Pathologic substrate of gastropathy in Anderson-Fabry disease.
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ABSTRACT:
SUBMITTER: Di Toro A
PROVIDER: S-EPMC7310490 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Pathologic substrate of gastropathy in Anderson-Fabry disease.
Di Toro Alessandro A Narula Nupoor N Giuliani Lorenzo L Concardi Monica M Smirnova Alexandra A Favalli Valentina V Urtis Mario M Alvisi Costanza C Antoniazzi Elena E Arbustini Eloisa E
Orphanet journal of rare diseases 20200622 1
In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulati ...[more]
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Project description:Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in deficiency of the enzyme alpha-galactosidase A. The worldwide incidence of Fabry's disease is reported to be in the range of 1 in 40,000-117,000, although this value may be a significant underestimate given under recognition of symptoms and delayed or missed diagnosis. Deficiency in alpha-galactosidase A causes an accumulation of neutral glycosphingolipids such as globotriaosylceramide (Gb3) in lysosomes within various tissues including the vascular endothelium, kidneys, heart, eyes, skin and nervous system. Gb3 accumulation induces pathology via the release of pro-inflammatory cytokines, growth-promoting factors and by oxidative stress, resulting in myocardial extracellular matrix remodelling, left ventricular hypertrophy (LVH), vascular dysfunction and interstitial fibrosis. Cardiac involvement manifesting as ventricular hypertrophy, systolic and diastolic dysfunction, valvular abnormalities and conduction tissue disease is common in AFD and is associated with considerable cardiovascular morbidity and mortality from heart failure, sudden cardiac death and stroke-related death.
| S-EPMC6082315 | biostudies-other
Project description:ObjectiveTo estimate the prevalence of prodromal clinical features of neurodegeneration in patients with Anderson-Fabry disease (AFD) in comparison to age-matched controls.MethodsThis is a single-center, prospective, cross-sectional study in 167 participants (60 heterozygous females and 50 hemizygous males with genetically confirmed AFD, 57 age-matched controls) using a clinical screening program consisting of structured interview, quantitative tests of motor function, and assessments of cognition, depression, olfaction, orthostatic intolerance, pain, REM sleep behavior disorder, and daytime sleepiness.ResultsIn comparison to age-matched controls (mean age 48.3 years), patients with AFD (mean age 49.0 years) showed slower gait and transfer speed, poorer fine manual dexterity, and lower hand speed, which was independent of focal symptoms due to cerebrovascular disease. Patients with AFD were more severely affected by depression, pain, and daytime sleepiness and had a lower quality of life. These motor and nonmotor manifestations significantly correlated with clinical disease severity. However, patients with AFD did not reveal extrapyramidal motor features or signs of significant cognitive impairment, hyposmia, orthostatic intolerance, or REM sleep behavior disorder, which commonly precede later neurodegenerative disease. In our cohort, there were no differences in neurologic manifestations of AFD between heterozygous females and hemizygous males.ConclusionsAside from cerebrovascular manifestations and small fiber neuropathy, AFD results in a distinct neurologic phenotype comprising poorer motor performance and specific nonmotor features. In contrast to functional loss of glucocerebrosidase in Gaucher disease, α-galactosidase deficiency in AFD is not associated with a typical cluster of clinical features prodromal for neurodegenerative diseases, such as Parkinson disease.
| S-EPMC4390387 | biostudies-literature
Project description:OBJECTIVE:Limited evidence is available about the early cardiac manifestation of Fabry disease (FD) in children. We aimed to evaluate cardiac involvement in children with FD by analysing serial structural and electrocardiographic changes. METHODS:The data were acquired from 22 children with FD [11 males; median age 9.8 (ranging 2.5-16) years]. Seven patients (5 males) were on enzyme replacement therapy (ERT) with Agalasidase alpha. Echocardiography, ECG and 24-h ECG monitoring recordings were acquired during routine annual clinical controls. ECG data were compared to a group of age-and gender-matched controls. RESULTS:At baseline, ECG and ECHO parameters of left ventricular mass were similar in both males and females. Three boys (all were on ERT) developed left ventricular hypertrophy (LVH) during two-year follow-up. The progression to LVH was accompanied by the appearance of frequent ventricular premature beats in two cases and supraventricular premature beats (SPBs) with T wave inversion in one case. T wave inversion and SPBs were detected in two younger relatives of a patient with LVH, in the absence of detectable LVH. Seven out of 22 patients had T wave abnormalities. Five of them were males (p = 0.03) all carrying the N215S mutation (p = 0.03). At baseline, median PR intervals were prolonged in FD subjects compared to controls [143 (122-177) vs. 122 (82-165) ms; p < 0.0001]. CONCLUSIONS:Cardiac complications of FD become apparent in childhood as subtle changes with slow but detectable progression over time, with males more frequently affected than females. Progression of LVH was apparent in three children despite ERT.
| S-EPMC3755562 | biostudies-literature
Project description:Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder leading to a wide array of clinical manifestations. Among these, gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea affect about half of the FD adults and more than half of FD children. GI symptoms could be the first manifestation of FD; however, being non-specific, they overlap with the clinical picture of other conditions, such as irritable bowel syndrome and inflammatory bowel disease. This common overlap is the main reason why FD patients are often unrecognized and diagnosis is delayed for many years. The present narrative review is aimed to promote awareness of the GI manifestations of FD amongst general practitioners and specialists and highlight the latest findings of this rare condition including diagnostic tools and therapies. Finally, we will discuss some preliminary data on a patient presenting with GI symptoms who turned to be affected by a variant of uncertain significance of alpha-galactosidase (GLA) gene.
| S-EPMC8005161 | biostudies-literature
Project description:Fabry's disease is an X-linked lysosomal storage disease most often associated with renal dysfunction and death due to renal failure in patients' fourth and fifth decades of life. However, cardiac manifestations including arrhythmias, angina and heart failure are common and probably underrecognized. Furthermore, Fabry's disease is now recognised as also affecting female carriers, who manifest signs later than males. A variant of Fabry's has been identified that only affects cardiac tissue, which presents as an unexplained hypertrophy of the left ventricle in middle-aged patients, possibly with women more affected than men. Given that epidemiological studies report a prevalence of Fabry's cardiomyopathy among middle-aged patients with cardiac hypertrophy to be anywhere from one to 12%, it is reasonable to screen these patients for alpha-galactosidase A deficiency. Although mortality data is lacking from randomised, controlled trials of galactosidase replacement therapy, there are some reports of improvement in cardiac endpoints. Therefore patients with known Fabry's disease should be screened early for cardiac involvement, as treatment benefit may not be seen once cardiac fibrosis has developed.
| S-EPMC3734744 | biostudies-other
Project description:BackgroundCardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.Case summaryWe discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.DiscussionRFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.
| S-EPMC7859597 | biostudies-literature
Project description:The clinical symptoms of Fabry disease are caused by progressive accumulation of unprocessed globotriaosylceramide metabolite within cells, inducing multiple organ damage. Enzyme replacement therapy (ERT) is the only strategy to restore enzymatic activity, but a reliable biomarker to assess treatment response does not exist. Here, we identify circulating miR-184 as a sensitive marker of response to ERT and of clinical outcome for cardiac and kidney involvement.
2021-11-06 | GSE162042 | GEO
Project description:ObjectivesCardiac involvement in Anderson-Fabry disease (AFD) results in myocardial lipid depositions. An early diagnosis can maximize therapeutic benefit. Thus, this study aims to investigate the potential of cardiac MRI (CMR) based parameters of left atrial (LA) function and strain to detect early stages of AFD.MethodsPatients (n = 58, age 40 (29-51) years, 31 female) with genetically proven AFD had undergone CMR including left ventricular (LV) volumetry, mass index (LVMi), T1, and late gadolinium enhancement, complemented by LA and LV strain measurements and atrial emptying fractions. Patients were stratified into three disease phases and compared to age and sex-matched healthy controls (HC, n = 58, age 41 [26-56] years, 31 female).ResultsA total of 19 early-, 20 intermediate-, and 19 advanced-phase patients were included. LV and LA reservoir strain was significantly impaired in all AFD phases, including early disease (both p < 0.001). In contrast, LA volumetry, T1, and LVMi showed no significant differences between the early phase and HC (p > 0.05). In the intermediate phase, LVMi and T1 demonstrated significant differences. In advanced phase, all parameters except active emptying fractions differed significantly from HC. ROC curve analyses of early disease phases revealed superior diagnostic confidence for the LA reservoir strain (AUC 0.88, sensitivity 89%, specificity 75%) over the LV strain (AUC 0.82).ConclusionsLA reservoir strain showed impairment in early AFD and significantly correlated with disease severity. The novel approach performed better in identifying early disease than the established approach using LVMi and T1. Further studies are needed to evaluate whether these results justify earlier initiation of therapy and help minimize cardiac complications.Key points• Parameters of left atrial function and deformation showed impairments in the early stages of Anderson-Fabry disease and correlated significantly with the severity of Anderson-Fabry disease. • Left atrial reservoir strain performed superior to ventricular strain in detecting early myocardial involvement in Anderson-Fabry disease and improved diagnostic accuracies of approaches already using ventricular strain. • Further studies are needed to evaluate whether earlier initiation of enzyme replacement therapy based on these results can help minimize cardiac complications from Anderson-Fabry disease.
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Project description:Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.
| S-EPMC6320967 | biostudies-literature
Project description:The Anderson-Fabry disease (AFD, or simply Fabry Disease, FD; MIM #301500) is a rare X-linked lysosomal storage disorder (Xq22.1) characterized by progressive renal failure, leading to morbidity through cardio- and cerebro-vascular involvement. Despite the classic phenotype, only cardiac involvement (cardiac variant of AFD; MIM 301500) is frequent in about 40% of male and 28% of female AFD patients, as reported by the Fabry Registry ( https://www.registrynxt.com ). Morphologically, the cardiac characteristic of the disease, occurs as left ventricular hypertrophy, is accompanied by myocardial fibrosis. Cardiologists may come across these patients during clinical and instrumental evaluation in individuals with non-specific symptoms such as chest pain and arrhythmias, or after instrumental evidence of left ventricular hypertrophy/hypertrophic cardiomyopathy (HCM; MIM 192600). A comprehensive cardiological work-up, including a cardiological visit, a baseline electrocardiogram (ECG) and imaging by both echocardiography (ECHO) and magnetic resonance (MRI) enables identification of the cardiac involvement in patients with a proven diagnosis of AFD. The heart involvement is present in up to 75% of AFD patients irrespective of their sex. Involvement includes ECG and echocardiography features which suggest AFD and not HCM. Cardiac imaging plays an important role in detecting this sub-type of cardiomyopathy, which, since 2001, has benefited from the introduction of the enzyme replacement therapy (ERT) in symptomatic and pre-symptomatic patients.
| S-EPMC6345038 | biostudies-literature