Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review.
Ontology highlight
ABSTRACT:
SUBMITTER: Caputo F
PROVIDER: S-EPMC8005161 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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.
| S-EPMC9935647 | biostudies-literature
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:This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the effects of enzyme replacement therapy with human alpha-galactosidase A. The study population comprised 20 patients (11 males, 9 females) aged 15-69 years (mean 39.7). Patients underwent a complete clinical and instrumental evaluation before starting and during enzyme replacement therapy. Median follow-up was 51.5 months (range 25-73). Nine patients (45%) complained of hearing symptoms (hearing loss, tinnitus); for six of them the onset and/or progression of the hearing loss were sudden. Vertigo or dizziness was reported by 6 patients (30%). Audiological evaluation showed a sensorineural hearing loss in 18 ears (45%; 10 in male patients, 8 in females). The hearing thresholds for 0.5, 1, 2 and 4 kHz frequencies ranged from 10 to 65 dB HL. Hearing loss was unilateral in 8 cases (40%; 4 in male patients, 4 in females). Also high frequency hearing loss for 4 and 8 kHz was evaluated. No signs of retro-cochlear lesions were observed by means of otoacoustic emissions and auditory brainstem response. Vestibular examinations showed a functional impairment in 7 ears (17.5%, all male patients). During enzyme replacement therapy the auditory function showed some degrees of worsening but no significant changes were observed at statistical analysis. In conclusion involvement of the inner ear is common in men and women with Fabry disease. In this study, a high incidence of cochlear hearing loss was found, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement showed a lower incidence and different pattern, thus suggesting that several patho-physiological mechanisms could play a role in determining inner ear damage in Fabry disease. Results obtained show that enzyme replacement therapy may stabilize hearing function; however, further studies on the physiopathology of the inner ear damage are needed.
| S-EPMC2882147 | biostudies-literature
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: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 accumulation in late-onset AFD and controls.
| S-EPMC7310490 | 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: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:IntroductionKohlmeier-Degos (K-D) disease is a rare obliterative vasculopathy that can present as a benign cutaneous form or with potentially malignant systemic involvement. The gastrointestinal tract is most frequently involved in systemic disease and mortality is often related to bowel perforations. Herein, we provide information to providers and patients regarding gastrointestinal K-D symptomology, pathology, treatment, and diagnosis, with a focus on the importance of timely diagnostic laparoscopy. We present three new cases of gastrointestinal K-D to highlight varying disease presentations and outcomes. BODY: Based on reviewed reports, perforation is preceded by at least one gastrointestinal symptom: abdominal pain/cramping, anorexia/weight loss, vomiting, diarrhea, nausea, gastrointestinal bleeding, obstipation, constipation, and abdominal fullness. Perforation most commonly occurs in the small intestine and often results in sepsis and death. Although underutilized, laparoscopy is the most sensitive and specific diagnostic technique, demonstrating serosal porcelain plaques similar to those on the skin and characteristic for K-D. The combination of eculizumab and treprostinil is presently the most effective treatment option for gastrointestinal K-D. The pathology of gastrointestinal K-D is characterized by an obliterative intimal arteriopathy eventuating in occlusive acellular deposits of mucin and collagen along with an extravascular pauci-cellular sclerosing process resembling scleroderma confined to the subserosal fat. C5b-9 and interferon-alpha are both expressed in all caliber of vessels in the affected intestine. While C5b-9 blockade does not prevent the intimal expansion, enhanced type I interferon signaling is likely a key determinant to intimal expansion by, causing an influx of monocytes which transdifferentiate into procollagen-producing myofibroblast-like cells.ConclusionPrompt laparoscopic evaluation is necessary in any K-D patient with an abdominal symptom to facilitate diagnosis and treatment initiation, as well as to hopefully decrease mortality. Those with gastrointestinal K-D should start on eculizumab as soon as possible, as onset of action is immediate.
| S-EPMC9022239 | biostudies-literature
Project description:Fabry disease (FD) is a rare, X-linked lysosomal storage disorder resulting in decreased or absent activity of the lysosomal enzyme alpha-galactosidase A. Subsequent accumulation of storage material can occur in virtually all cells of the body. Organs and structures affected by storage material deposition include the heart, the kidney, the central and peripheral nervous system and the cornea of the eyes. Progressive cardiac hypertrophy, arrhythmias, cardiac fibrosis, heart failure and cardiac death are common characteristics of cardiac involvement. Renal depositions of glycosphingolipids are already detectable in childhood. An early clinical sign of Fabry renal involvement is albuminuria, often preceding a detectable loss of kidney function. Later in life Fabry patients may exhibit a progressive decline of their kidney function leading to end-stage renal disease (ESRD). The clinical presentation of Fabry patients regarding renal involvement depends on the underlying mutation in the GLA gene. Classically affected males typically show a gradual decrease in kidney function, patients with mild or late onset mutations as well as a subgroup of females may exhibit only little or no renal abnormalities. This review summarizes the characteristics of renal involvement in FD, the diagnostics necessary to evaluate the degree of renal impairment and possible treatment options.
| S-EPMC8102258 | biostudies-literature
Project description:PurposeFabry disease is a rare multisystemic disorder caused by functional deficiency of the lysosomal enzyme alpha-galactosidase A. Gastrointestinal (GI) signs and symptoms are among the earliest clinical manifestations in patients with Fabry disease but are often nonspecific, misdiagnosed, and untreated. No instruments have been developed specifically to assess GI signs and symptoms in Fabry disease. The FABry disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI) was developed to address this unmet need and is intended for use in clinical trials (24-h FABPRO-GI) and real-world settings (7-day FABPRO-GI).MethodsFindings from a literature review, expert advisory meetings, and patient concept elicitation interviews (CEIs) were summarized into conceptual models. These conceptual models were used to develop preliminary versions of the 24-h and 7-day FABPRO-GI. Cognitive debriefing interviews (CDIs) were conducted with additional patients to assess content validity, including understandability, relevance, and comprehensiveness of the preliminary versions of the 24-h and 7-day FABPRO-GI.ResultsLiterature review (n = 17 articles), expert advisory meetings (n = 5), and patient CEIs (n = 17) identified mostly overlapping Fabry disease-related GI signs and symptoms, including abdominal cramps, bloating, and diarrhea, and informed development of the preliminary 24-h and 7-day FABPRO-GI. CDIs (n = 15) provided evidence of content validity and informed revisions of the 24-h and 7-day FABPRO-GI.ConclusionWith evidence of content validity, the 24-h and 7-day FABPRO-GI are the first Fabry disease-specific patient-reported outcomes to assess GI signs and symptoms in patients with Fabry disease with potential for use in clinical trials and real-world settings, respectively.
| S-EPMC8481178 | biostudies-literature