored in the context of their significance in the FD signs. The sum of clinical feature scores constituted the FD risk score. Then, medical records of patients with the highest FD risk score were reviewed by physicians who decided whether to refer a patient for additional tests or not. One patient who obtained a high-FD risk score was referred for DBS assay and confirmed to have FD. The presented NLP-based, decision-support scoring system achieved AUC of 0.998, which demonstrates that the applied approach enables for accurate identification of FD-suspected patients, with a high discrimination power.

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OBJECTIVE: To establish cut-off values of lysosomal storage disease (LSD)-related enzymes by tandem mass spectrometry. METHODS: A total of 26 689 newborns and 7 clinically confirmed LSD children underwent screening for LSDs (glycogen storage disease typeⅡ, Fabry disease, mucopolysaccharidosis type Ⅰ, Krabbe disease, Niemann-Pick disease A/B and Gaucher disease). The activities of LSD-related enzymes were detected by tandem mass spectrometry. The 20% of the median enzyme activity of each batch of acid β-glucocerebrosidase, acid sphingomyelinase, β-galactocerebroside, α- L-iduronidase and acid α-glucosidase, and the 30% of the median enzyme activity of α-galactosidase were taken as cut-off values of corresponding enzymes. The genetic diagnosis was performed in neonates whose enzyme activity was lower than 70% of the cut-off value. RESULTS: The enzyme activities of 7 clinically confirmed cases were all lower than the cut-off values. Among 26 689 newborns, 142 cases (0.53%) were suspected positive for LSDs, including 25 cases of β-galactocerebroside deficiency, 1 case of α- L-iduronidase deficiency, 19 cases of α-galactosidase deficiency, and 97 cases of acid α-glucosidase deficiency. Eight infants were genetically diagnosed with LSDs, including 3 cases of glycogen storage disease type Ⅱ, 3 cases of Krabbe disease, and 2 cases of Fabry disease, with a positive predictive value of about 5.6%. Cut-off values ​​of the 6 LSD enzyme activities all showed a downward trend from March to August, and an upward trend from September to December. There was a statistically significant difference in LSD enzyme activity among different months ( P

Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first-tier enzyme quantitation and second-tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G A (p.Ala143Thr) aka A143T and the majority of non-A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.

La malattia di Fabry comprende una estrema varietà fenotipica in relazione con il grande numero di organi e sistemi coinvolti. La diagnosi di malattia di Fabry è complessa a causa del numero di organi/sistemi coinvolti e dei fenotipi clinici non specifici e della sua rarità. La progressione clinica della malattia si manifesta tra i 30-40 anni quando per i numerosi organi coinvolti compaiono manifestazioni cliniche quali insufficienza cardiaca, renale ed eventi cerebrovascolari. La morte di solito sopraggiunge durante la quarta/quinta decade di vita ed è secondaria all’interessamento cardiaco, renale o cerebrale anche se l’avvento della dialisi e della terapia enzimatica sostitutiva stanno sensibilmente prolungando la vita media dei pazienti. Seppur conosciuto in dettaglio il gene che causa la malattia e la sua funzione, ad oggi appare ancora poco chiaro il perché la malattia presenti un’ampia eterogeneità di presentazione clinica, anche all’interno della stessa famiglia. I fattori che potrebbero giocare un ruolo nella modulazione fenotipica della malattia di Fabry sono molteplici e non ancora studiati (fattori ambientali, fattori epigenetici, altri geni modulatori).mI mitocondri rappresentano “la centralina energetica della cellula” [202). Sono organelli intracellulari che svolgono diverse funzioni, la più importante delle quali è rappresentata dalla produzione di energia sotto forma di ATP mediante la fosforilazione ossidativa. Il mitocondrio è l’unico organellodelle cellule animali dotato di un proprio genoma, il DNA mitocondriale (mtDNA). In ogni mitocondrio si trovano da 2 a 10 copie di mtDNA, ed in ogni cellula più di 1000 copie. Il mtDNA è una molecola circolare di DNA a doppio filamento, costituito da 16569 paia basi, che codifica 37 geni: 13 codificano peptidi della catena respiratoria mitocondriale, 2 RNA ribosomali e 22 RNA transfer (tRNA). Tutte le altre proteine mitocondriali (comprese le 67 subunità che concorrono a formare i cinque complessi della catena respiratoria) sono codificate dal DNA nucleare. L’mtDNA umano è caratterizzato da un elevato tasso evolutivo che è 10 – 20 volte quello dei geni del nucleo; la sua variazione di sequenza si è perciò generata lungo linee di radiazione materna esclusivamente per l’accumulo sequenziale di nuove mutazioni. Nel tempo questo processo di divergenza molecolare ha dato origine ad entità monofiletiche dette aplogruppi. Un valido strumento per determinare se eventuali polimorfismi mitocondriali possano agire come fattori di suscettibilità o di protezione nell’insorgenza di malattie neurodegenerative è stato fornito proprio dall’analisi degli aplogruppi mitocondriali, definiti come clusters di genomi mitocondriali continente-specifici correlati all’evoluzione e definiti in base alla presenza di ancestrali e stabili polimorfismi.. La presenza di stabili siti polimorfici all’interno della regione codificante definisce l’aplogruppo, mentre la maggior parte delle mutazioni che si osservano sia nelle sequenze codificanti che nella regione di controllo e che si realizzano all’interno di preesistenti aplogruppi definiscono il tipo individuale di mtDNA, o aplotipo [172]. È stato ipotizzato che variazioni all’interno del mtDNA possano causare sottili differenze nelle proteine codificate ed indurre una modificazione, seppur minima, nelle attività della fosforilazione ossidativa e nella produzione di specie reattive dell’ossigeno, o viceversa agire come fattori protettivi, con effetto benefico sulla catena di trasporto di elettroni e/o per la produzione di radicali liberi. In questi ultimi anni la ricerca è stata finalizzata alla comprensione di un eventuale ruolo degli aplogruppi nella modulazione dell’espressione dei geni mitocondriali durante l’evoluzione e i processi di adattamento del genere umano; si è iniziato inoltre ad indagare se la variabilità del genoma mitocondriale potesse svolgere un’azione protettiva o, viceversa, agire come fattore di rischio nell’insorgenza di malattie neurodegenerative come il morbo di Parkinson (192), la malattia di Friedreich (203), la Sclerosi Laterale Amiotrofica [196]), la malattia di Alzheimer e Corea di Huntington [172]. Benchè numerose mutazioni del gene GLA siano state associate alle forme classiche e tardive, una definitiva correlazione genotipo-fenotipo none stata dimostrata e la diagnosi e classificazione della malattia on possono essere effettuate solo su base genetica. Il deposito dei substrati è correlato al danno tissutale nella malattia di Fabry; tuttavia, i meccanismi molecolari sottostanti restano non completamente conosciuti. I pazienti affetti da malattia di Fabry presentano un importante danno 44 ossidativo proteico e lipidico, ridotte difese antiossidanti e aumentali livelli di citochine e biomarcatori infiammatori [204–205]. L’eccesso di GB3 intracellulare induce stress ossidativo e un up-regulation dell’espressione delle molecole di adesione cellulare nelle cellule endoteliali vascolari [206]. Inoltre è stato ipotizzato che si verifica uno stato proossidante che è correlato e sembra essere indotto dal GB3 nei pazienti con malattia di Fabry [207]Lo scopo del nostro progetto multicentrico è stato quello di valutare il ruolo dello stress ossidativo nella malattia di Fabry. In particolare abbiamo valutato (I) se vi sono segni di stress ossidativo nel sangue; (II) se esiste un’associazione tra biomarcatori di stress ossidativo e manifestazion i cliniche della malattia e/o una differenza tra forma classica e varianti late onset; (III) se i parametri dello stress ossidativo nel tempo si correlano con il Lyso-Gb3 e l’insorgenza e progressione della malattia, in un sottogruppo di 8 soggetti/paziente naive al trattamento con normali livelli di Lyso-Gb3, al fine di valutare se i biomarkers di stress ossidativo possano presentare marcatori precoci della malattia Questo progetto si proponeva inoltre di valutare la frequenza degli aplogruppi mitocondriali, un loro possibile ruolo di suscettibilità genetica nel determinismo della malattia di Fabry, e se essi potessero influenzare lo stato di stress ossidativo plasmatico in tali pazienti; tuttavia l’analisi dei dati, relativi a questo secondo obiettivo , sul gruppo dei pazienti arruolati non ha permesso di ottenere risultati rilevanti, chiari e definitivi pertanto il nostro gruppo si propone di proseguire un ulteriore approfondimento in questo campo di ricerca scientifica, raccogliere più dati estendendo l’analisi su un maggior numero di pazienti e quindi coinvolgendo più centri. Fabry disease comprises a wide phenotypic variability in relation to the large number of organs and systems involved. The diagnosis of Fabry disease is complex due to the number of organs/systems involved, to the non-specific clinical manifestationa and to its rarity. Clinical progression of the disease occurs between 30-40 years when clinical manifestations because of the involvement of important organs such as heart failure, renal failure and cerebrovascular events. Death usually occurs during the fourth/fifth decade of life and it is secondary to cardiac, renal or cerebral involvement even if the advent of dialysis and enzyme replacement therapy are significantly prolonging the average life of patients. Although the gene that causes the disease and its function is known in detail, it still appears today unclear the wide heterogeneity of clinical presentation that characterizes this disorder, within the same family, too. Factors that might play a role in phenotypic modulation of Fabry disease are multiple and not yet studied (environmental factors, epigenetic factors, other modulatory genes).Mitochondria represent "the energy central unit of the cell" [202].They are intracellular organelles that perform different functions, the most important of which is represented by the production of energy in the form of ATP through oxidative phosphorylation. The mitochondrion is the only organelle with its own genome, mitochondrial DNA (mtDNA). In each mitochondrion there are from 2 to 10 copies of mtDNA, and in each cell more than 1000 copies. The mtDNA is a circular molecule of double-stranded DNA, consisting of 16569 base pairs, encoding 37 genes: 13 encode mitochondrial respiratory chain peptides, 2 ribosomal RNAs and 22 RNAs transfer (tRNA). All other mitochondrial proteins (including the 67 subunits that contribute to form the five complexes of the respiratory chain) are encoded by nuclear DNA. Human mtDNA is characterized by a high evolutionary rate that is 10 – 20 times that of genes of the nucleus; its sequence variation was therefore generated along lines of maternal radiation exclusively for the sequential accumulation of new mutations. Over time this process of molecular divergence has given rise to monophyletic entities called haplogroups. A valid tool to determine if any mitochondrial polymorphisms can act as susceptibility or protective factors in the onset of neurodegenerative diseases was provided precisely from the analysis of mitochondrial haplogroups, defined as clusters of mitochondrial genomes continent-specific related to evolution and defined by the presence of ancestral and stable polymorphisms. The presence of stable polymorphic sites within the coding region defines the haplogroup, on the other hand most of the mutations that are observed are both in the coding sequences and in the control region and that occur within pre-existing haplogroups define the individual mtDNA type, or haplotype [172]. It has been hypothesized that variations within the mtDNA can cause subtle differences in the encoded proteins and induce a modification, albeit minimal, in the activities of oxidative phosphorylation and in the production of reactive species of oxygen, or they act as protective factors, with a beneficial effect on the transport chain of electrons and/or for the production of free radicals. In recent years, research has been aimed at understanding a possible role of haplogroups in the modulation of mitochondrial gene expression during evolution and in the human processes of adaptation ; it has also begun to investigate whether the variability of the genome mitochondrial could perform a protective action or, conversely, it acts as a risk factor in the onset of neurodegenerative diseases such as Parkinson's disease (192), the disease of Friedreich (203), Amyotrophic Lateral Sclerosis [196]), Alzheimer's disease and Huntington [172]. Although numerous mutations of the GLA gene have been associated with the classic and late forms, one definitive genotype-phenotype correlation has not been demonstrated and the diagnosis and classification of disease can only be made on a genetic basis. Substrate deposition is related to tissue damage in Fabry disease; however, the underlying molecular mechanisms remain unclear fully known. Patients with Fabry disease have an important impairment of protein and lipid oxidative processes , reduced antioxidant defenses and increased levels of inflammatory cytokines and biomarkers [204–205]. the high level intracellular GB3 induces oxidative stress and up-regulation of the expression of cell adhesion molecules in vascular endothelial cells [206]. Furthermore it has been hypothesized that a pro-oxidant state occurs which is related and appears to be induced by GB3 in patients with Fabry disease [207]The aim of our multicenter project was to evaluate the role of oxidative stress in Fabry disease. In particular we evaluated (I) whether there are signs of oxidative stress in the blood; (II) whether there is an association between biomarkers of oxidative stress and clinical manifestations of the disease and/or a difference between the classic form and late onset variants; (III) whether the stress parameters over time correlate with Lyso-Gb3 and disease onset and progression, in a subset of 8 treatment-naive subjects/patients with normal Lyso-Gb3 levels, in order to evaluate whether biomarkers of oxidative stress may present early markers of the disease This project also aimed to evaluate the frequency of mitochondrial haplogroups, their possible role of genetic susceptibility in the determinism of Fabry disease, and if they could influence the state of plasma oxidative stress in such patients; however, the analysis of the data, concerning this second aim, on the group of enrolled patients did not allow to obtain relevant , clear and definitive results therefore our group proposes to pursue a further deepening in this field of scientific research, to collect more data by extending the analysis on a greater number of patients and therefore involving more centres.

Fabry disease (FD) is an X-linked, systemic lysosomal deposition disease caused by alpha-galactosidase A (AGAL) enzyme deficiency deriving out of changes on the GLA gene. Though several mutations have been described, one must consider that even a specific mutation may present with variable clinical expression within the same family. Typically described as a disease that affects hemizygous men with no residual AGAL activity, we describe a novel FD mutation (first case of GLA T194A variant worldwide) in a 49-year-old woman presenting with a classic phenotype of FD. The patient investigation highlighted a previously not described mutation in exon 4 of the GLA gene, as for the substitution of threonine for alanine. The same mutation was identified in her children, one of them presenting with end-stage kidney disease (ESKD) in early adulthood.

Introduction: Fabry disease (FD) is an inborn error of metabolism characterized by α-galactosidase A deficiency. The primary objective was to evaluate the genetic and phenotypic profile of Fabry disease in hemodialysis. Methods: Observational cohort study to determine the incidence of genetic variations and phenotypic changes for FD in hemodialysis patients in the Paraiba Valley and Eastern São Paulo. Genetic testing for the GLA gene was performed for men and women over 12 years of age at the hemodialysis clinics between January 2016 and December 2019 as a screening protocol. Results: The cases came from screening exams of the index case among patients with chronic kidney disease, resulting in 17 families and totaling 82 patients under study. The classification of the most prevalent variant was that of uncertain significance (54%), followed by the pathogenic variant (46%). Five patients in two families were described with two types of variants not previously described in the literature, with pathogenic behavior. Comparing the types of variants, the presence of a pathogenic variant was associated with higher levels of lysoGB3, lower values for alpha-GAL activity and higher frequency of symptoms related to FD. Conclusion: We characterized an extensive population of patients with FD variants with rich genetic, clinical and biomarker details. We believe that this study can help to better characterize the Brazilian population with FD and the most frequent types of variants. RESUMO Introdução: A doença de Fabry (DF) é um erro inato do metabolismo caracterizado pela deficiência da enzima α-galactosidase A. O objetivo primário foi avaliar o perfil genético e fenotípico da doença de Fabry em hemodiálise. Métodos: Estudo de coorte observacional para determinar a incidência de variações genéticas e alterações fenotípicas para DF em pacientes em hemodiálise no Vale do Paraíba e Zona Leste de São Paulo. O teste genético para o gene GLA foi realizado para homens e mulheres em todos os pacientes das clínicas de hemodiálise maiores de 12 anos entre janeiro de 2016 a dezembro de 2019 como protocolo de rastreio. Resultados: Os casos foram provenientes de exames de triagem do caso índice entre pacientes portadores de doença renal crônica, resultando em 17 famílias e totalizando 82 pacientes em estudo. A classificação da variante mais prevalente foi a de significado incerto (54%), seguida da variante patogênica (46%). Foram descritos 5 pacientes em duas famílias com dois tipos de variantes ainda não previamente descritos na literatura com comportamento patogênico. Na comparação entre os tipos de variantes, a presença de variante patogênica foi associada a maiores níveis de lysoGB3, menores valores da atividade da alfa-GAL e maior frequência de sintomas relativos à DF. Conclusão: Caracterizamos uma extensa população de pacientes com variantes para DF com riqueza de detalhes de genética, clínica e de biomarcadores. Acreditamos que este estudo possa auxiliar na melhor caracterização da população brasileira com DF e nos tipos mais frequentes de variantes.

Fabrijeva bolest je rijetka, multisistemska X-vezana nasljedna lizosomska bolest nakupljanja, u kojoj nedostatna aktivnost enzima α-galaktozidaze A dovodi do nakupljanja globotriaozilceramida u zahvaćenim tkivima u tijelu. Srčane komplikacije Fabrijeve bolesti javljaju se u sklopu klasične varijante bolesti s ranim početkom, koja se češće viđa u muškaraca, i u sklopu srčane ili atipične varijante bolesti s kasnijim početkom. Srčane komplikacije Fabrijeve bolesti uključuju hipertrofiju lijeve klijetke, fibrozu miokarda, valvularnu bolest, zatajenje srca, aritmije, koronarne komplikacije i iznenadnu srčanu smrt. Ove komplikacije imaju veliki prognostički utjecaj na Fabrijevu bolest te predstavljaju glavni uzrok smrti bolesnika. Najčešće korištene metode u dijagnostici srčanih komplikacija su elektrokardiografija, ehokardiografija, magnetska rezonancija srca i određivanje laboratorijskih biomarkera. Napredak u slikovnim metodama prikaza srca poboljšao je dijagnozu i evaluaciju Fabrijeve kardiomiopatije, a uz bolje razumijevanje patofiziologije bolesti, i terapijske opcije specifične za Fabrijevu bolest brzo se razvijaju. Osnovni cilj liječenja jest spriječiti progresiju bolesti i ireverzibilno oštećenja organa. Glavni trenutno odobreni tretmani specifični za Fabrijevu bolest uključuju enzimsku nadomjesnu terapiju (ERT) i farmakološko šaperonsko liječenje migalastatom. Započeto u ranoj fazi bolesti, liječenje postiže bolji ishod, može usporiti progresiju bolesti te ima pozitivan učinak na srčane komplikacije, stoga su pravodobno prepoznavanje i rani početak liječenja krucijalni. Nastale srčane komplikacije zbrinjavaju se konvencionalnim liječenjem u skladu s važećim smjernicama, uz nekoliko upozorenja u skladu sa samom prirodom Fabrijeve bolesti. Suradnja raznih specijalista i stručnjaka te holistički pristup liječenju esencijalni su za optimalnu skrb ovih bolesnika koji zahtijevaju cijeloživotno praćenje. Cilj ovog rada je pružiti cjelovit pregled dosadašnjih spoznaja o patofiziologiji, dijagnozi, pristupu i liječenju srčanih komplikacija Fabrijeve bolesti., Fabry disease (FD) is a rare, multisystemic X-linked inherited lysosomal storage disorder, in which the deficient activity of the enzyme α-galactosidase A leads to the accumulation of globotriaosylceramide in affected tissues in the body. Cardiac involvement in Fabry disease occurs as a part of the classic, early-onset variant of the disease, more commonly seen in men, as well as in the cardiac or atypical, late-onset variant of the disease. Cardiovascular involvement can manifest as a left ventricular hypertrophy, myocardial fibrosis, valve disease, heart failure, arrhythmias, coronary complications and sudden cardiac death. These complications carry a major prognostic impact on Fabry disease, representing the main cause of death in patients. Most commonly used diagnostic methods in evaluation of cardiac involvement include electrocardiography, echocardiography, cardiac magnetic resonance imaging and laboratory biomarkers. Advances in cardiac imaging techniques have improved the diagnosis and staging of Fabry cardiomyopathy, while with the better understanding of pathophysiology of the disease, the FD-specific treatment landscape is evolving rapidly. The main goal of the treatment is to prevent disease progression and irreversible organ damage. Currently, the main approved FD-specific treatments include enzyme replacement therapy (ERT) and the pharmacological chaperone migalastat. If instituted early in the disease course, the treatment has shown to achieve a better outcome and might slow the disease progression,while also having a positive effect on cardiac complications. Therefore, early recognition and treatment are crucial. Cardiac complications are treated with conventional treatment by the current guidelines, incorporating a few caveats considering the very nature of Fabry's disease. The cooperation of various specialists and experts as well as a holistic approach to treatment are essential for optimal care of these patients who require lifelong monitoring. The goal of this thesis is to provide a comprehensive overview of current knowledge on the pathophysiology, diagnosis, approach and the treatment of cardiac complications of Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder where impaired α-galactosidase A enzyme activity leads to the intracellular accumulation of undegraded glycosphingolipids, including globotriaosylsphingosine (lyso-Gb3) and related analogues. Lyso-Gb3 and related analogues are useful biomarkers for screening and should be routinely monitored for longitudinal patient evaluation. In recent years, a growing interest has emerged in the analysis of FD biomarkers in dried blood spots (DBSs), considering the several advantages compared to venipuncture as a technique for collecting whole-blood specimens. The focus of this study was to devise and validate a UHPLC-MS/MS method for the analysis of lyso-Gb3 and related analogues in DBSs to facilitate sample collection and shipment to reference laboratories. The assay was devised in conventional DBS collection cards and in Capitainer®B blood collection devices using both capillary and venous blood specimens from 12 healthy controls and 20 patients affected with FD. The measured biomarker concentrations were similar in capillary and venous blood specimens. The hematocrit (Hct) did not affect the correlation between plasma and DBS measurements in our cohort (Hct range: 34.3–52.2%). This UHPLC-MS/MS method using DBS would facilitate high-risk screening and the follow-up and monitoring of patients affected with FD.

Fabry disease (FD) is an X-linked lysosomal storage disorder with multi-system involvement including cerebrovascular disease. Patients with FD also have a high risk of ischaemic stroke and TIA. White matter hyperintensities are common, but their clinical impact on cognition remains uncertain. Previous studies have examined the neuropsychological profile of FD, but have been inconclusive in part due to methodological limitations including small sample sizes. We sought to address these limitations in a case-control study of 26 patients with Fabry disease with mild to moderate disease symptoms matched with 18 healthy controls for age and premorbid intellectual level. We obtained detailed neuropsychological data and MRI neuroimaging data on the severity of white matter changes. Mood was accounted for as a possible confounder. Our results showed significant compromise of executive functions and information processing speed for the FD group. Error analyses suggested that the compromise of executive functions could not be entirely accounted for by slowed information processing speed. We demonstrated significant correlations between cognitive decline and the overall volume of white matter hyperintensities in the FD group. Our results point to significant compromise of cognition in FD even without stroke or mood difficulties. This suggests that neuropsychological assessment and rehabilitation should be routinely offered to patients with FD.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by the mutation in the α-galactosidase A gene that leads to a consequently decreased α-galactosidase A enzyme activity and a series of clinical presentations. However, FD accompanied with aseptic meningitis can be relatively scarce and rarely reported, which leads to significant clinical misdiagnosis of this disease.Sixteen patients diagnosed with FD based on a decreased activity of α-galactosidase A enzyme and/or genetic screening were identified through a 6-year retrospective chart review of a tertiary hospital. Clinical presentations, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analyzed in cases of aseptic meningitis associated with FD.Three out of 16 cases exhibited aseptic meningitis associated with FD. There was one female and two male patients with a mean age of 33.3 years. A family history of renal failure or hypertrophic cardiomyopathy was found in 3 cases. All cases presented with a persistent or intermittent headache and recurrent ischemic stroke. The cerebrospinal fluid analyses showed mild pleocytosis in 2 patients and an elevated level of protein in all patients. Cerebrospinal fluid cytology revealed activated lymphocytes, suggesting the existence of aseptic meningitis. In the literature review, up to 9 cases presenting with FD and aseptic meningitis were found, which bore a resemblance to our patients in demographic and clinical characteristics.Our cases suggested that aseptic meningitis in FD might be under-detected and easily misdiagnosed, and should be more thoroughly examined in further cases.

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.

Fabry disease (FD) manifests decreased α-galactosidase A (α-Gal A) activity and multiorgan damage. There are some undiagnosed cases of the condition among patients on dialysis. The prevalence of FD may also vary with the region. Among 227 male patients undergoing maintenance hemodialysis in Awaji Island, a remote island in Japan, 201 (88.5%) were included in this study. Patients with α-Gal A activity

Objectives Gaucher disease type 1 (GD1) and Fabry disease (FD) are the two most common lysosomal storage diseases. For over three decades, effective enzyme replacement therapies (ERTs) have changed the fate of patients and offered a longer chance of survival and improve their quality of life. Methods The clinical and molecular findings, endocrinological features and metabolic status of 26 patients (16 with FD, and 10 with GD1) were evaluated. The results were compared to age- and gender-matched healthy individuals. Results Patients with GD1 and FD were followed for 7.2 ± 4.7 and 6.4 ± 4.3 years, respectively. Calcium and magnesium levels in patients with GD1 were lower than in controls (p=0.01; p=0.002). Osteoporosis was detected in 20% (n=2) of GD1 patients and 12.5% (n=2) of FD patients. The HbA1c value of GD1 patients was significantly lower than both in control and Fabry patients (p=0.004; and p=0.007, respectively). There was a negative correlation between LysoGb3 and female gender (p=0.04; r=−0.49), but no correlation was found with any other biochemical parameters. There was a negative correlation between the LysoGb1 level and the neutrophil (p=0.03; r=−0.711) and thrombocyte levels (p=0.02; r=−0.767), and a positive correlation with ferritin levels (p Conclusion Long time effective ERT seems to have beneficial effects on metabolic and hormonal status as well as primary target organs in both FD and GD1 patients.

A number of genes that cause inherited kidney disorders reside on the X chromosome. Given that males have only a single active X chromosome, these disorders clinically manifest primarily in men and boys. However, phenotypes in female carriers of X-linked kidney conditions are becoming more and more recognized. This article reviews the biology of X inactivation as well as the kidney phenotype in women and girls with a number of X-linked kidney disorders including Alport syndrome, Fabry disease, nephrogenic diabetes insipidus, X-linked hypophosphatemic rickets, Dent disease, and Lowe syndrome.

Introduction: Bradyarrhythmias are an established red flag for storage cardiac conditions including Anderson-Fabry disease (AFD). The prevalence of bradyarrhythmias requiring a pacemaker (PM) and their timing in AFD is unresolved. We evaluated prevalence and predictors of PM requirement in a large AFD cohort, investigating the occurrence of bradyarrhythmias as initial versus late manifestation. Methods: we retrospectively evaluated 82 consecutive AFD patients referred to our multidisciplinary referral centre from 1994 to 2020 with a median follow up of 6.9 years, identifying those requiring pacing. Univariable analysis was performed to identify cardiac features associated with PM implantantion. Results: Five of 82 (6%) AFD patients required PM implantation (5/39, i.e. 13% of those with cardiac involvement), always in the context of advanced cardiomyopathy. In none, bradyarrhythmias were the presenting feature. Indications included sick sinus syndrome in 3 patients, advanced atrio-ventricular block in 2 patients. QRS prolongation during follow up strongly correlated with the onset of bradyarrhythmias. Conclusions: Severe bradyarrhythmias are relatively frequent in patients with AFD cardiomyopathy, but do not represent a mode of presentation, occurring late in the disease course and always in the context of advanced cardiac involvement. Monitoring QRS variations over time may help to identify patients requiring pacing.

Objective White matter lesions (WML) in multiple sclerosis (MS) differ from vascular WML caused by Fabry disease (FD). However, in atypical cases the discrimination can be difficult and may vary between individual raters. The aim of this study was to evaluate interrater reliability of WML differentiation between MS and FD patients. Materials and methods Brain MRI scans of 21 patients with genetically confirmed FD were compared to 21 matched patients with MS. Pseudonymized axial FLAIR sequences were assessed by 6 blinded raters and attributed to either the MS or the FD group to investigate interrater reliability. Additionally, localization of WML was compared between the two groups. Results The median age of patients was 46 years (IQR 35–58). Interrater reliability was moderate with a Fleiss' Kappa of 0.45 (95%CI 0.3–0.59). Overall, 85% of all ratings in the MS group and 75% in the FD group were correct. However, only 38% of patients with MS and 33% of patients with FD were correctly identified by all 6 raters. WML involving the corpus callosum (p p p = 0.03) were more frequently observed in MS patients. Conclusion Interrater reliability regarding visual differentiation of WML in MS from vascular WML in FD on standard axial FLAIR images alone is only moderate, despite the distinctive features of lesions in each group.

BACKGROUND Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by a deficiency of the enzyme α-galactosidase A. CASE SUMMARY Herein, we analyzed a four-generation Chinese family. The proband is a 57-year-old woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago. Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm, left ventricular end-diastolic diameter of 63.1 mm, and moderate-to-severe mitral regurgitation. Cardiac magnetic resonance indicated an enlarged left heart and right atrium, decreased left ventricular systolic and diastolic function, a left ventricular ejection fraction of 20%, and thickening of the left ventricular septum. In March 2019, gene and enzyme activity tests confirmed the diagnosis of FD. Her son was diagnosed with FD after gene and enzyme activity assay, and was prescribed agalsidase-β for enzyme replacement therapy in July 2020. Two sisters of the proband were also diagnosed with FD by genetic testing. Both of them had a history of atrial fibrillation. CONCLUSION A novel mutation was identified in a Chinese family with FD, in which the male patient had a low level of enzyme activity, early-onset, and severe organ involvement. Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.

To evaluate the effects of Fabry disease (FD) on the retinal microvasculature and choroidal vascular and structural characteristics.This study included 10 patients with FD and 10 age-matched healthy controls. Binarized enhanced depth imaging optical coherence tomography (OCT) images were used to measure the total choroidal area, luminal area, and stromal area with ImageJ software. The choroidal vascularity index (CVI) was assessed. The vessel densities (VD) of the retinal capillary plexuses and foveal avascular zone (FAZ) area were measured with OCT-angiography.The most common anterior segment finding was cornea verticillata (60.0%) and the most frequent posterior segment finding was vascular tortuosity (50.0%). Intraretinal hyperreflective foci on B-scan OCT was observed in 50.0% of the cases. In Fabry cases, a linear mixed model with random intercept revealed that 1% change in CVI was related to -0.009 mmThe significant negative associations between FAZ measurements and CVI suggest a possible interaction between the choroidal and retinal microvasculature of patients with FD. These alterations were more pronounced in the presence of hyperreflective foci and retinal vascular tortuosity.

Although the use of specific MRI criteria has significantly increased the diagnostic accuracy of multiple sclerosis (MS), reaching a correct neuroradiological diagnosis remains a challenging task, and therefore the search for new imaging biomarkers is crucial. This study aims to evaluate the incidence of one of the emerging neuroradiological signs highly suggestive of MS, the central vein sign (CVS), using data from Fabry disease (FD) patients as an index of microvascular disorder that could mimic MS.In this retrospective study, after the application of inclusion and exclusion criteria, MRI scans of 36 FD patients and 73 relapsing-remitting (RR) MS patients were evaluated. Among the RRMS participants, 32 subjects with a disease duration inferior to 5 years (early MS) were also analyzed. For all subjects, a Fazekas score (FS) was recorded, excluding patients with FS = 0. Different neuroradiological signs, including CVS, were evaluated on FLAIR T2-weighted and spoiled gradient recalled echo sequences.Among all the recorded neuroradiological signs, the most striking difference was found for the CVS, with a detectable prevalence of 78.1% (57/73) in RRMS and of 71.4% (25/32) in early MS patients, while this sign was absent in FD (0/36).Our results confirm the high incidence of CVS in MS, also in the early phases of the disease, while it seems to be absent in conditions with a different etiology. These results corroborate the possible role of CVS as a useful neuroradiological sign highly suggestive of MS.• The search for new imaging biomarkers is crucial to achieve a correct neuroradiological diagnosis of MS. • The CVS shows an incidence superior to 70% in MS patients, even in the early phases of the disease, while it appears to be absent in FD. • These findings further corroborate the possible future central role of CVS in distinguishing between MS and its mimickers.

The presence of myeloid bodies (MBs) is classically associated with Fabry disease (FD). However, MBs are also identified in patients without clinical evidence of FD. We attempt to further understand the clinicopathologic significance of incidental MBs in those without FD. Among the 4400 renal biopsies accessioned at the University of Rochester Medical Center from 2010 to 2021, we identified 32 cases showing MBs, 6 of which had FD. Medications were compared between a non-FG and a control-group of randomly selected cases without MBs (non-MBs). Both Fabry-group (FG) and non-Fabry-group (non-FG) were predominantly middle-aged (mean 48 years vs 56, respectively). Non-FG had slight female predominance (1:4), while all in FG were female. The majority of both non-FG and non-MBs cohort were on the same medications reported to cause phospholipidosis except sertraline and hydralazine (

Background: Fabry disease is an inherited lysosomal storage disease affecting multiple organs with complications, including cardiomyopathy such as left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) has been the main treatment for Fabry patients since 2001. However, the indications of ERT are not clearly defined. We performed a meta-analysis according to previous studies to review the benefit of ERT for LVH improvement in Fabry patients. Methods: We performed a literature search from the National Center for Biotechnology Information (NCBI) and PubMed database without restriction of years for systematic review purposes. We performed a systematic review of clinical cohort studies and trials using a pooled analysis of proportions. We calculated the pooled proportions and the confidence intervals (CI) for left ventricular mass index (LVMI) for both ERT treatment and ERT treatment-naïve groups. The results for before ERT treatment and after ERT treatment are also investigated. Results: A total of 5 cohort studies and 2 randomized controlled trials (RCTs), involving a total of 552 participants (267 on ERT treatment versus 285 on naïve treatment), met the inclusion criteria. The pooled proportions analysis showed that the difference in means of LVMI between the ERT treatment group and the ERT treatment-naïve group was -0.149 [95% CI: -0.431, 0.132]. Effect differences favored the ERT treatment group over the ERT treatment-naïve group (p = 0.034). Another analysis included 3 cohort studies and 1 RCT with 442 participants (228 on before ERT and 214 on 4 years after ERT). The pooled proportions analysis showed that the difference in means of LVMI between the before ERT treatment group and the after ERT treatment group was -0.448 [95% CI: -0.787, -0.108]. It favored the 4 years after ERT group over the before ERT group (p = 0.037). Conclusions: Based on the currently available data, our meta-analysis showed that there are beneficial effects on LVH improvement with ERT in Fabry disease patients. It is better to start ERT as soon as we have diagnoses in female carriers and atypically affected males. Further research is needed to investigate the role of ERT in LVH improvement.

Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. Cardiac involvement is common in FD and is responsible for impaired quality of life and premature death. The classic cardiac involvement is a nonobstructive form of hypertrophic cardiomyopathy, usually manifesting as concentric left ventricular hypertrophy, with subsequent arrhythmogenic intramural fibrosis. Treatment of patients with FD should be directed to prevent the disease progression to irreversible organ damage and organ failure. The aim of this review is to describe the current state of knowledge regarding cardiovascular involvement in FD, focusing on clinical and instrumental features, cardiovascular management, and targeted therapy.

Fabry disease (FD) is an X-linked lysosomal disorder caused by α-galactosidase A enzyme deficiency. Gastrointestinal (GI) manifestations are reported in FD with a prevalence of about 50%, usually treated by Enzymatic Replacement Therapy (ERT) or oral treatment. Since FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) can be involved in GI manifestations and dysbiosis in FD patients, a low-FODMAP diet could represent an alternative adjunctive treatment in FD subjects, as well as being useful for reducing symptoms in Irritable Bowel Syndrome (IBS). We retrospectively assessed data from 36 adult FD patients followed at the Inherited Metabolic Rare Diseases Adult Centre of the University Hospital of Padova (mean age 47.6 ± 16.2 years). Patients were screened for GI symptoms by IBS severity score and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires. In symptomatic patients, the low-FODMAP diet was proposed in order to improve GI manifestations; it consists of a phase of elimination of fermentable saccharides, succeeded by a gradual reintegration of the same. Severe or moderate GI symptoms were found in 61.1% of patients, with no correlation to the therapy in use, and significantly more severe in the classical form of FD. The protocol was completed by seven patients affected by severe GI manifestations, significantly higher than the others. The low-FODMAP diet significantly improved indigestion, diarrhoea, and constipation. This dietetic protocol seemed to have a positive impact on intestinal symptoms, by identifying and reducing the intake of the foods most related to the onset of disorders and improving the clinical manifestations. A low-FODMAP diet may be an effective alternative approach to improve intestinal manifestations and quality of life, and nutrition can play an important role in the multidisciplinary care of patients with FD.

Metabolic and overload disorders are a heterogeneous group of relatively uncommon but important diseases. While imaging plays a key role in the early detection and accurate diagnosis in specific organs with a pivotal role in several metabolic pathways, most of these diseases affect different tissues as part of a systemic syndromes. Moreover, since the symptoms are often vague and phenotypes similar, imaging alterations can present as incidental findings, which must be recognized and interpreted in the light of further biochemical and histological investigations. Among imaging modalities, MRI allows, thanks to its multiparametric properties, to obtain numerous information on tissue composition, but many metabolic and accumulation alterations require a multimodal evaluation, possibly using advanced imaging techniques and sequences, not only for the detection but also for accurate characterization and quantification. The purpose of this review is to describe the different alterations resulting from metabolic and overload pathologies in organs and tissues throughout the body, with particular reference to imaging findings.

Background: Fabry disease (FD) is an X-linked, lysosomal storage disorder leading to severe cardiomyopathy in a significant proportion of patients. To identify ECG markers that reflect early cardiac involvement and disease progression, we conducted a long term retrospective study in a large cohort of FD patients. Methods: A total of 1995 ECGs from 133 patients with classical FD (64% females, 80% treated with enzyme replacement therapy), spanning 20 years of follow-up, were compared to ECGs from 3893 apparently healthy individuals. Generalized linear mixed models were used to evaluate the effect of age, FD and sex on: P-wave duration, PR-interval, QRS-duration, QTc, Cornell index, spatial QRS-T angle and frontal QRS-axis. Regression slopes and absolute values for each parameter were compared between FD patients and control subjects. Results: At a younger age (

Objective: This scoping review aims to assess the current evidence involving the screening, diagnosis and classification, risk stratification, and surveillance of patients with Fabry Disease (FD). Introduction: Due to its heterogeneous presentation and rare frequency, FD is significantly misdiagnosed. Understanding how to assess FD patients is crucial to ensure appropriate screening, early diagnosis, accurate classification, and timely treatment. A preliminary search of PubMed and the Cochrane Database of Systematic Reviews was conducted, and no published or underway systematic reviews or scoping reviews on our research question were identified. Inclusion criteria: We will include human-based research articles based on qualitative or quantitative methods published in peer-reviewed journals that describe methods to assess FD patients, particularly those related to diagnosis and classification, screening, stratification, and follow-up. Only articles with full text available, published between 2017 and 2023, and written in English and Spanish will be included. Methods: The search strategy will be developed by a librarian and conducted on six databases. Selection of studies will be independently conducted by calibrated reviewers through the title, abstract, and full-text screening, followed by data charting. Quantitative (e.g., frequencies and percentages) and qualitative (e.g., classification of assessment methods) synthesis will be conducted.

BackgroundA small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET).MethodsSixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat.ResultsNo change in LV mass was detected at 18 months compared to baseline (95.2 g/m2(66.0–184.0) vs 99.0 g/m2(69.0–121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848–882) vs 860.0 ms (833.0–875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70–21.50) vs 14.50 mL/kg/min (11.70–18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2(72.0 (63.0–80.0) vs 69.0 (53.0–77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6–76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance.ConclusionIn treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others.Trial registration numberNCT03838237.

Background In Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in patients with Fabry disease are limited. In the present study, the pathologic findings of patients with Fabry nephropathy receiving enzyme replacement therapy (ERT) and untreated patients without albuminuria were investigated. Methods The present study included 15 patients with Fabry disease who underwent renal biopsy while receiving ERT (group 1: n = 9, age 19–58 years, two males and seven females) or before ERT initiation (group 2: n = 6, age 11–66 years, one male and five females). All patients in group 2 were normoalbuminuric. Results Group 1 showed improved clinical symptoms, such as acroparesthesia. The ERT duration was 1.2 to 8 years and seven of the nine patients showed GL3 deposits in various kidney cells and segmental foot process effacement (FPE) of podocytes. GL3 deposits and FPE were not observed in the two remaining patients in group 1. Group 2 showed segmental FPE and podocyte GL3 deposits. Most patients in group 2 also showed GL3 deposits in the mesangium, endothelium, or tubular epithelium. Conclusion The study results showed that segmental FPE and GL3 deposits can persist in Fabry nephropathy despite ERT. In addition, segmental FPE and GL3 deposits were observed in various kidney cells in normoalbuminuric patients with Fabry disease. These findings indicated that kidney biopsies at baseline and follow-up evaluation of Fabry nephropathy are essential for timely ERT initiation and ERT response assessment.

Introduction: Fabry disease is a rare metabolic, multisystemic, and X-linked lysosomal storage disorder. The involvement of the autonomic nervous system is well defined; however, data on the variability of the blood pressure (BP) and heart rate in Fabry disease are largely missing. In this study, we aimed to examine the circadian variations of BP and heart rate variability in Fabry disease patients. Methods: We recruited 31 consecutive adult (age >18 years) Fabry disease patients (16 males and 15 females) who were regularly followed up in our outpatient clinic between July 2019 and March 2020. We performed ambulatory blood pressure monitoring and echocardiography in all patients. We used standard deviation (SD), coefficient of variation (CV), and average real variability as the measures of variability. We constructed 2 control groups for propensity score matching using age, sex, and eGFR parameters in the first group and adding antihypertensive drug use to the above parameters in the second group. Results: All BP measurements were significantly lower in the FD group compared to that of the control groups, except the nighttime systolic BP. Regarding nondipping and reverse dipping statuses, FD patients and controls were similar. We found that none of the BP variability measures were higher in FD patients. Regarding heart rate variability data, both the nighttime SD and CV were significantly lower in FD patients compared to those of the controls. Conclusion: A decrease in heart rate variability, rather than an increase in BP variability, might be an early marker of autonomic involvement in FD.

Lysosomal storage disorders are an agglomeration of genetic disorders such as Fabry disease, Gaucher disease, Pompe disease, Krabbe’s disease and mucopolysaccharidosis that typically impairs the prime orangs of humans, including brain, heart, musculoskeletal system, spleen, eye, and lungs. Patients with lysosomal storage disorders face mild to severe complications and even death. In order to address these health concerns, scientists are working by dint off, various therapies are introduced such as gene therapy, typical oral medicines, organ/ cell transplantation etc. However, hematopoietic stem cell transplantation and enzyme replacement therapy came out as best stakeholders to treat aforementioned disorders. Nonetheless, according to suggested data, it is concluded that presently enzyme replacement therapies are somehow ineffective for many lysosomal storage disorders till today. But we believe that in near future, as more and more research will be progressed, the ultimate therapy to these disorders will be developed.

We describe a 55 year old male diagnosed with cardiomyopathy due to Fabry disease. Biochemical testing of blood spot and plasma showed low-normal alpha-galactosidase A (α-Gal A) levels. Genetic testing revealed somatic mosaicism for GLA c.901C>T, p.(Arg301Ter). Usually, males with Fabry disease due to loss of function variants in GLA show symptoms of the multisystemic features of the condition early in life, and have very low levels of the α-Gal A enzyme. This demonstrates that the diagnosis of Fabry disease in males with cardiomyopathy should still be considered even in the context of a normal plasma enzyme assay.

Aims Fabry disease (FD) is an X‐linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of globotriaosylceramide in multi‐organ systems, and variant clinical manifestations. We aimed to detail the clinical and genetic spectrum of FD in Chinese families. Methods and results Five male probands with unexplained left ventricular hypertrophy and their family members were investigated. Genetic screening was available in 11 subjects of the 5 families, 10 of whom proved to be carriers of either GLA gene mutation, including 3 previous reported missense mutations (c.128G > A, c.811G > A, c.950T > C), 1 novel missense mutation (c.37G > C), and 1 novel deletion mutation (c.1241delT). A total of 17 patients were definitely or possibly diagnosed of FD, given their clinical manifestations and hereditary nature of FD. Echocardiography demonstrated normal cardiac structure and function in six female patients. Electrocardiographic pre‐excitation occurred in 80% (4/5) of men and 16.7% (1/6) of women. Six patients (6/14, 42.9%) had chronic kidney disease with decreased renal function and all were male (6/7, 85.7%). Six patients presented with acroparesthesia, hypohidrosis, or both. Three female patients and two male patients experienced sudden death, and one male patient with the mutation (c.128G > A) died of progressive heart failure, between 41 and 66 years of age. Conclusions We reported five unrelated families of FD with different GLA mutations. Clinical manifestations were highly heterogeneous between male and female patients even within the same family. Female patients showed relatively low risks of structural heart disease and renal insufficiency. However, the long‐term outcomes might be adverse in both sexes. Our study underlines the importance of molecular screening of the GLA gene for early identification and clinical decision making in patients with FD.

ObjectiveThis study describes the influence of sex and disease phenotype on the occurrence of cardiac events in Fabry disease (FD).MethodsCardiac events from birth to last visit (median age 50 years) were recorded for 213 patients with FD. Patients were categorised as follows : men with classical FD (n=57), men with non-classical FD (n=26), women with classical FD (n=98) and women with non-classical FD (n=32), based on the presence of classical FD symptoms, family history (men and women), biomarkers and residual enzyme activity (men). Event rates per 1000 patient-years after the age of 15 years and median event-free survival (EVS) age were presented. Influence of disease phenotype, sex and their interaction was studied using Firth’s penalised Cox regression.ResultsThe event rates of major cardiovascular events (combined endpoint cardiovascular death (CVD), heart failure (HF) hospitalisation, sustained ventricular arrhythmias (SVAs) and myocardial infarction) were 11.0 (95% CI 6.6 to 17.3) in men with classical FD (EVS 55 years), 4.4 (95% CI 2.5 to 7.1) in women with classical FD (EVS 70 years) and 5.9 (95% CI 2.6 to 11.6) in men with non-classical FD (EVS 70 years). None of these events occurred in women with non-classical FD. Sex and phenotype significantly influenced the risk of major adverse cardiovascular event. CVD was the leading cause of death (75%) to which HF contributed most (42%). The overall rate of SVA was low (14 events in nine patients (4%)).ConclusionsSex and phenotype greatly influence the risk and age of onset of cardiac events in FD. This indicates the need for patient group-specific follow-up and treatment.

Background Fabry disease (FD) remains poorly recognized, especially in children in China. Considering the diversity and nonspecific clinical manifestations accompanying with life-threatening aspect of this disease, methods to improve effective screening and management of the suspects are needed. This study aims to explore how it can be done effectively from a multidisciplinary perspective for children with FD at a tertiary children’s hospital in China. Methods A multidisciplinary team (MDT) of pediatric FD experts was launched at Children’s Hospital of Fudan University. Children with high-risk characteristics were referred by the MDT screening team using the dried blood spot (DBS) triple-test (α-galactosidase A, globotriaosylsphingosine, GLA gene). For newborns who were undergoing genetic testing in the hospital, the GLA gene was listed as a routine analysis gene. Evaluation, family screening, and genetic counselling were implemented after screening by the MDT management team. Results Before the establishment of the MDT, no case was diagnosed with FD in the hospital. However, twelve months following the MDT program's implementation, thirty-five children with high-risk profiles were referred for screening by DBS triple-test, with a yield of diagnosis of 14.3% (5/35). These 5 diagnosed children were referred due to a high-risk profile of pain accompanied by dermatological angiokeratoma and hypohidrosis (n = 2), pain accompanied by abnormal liver function (n = 1), pain only (n = 1), and unexplained renal tubular dysfunction (n = 1). Two neonates were detected early with GLA mutations in the hospital, with a yield of detection of 0.14% (2/1420). Furthermore, another 3 children diagnosed with FD were referred from other hospitals. Family screening of these 10 diagnosed children indicated that 9 boys inherited it from their mothers and 1 girl inherited it from her father. Four of them started to receive enzyme replacement therapy. Conclusion Screening and management of children with FD is effective based on a defined screening protocol and a multidisciplinary approach. We should pay more attention to the high-risk profiles of pain, angiokeratoma, decreased sweating, and unexplained chronic kidney disease in children.

Neurofilament Light Chain (NfL) serum concentration is a new noninvasive marker of neurodegenerative disorders. Fabry disease (FD) leads to accumulation of glycosphingolipids in tissues leading to progressive damage of critical body systems and organs, including peripheral and central nervous system. There are no established serum markers of neurodegeneration in FD. Our cross-sectional single-center study was designed to prove the concept that serum NfL levels could reflect the severity of cognitive impairment and indirectly, the level of central nervous system involvement in women at earlier stages of FD. Twelve women with a diagnosis of FD confirmed by genetic tests and 12 matched healthy subjects were included. Serum concentrations of NfL were measured in all subjects together with neuropsychological tests that included Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA). Quality of life was assessed with the Short Form Survey (SF-36). FD patients and healthy subjects did not differ with respect to serum NfL concentration, results of neuropsychological tests and quality of life. There was a significant positive correlation between NfL and globotriaosylosphingosine (lyso-Gb3) concentration in women with FD (R = 0,69, p = 0.01). There was also a correlation between NfL concentration and MoCA score but not MMSE score. Receiver operating characteristic (ROC) analysis showed that the best predictor for Mild Cognitive Impairment in both groups was eGFR. Serum NfL concentration does not appear to predict the degree of nervous system involvement in women with FD.