RESUMO
[This corrects the article DOI: 10.3389/fgene.2023.1122893.].
RESUMO
Background: Anderson-Fabry disease (AFD) is an X-linked disease that results from reduced activity of the enzyme galactosidase alpha (GLA). When the GLA gene sequence is altered by mutations that alter the normal DNA sequence, variants of the alpha-galactosidase A enzyme are produced, which may or may not function. These mutations are responsible for Fabry disease, and to date, over 800 different mutations of the gene have been described in patients with Anderson-Fabry disease. In this case, we report the case of a woman who is the sole family member with this type of mutation. Case presentation: We report a case of a 52-year-old woman with end-stage chronic kidney disease in dialysis treatment. The patient's alpha-galactosidase activity was 6.6 nmol/ml/h in whole blood, and lyso-GB3 levels were 11.45 nmol/L (normal range < 2.3 nmol/L). Alpha-galactosidase A gene sequence analysis revealed a pathogenic variant of c.947dupT in exon 6, leading to the p. I317NfsTer16 amino acid substitution. The genetic analysis did not detect the same mutation in any of the other screened family members. Conclusion: The international Fabry disease genotype-phenotype database (dbFGP) reports a pathogenic variant c.947dupT in exon 6 that is probably associated with a classical phenotype of Fabry disease. In this case report, we report the case of a woman who is the sole family member with this type of pathogenic variant. Similar situations have not been described in the literature for this pathogenic variant, and it represents an important case of inter- and intrafamilial variability in patients with Fabry disease. The literature shows that de novo pathogenic variants are frequently found in the context of Fabry disease.
RESUMO
Fabry disease (FD) is a recessive monogenic disease linked to chromosome X due to more than two hundred mutations in the alfa-galactosidase A (GLA) gene. Modifications of the GLA gene may cause the progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriasylsphingosine (lyso-Gb3), in lysosomes of several types of cells of the heart, kidneys, skin, eyes, peripheral and central nervous system (not clearly and fully demonstrated), and gut with different and pleiotropic clinical symptoms. Among the main symptoms are acroparesthesias and pain crisis (involving the peripheral nervous system), hypohidrosis, abdominal pain, gut motility abnormalities (involving the autonomic system), and finally, cerebrovascular ischemic events due to macrovascular involvement (TIA and stroke) and lacunar strokes and white matter abnormalities due to a small vessel disease (SVS). Gb3 lysosomal accumulation causes cytoplasmatic disruption and subsequent cell death. Additional consequences of Gb3 deposits are inflammatory processes, abnormalities of leukocyte function, and impaired trafficking of some types of immune cells, including lymphocytes, monocytes, CD8+ cells, B cells, and dendritic cells. The involvement of inflammation in AFD pathogenesis conflicts with the reported poor correlation between CRP levels as an inflammation marker and clinical scores such as the Mainz Severity Score Index (MSSI). Also, some authors have suggested an autoimmune reaction is involved in the disease's pathogenetic mechanism after the α-galactosidase A deficiency. Some studies have reported a high degree of neuronal apoptosis inhibiting protein as a critical anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Notably, this apoptotic upregulation did not change after treatment with enzymatic replacement therapy (ERT), with a further upregulation of the apoptosis-inducing factor after ERT started. Gb3-accumulation has been reported to increase the degree of oxidative stress indexes and the production of reactive oxygen species (ROS). Lipids and proteins have been reported as oxidized and not functioning. Thus, neurological complications are linked to different pathogenetic molecular mechanisms. Progressive accumulation of Gb3 represents a possible pathogenetic event of peripheral nerve involvement. In contrast, central nervous system participation in the clinical setting of cerebrovascular ischemic events seems to be due to the epitheliopathy of Anderson-Fabry disease with lacunar lesions and white matter hyperintensities (WMHs). In this review manuscript, we revised molecular mechanisms of peripheral and central neurological complications of Anderson-Fabry Disease. The management of Fabry disease may be improved by the identification of biomarkers that reflect the clinical course, severity, and progression of the disease. Intensive research on biomarkers has been conducted over the years to detect novel markers that may potentially be used in clinical practice as a screening tool, in the context of the diagnostic process and as an indicator of response to treatment. Recent proteomic or metabolomic studies are in progress, investigating plasma proteome profiles in Fabry patients: these assessments may be useful to characterize the molecular pathology of the disease, improve the diagnostic process, and monitor the response to treatment.
Assuntos
Doença de Fabry , Criança , Humanos , Doença de Fabry/complicações , Doença de Fabry/genética , Proteômica , Sistema Nervoso Periférico , Biomarcadores , InflamaçãoRESUMO
Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1ß following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study.
RESUMO
Anderson-Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson-Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy-lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.
Assuntos
Células Endoteliais/metabolismo , Doença de Fabry/tratamento farmacológico , Doença de Fabry/metabolismo , MicroRNAs/metabolismo , Animais , Autofagia , Circulação Cerebrovascular , Constrição Patológica , Terapia de Reposição de Enzimas , Doença de Fabry/fisiopatologia , Globosídeos/química , Glicolipídeos/metabolismo , Humanos , Lisossomos/química , Camundongos , Microcirculação , Mitocôndrias/metabolismo , Isoformas de Proteínas , Transdução de Sinais , Esfingolipídeos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Triexosilceramidas/química , Triexosilceramidas/metabolismo , alfa-Galactosidase/metabolismoRESUMO
BACKGROUND: We report an unusual case of infective colitis by Yersinia enterocolitica complicated by microliver abscesses mimicking multiple liver metastases in a 79 yr old female without any risk factors for bacteriaemia by this pathogen. CASE PRESENTATION: The patient was admitted to the Internal Medicine with Stroke Care ward of University Policlinico "P. Giaccone" in Palermo because of the appearance of diarrhoea. After the antimicrobial treatment for infective colitis, the clinicians observed a persistently increased white blood cells (WBC) count and multiple hepatic lesions; after having excluded any neoplastic disease and inflammatory bowel disease (IBD), blood cultures positive for Y. enterocolitica allowed to establish the final diagnosis was infective micro liver abscesses consequent to infective colitis due to Y. enterocolitica, which were successfully treated with cefixime and doxycycline. CONCLUSIONS: This case report should make clinicians reflect on how complex the differential diagnosis between microliver abscesses and metastasis could be and the possibility of bacteriaemia by Y. enterocolitica even without iron overload conditions.
Assuntos
Colite/diagnóstico , Abscesso Hepático/diagnóstico , Neoplasias Hepáticas/diagnóstico , Yersiniose/diagnóstico , Yersinia enterocolitica/isolamento & purificação , Idoso , Antibacterianos/uso terapêutico , Bacteriemia/complicações , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Colite/complicações , Colite/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Abscesso Hepático/tratamento farmacológico , Abscesso Hepático/etiologia , Resultado do Tratamento , Yersiniose/complicações , Yersiniose/tratamento farmacológicoRESUMO
Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry's disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease.
Assuntos
Doença de Fabry , Terapia de Reposição de Enzimas , Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Feminino , Terapia Genética , Humanos , Rim , Masculino , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêuticoRESUMO
Fabry's disease is a genetic disorder of X-linked inheritance caused by mutations in the alpha galactosidase A gene resulting in deficiency of this lysosomal enzyme. The progressive accumulation of glycosphingolipids, caused by the inadequate enzymatic activity, is responsible of organ dysfunction and thus of clinical manifestations. In the presence of a high clinical suspicion, a careful physical examination and specific laboratory tests are required, finally diagnosis of Fabry's disease is confirmed by the demonstration of absence or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females; in fact the performance of enzymatic activity assay alone in women is inconclusive. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. Because of its multisystemic involvement Fabry's disease may present a large spectrum of clinical manifestations as acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement (renal insufficiency, proteinuria, left ventricular hypertrophy, strokes). Enzyme replacement therapy with recombinant α- galactosidase A is actually the specific therapy for Fabry disease. Early beginning of this treatment has shown beneficial effects in particular in cardiac and renal disease, a less efficacy it has been reported in central nervous system involvement. ERT has shown to be associated to a significant reduction of Gb3 accumulation in several tissues, in particular heart and kidney; moreover it improves pain related quality of life. Next generation lysosomal storage disorder treatment is based on new strategic approaches as stem cell based therapy, pharmacological chaperones, viral gene therapy; concerning Fabry's disease, it has been recently addressed to great interest this last innovative method, that is to say viral gene therapy, for delivering recombination enzyme into main involved tissues; promising results have been reported in animal models. Great efforts have been made and are still required in this field in order to make available a more effective, safer, advantageous therapeutic strategy for patients with Fabry's disease.
Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Fabry/genética , Doença de Fabry/terapia , Terapia Genética/métodos , Doenças Raras/genética , Doenças Raras/terapia , Triexosilceramidas/metabolismo , alfa-Galactosidase/genética , Animais , Biomarcadores/análise , Dependovirus/genética , Modelos Animais de Doenças , Terapia de Reposição de Enzimas/efeitos adversos , Terapia Genética/efeitos adversos , Vetores Genéticos , Humanos , Isoenzimas/administração & dosagem , Isoenzimas/uso terapêutico , Camundongos , Mutação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , alfa-Galactosidase/administração & dosagem , alfa-Galactosidase/uso terapêuticoRESUMO
BACKGROUND: Anderson-Fabry disease (AFD) is an inborn lysosomal enzymopathy resulting from the deficient or absent activity of the lysosomal exogalactohydrolase, α-galactosidase A. This deficiency, results in the altered metabolism of glycosphingolipids which leads to their accumulation in lysosomes, thus to cellular and vascular dysfunction. To date, numerous mutations (according to recent data more than 1000 mutations) have been reported in the GLA intronic and exonic mutations. Traditionally, clinical manifestations are more severe in affected hemizygous males than in females. Nevertheless, recent studies have described severe organ dysfunction in women. THE AIM OF THE STUDY: This study reports clinical, biochemical, and molecular findings of the members of three Sicilian families. The clinical history of these patients highlights a remarkable interfamilial and intrafamilial phenotypic variability which characterizes Fabry disease relative to target organs and severity of clinical manifestations. DISCUSSION: Our findings, in agreement with previous data, report a little genotype-phenotype correlation for the disease, suggesting that the wide phenotypic variability of Anderson-Fabry disease is not completely ascribable to different gene mutations but other factors and mechanisms seem to be involved in the pathogenesis and clinical expression of the disease. Moreover, this study emphasies the importance of pedigree analysis in the family of each proband for identifying other possibly affected relatives.
RESUMO
BACKGROUND: Anderson/Fabry disease expresses a wide range of clinical variability in patients that it is possible to explain referring to a genetic variability with numerous mutations described in the literature (more than 600). METHODS: We report some clinical cases of some members of a Sicilian family to express phenotypical variability of this disease in subjects with the same genetic mutation RESULTS: The first case was a 59-year-old female. Brain MRI revealed right frontal periventricular white matter of likely vascular-degenerative origin. The proband's alpha galactosidase A activity was 3.7nmol/mL/h. Molecular genetics revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C>T. The second case was a 30year-old male affected by acroparesthesias and hypoidrosis since he was an adolescent. Renal impairment was first detected at age 29; it began with high plasma levels of creatinine and microalbuminuria date. The third case was a 41year-old daughter that presented with acroparesthesias, hypoidrosis since she was very young. The patient's alpha galactosidase A activity was 4.1nmol/mL/h, in whole blood, which is compatible with heterozygote subject for Fabry's disease or healthy control. The fourth case was a male grandson of the proband, 9year-old child. He had a classic gastrointestinal involvement. He complained of recurrent abdominal pain, post prandial bloating and pain. This child's enzyme activity was 1.65nmol/mL/h. In cases 2, 3, and 4, molecular genetics revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C
Assuntos
Doença de Fabry/enzimologia , Doença de Fabry/genética , Predisposição Genética para Doença , Polimorfismo Genético , alfa-Galactosidase/genética , Adolescente , Adulto , Sequência de Bases , Criança , Doença de Fabry/patologia , Família , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Desnaturação de Ácido Nucleico , LinhagemRESUMO
AIMS: The previous literature has suggested that the iatrogenic atrial septal defects (IASDs) may follow left atrial (LA) access by transseptal (TS) puncture, especially in the case of a single TS for more than one catheter. The aim of the present study is to describe the prevalence of patent foramen ovale (PFO) and IASDs in a cohort of atrial fibrillation (AF) patients undergoing redo catheter ablation (CA) procedures in a high-volume centre accessing LA by a standardized single TS puncture. METHODS AND RESULTS: Patients (n = 197) who underwent at least one redo AFCA, between 2004 and 2012, were retrospectively enroled. Transoesophageal echocardiography was performed before each procedure during which LA was accessed via a PFO, if present, or by single TS for both the mapping and ablation catheters. At baseline, PFO was detected in 43 (21.8%) patients. Clinical and echocardiographic parameters recorded did not differ within patients presenting with or without PFO. Left atrium was accessed via PFO in 39 (90.7% of those with PFO) patients during the first procedure. New-onset IASD occurred in 11 (5.6%) patients following the first procedure and in 1 (2.2%) patient following the second procedure. The clinical and echocardiographic parameters did not differ within the patients irrespective of whether IASD was reported or not. No TS-related complications occurred. CONCLUSION: In the present cohort, LA access by PFO or single TS for both the mapping and ablation catheters lead to a small risk of asymptomatic IASD, not increased by redo procedures, confirming that it represents a safe approach. No clinical and/or echocardiographic parameters seemed to predict IASD occurrence.
Assuntos
Fibrilação Atrial/cirurgia , Septo Interatrial/lesões , Ablação por Cateter/efeitos adversos , Traumatismos Cardíacos/epidemiologia , Doença Iatrogênica , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Septo Interatrial/diagnóstico por imagem , Ecocardiografia Doppler em Cores , Ecocardiografia Transesofagiana , Feminino , Traumatismos Cardíacos/diagnóstico , Hospitais com Alto Volume de Atendimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Punções/efeitos adversos , Reoperação , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
The narrow complex tachycardias (NCTs) are defined by the presence in a 12-lead electrocardiogram (ECG) of a QRS complex duration less than 120ms and a heart rate greater than 100 beats per minute; those are typically of supraventricular origin, although rarely narrow complex ventricular tachycardias have been reported in the literature. As some studies document, to diagnose correctly the NCTs is an arduous exercise because sometimes those have similar presentation on the ECG. In this paper, we have reviewed the physiopathological, clinical, and ECG findings of all known supraventricular tachycardias and, in order to reduce the possible diagnostic errors on the ECG, we have proposed a quick and accurate diagnostic algorithm for the differential diagnosis of NCTs.
Assuntos
Algoritmos , Erros de Diagnóstico/prevenção & controle , Eletrocardiografia/métodos , Taquicardia Supraventricular/diagnóstico , Fibrilação Atrial , Flutter Atrial , Nó Atrioventricular , Diagnóstico Diferencial , Frequência Cardíaca , Humanos , Taquicardia Supraventricular/classificação , Taquicardia Supraventricular/fisiopatologiaRESUMO
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A. FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations (Table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional control of the vessels, secondary to endothelial dysfunction as a consequence of α-galactosidase A deficiency. The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas (Fig. 19 A, B), irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, intestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index (MSSI) (Table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases.
Assuntos
Sistema Nervoso Central/patologia , Doença de Fabry/complicações , Rim/patologia , Pele/patologia , Fatores Etários , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/ultraestrutura , Terapia de Reposição de Enzimas , Doença de Fabry/genética , Doença de Fabry/metabolismo , Doença de Fabry/patologia , Feminino , Humanos , Rim/metabolismo , Rim/ultraestrutura , Masculino , Qualidade de Vida , Índice de Gravidade de Doença , Caracteres Sexuais , Pele/metabolismoRESUMO
Characteristic clinical manifestations of AFD such as acroparesthesias, angiokeratoma, corneal opacity, hypo/ and anhidrosis, gastrointestinal symptoms, renal and cardiac dysfunctions can occur in male and female patients, although heterozygous females with AFD usually seem to be less severely affected. The most prominent CNS manifestations consist of cerebrovascular events such as transient ischaemic attacks (TIAs) and (recurrent) strokes. For the most part, CNS complications in AFD have been attributed to cerebral vasculopathy, including anatomical abnormalities. The natural history of Fabry patients includes transitory cerebral ischaemia and strokes, even in very young persons of both genders. The mechanism is partly due to vascular endothelial accumulation of Gb-3. White matter lesions (WML) on occur MRI. Both males and females can be safely treated with enzyme replacement; and thus screening for Fabry disease of young stroke populations should be considered. There are, however, no hard data of treatment effect on mortality and morbidity. Stroke in Anderson-Fabry disease study of 721 patients with cryptogenic stroke, aged 18-55 years, showed a high prevalence of Fabry disease in this group: 5% (21/432) of men and 3% (7/289) of women. Combining results of both sexes showed that 4% of young patients with stroke of previously unknown cause had Fabry disease, corresponding to about 1-2% of the general population of young stroke patients. Cerebral micro- and macro-vasculopathy have been described in Fabry disease. Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. Another Neurologic hallmark of Fabry disease (FD) includes small fiber neuropathy as well as cerebral micro- and macroangiopathy with premature stroke. Cranial MRI shows progressive white matter lesions (WML) at an early age, increased signal intensity in the pulvinar, and tortuosity and dilatation of the larger vessels. Conventional MRI shows a progressive load of white matter lesions (WMLs) due to cerebral vasculopathy in the course of FD. Another study has been conducted to quantify brain structural changes in clinically affected male and female patients with FD. The peripheral neuropathy in Fabry disease manifests as neuropathic pain, reduced cold and warm sensation and possibly gastrointestinal disturbances. Patients with Fabry disease begin having pain towards the end of the first decade of life or during puberty. Children as young as 6 years of age have complained of pain often associated with febrile illnesses with reduced heat and exercise tolerance. The patients describe the pain as burning that is often associated with deep ache or paresthesiae. Some patients also have joint pain. A high proportion of patients with Fabry disease is at increased risk of developing neuropsychiatric symptoms, such as depression and neuropsychological deficits. Due to both somatic and psychological impairment, health-related quality of life (QoL) is considerably reduced in patients with Fabry disease. Targeted screening for Fabry disease among young individuals with stroke seems to disclose unrecognized cases and may therefore very well be recommended as routine in the future. Furthermore, ischemic stroke is related to inflammation and arterial stiffness and no study had addressed this relationship in patients with AF disease and cerebrovascular disease, so this topic could represent a possible future research line.
Assuntos
Doença de Fabry/complicações , Ataque Isquêmico Transitório/etiologia , Acidente Vascular Cerebral/etiologia , Fatores Etários , Circulação Cerebrovascular , Doença de Fabry/diagnóstico , Doença de Fabry/epidemiologia , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/epidemiologia , Masculino , Prevalência , Pulvinar/irrigação sanguínea , Pulvinar/patologia , Índice de Gravidade de Doença , Caracteres Sexuais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , alfa-Galactosidase/metabolismoRESUMO
BACKGROUND: The 12-lead electrocardiogram (ECG) is considered an essential screening tool for hypertrophic cardiomyopathy (HCM). A vast array of ECG abnormalities has been described in HCM, although their relationship to left ventricle (LV) morphology and degree of hypertrophy appears elusive. Aim of this study was to assess the relationship of ECG patterns with the HCM phenotype assessed according to the novel opportunities offered by cardiac magnetic imaging (CMR). METHODS: CMR and 12-lead ECG were performed in 257 HCM patients. Severity of ECG abnormalities was defined by the sum of 9 criteria: abnormal cardiac rhythm, QRS duration ≥ 100 ms, Romhilt-Estes score ≥ 5, fascicular block (LAHB) and/or bundle-branch block (LBBB or RBBB), ST-T abnormalities, ST-T segment elevation ≥ 0.2 mV, prolonged QTc interval, pathological Q waves, absence of normal Q wave. Four ECG groups were identified: normal (0 criteria); mildly abnormal (1-3 criteria); moderately abnormal (4-6 criteria); markedly abnormal (7-9 criteria). RESULTS: There was a direct relationship between severity of ECG abnormalities and HCM phenotype. LV mass index was normal in most patients with normal ECG and progressively increased with each class of ECG score, from 70.9 ± 18.6g/m(2) in patients with normal ECG to 107.1 ± 55.1g/m(2) among those with markedly abnormal ECG (p=<0.0001). Likewise, the prevalence and extent of late gadolinium enhancement (LGE) increased significantly with the ECG score, from 37% in patients with normal ECG to 93% in patients with markedly abnormal ECG (overall p=0.0012). A normal ECG had a negative predictive accuracy of 96% for markedly increased LV mass (>91 g/m(2) for men and >69 g/m(2) for women), and of 100% for maximum LV thickness ≥ 30 mm. CONCLUSIONS: In a large HCM cohort, the number and severity of ECG abnormalities were directly related to phenotypic expression as revealed by CMR. Although false negative ECG findings remain a challenge in population screenings for HCM, a normal ECG proved effective in ruling out severe LV hypertrophy, suggesting potential implications for long-term follow-up of HCM patients and family members. A simple score for quantification of ECG abnormalities in HCM patients is proposed.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Eletrocardiografia/métodos , Imagem Cinética por Ressonância Magnética/métodos , Fenótipo , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Current definition of persistent atrial fibrillation (PAF) enrolls a heterogeneous population with different atrial fibrillation (AF) exposure and degree of atrial substrate. Study aims were to evaluate acute and long-term results of electrical cardioversion (ECV) and to identify temporal cutoff of previous AF exposure to reclassify PAF in subgroups with different chance of sinus rhythm (SR) maintenance. METHODS: Five hundred twenty-one patients (66% men; age 69 ± 10 years) with PAF undergoing ECV, were divided in four groups according to AF duration at the time of ECV: group A with AF ≤2 months (141 patients); group B with AF >2 and ≤4 months (176 patients); group C with AF >4 and ≤6 months (89 patients); and group D with AF >6 months and <1 year (115 patients). RESULTS: There was no difference in term of acute success among groups (98.5% vs 97.1% vs 98.9% vs 96.5%, respectively, P = 0.95). At 5-year follow-up, 198 (41%) patients were in SR: 50% in group A, 44% in group B, 42% in group C, and 25% in group D (P < 0.001). At the multivariate analysis, previous ECV (hazard ratio [HR] 1.55, P < 0.001), left atrium enlargement (HR 1.39, P = 0.013), and AF duration >6 months at time of procedure (HR 1.59, P = 0.001) independently predict ECV failure. CONCLUSION: ECV is associated with high acute success rate and low complications rate. Long-term results are strongly related with AF duration at time of ECV: a cutoff of >6 months helps in selecting patients that can take greater advantage of the procedure.
Assuntos
Fibrilação Atrial/mortalidade , Fibrilação Atrial/prevenção & controle , Cardioversão Elétrica/mortalidade , Doença Aguda , Idoso , Doença Crônica , Intervalo Livre de Doença , Feminino , Humanos , Itália/epidemiologia , Masculino , Prevalência , Sobrevida , Análise de Sobrevida , Resultado do TratamentoRESUMO
Anderson-Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The complete genomic and cDNA sequences of the human alpha-galactosidase A gene have been determined and to date, several disease-causing alpha-galactosidase A mutations have been identified, including missense mutations, small deletions/insertions, splice mutations, and large gene rearrangements We report a case of a 56-year-old woman with recurrent cryptogenic strokes. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. She did not show other typical signs of Fabry disease such as acroparesthesias and angiokeratoma. The patient's alpha-galactosidase A activity was 4.13 nmol/mL/h in whole blood. Alpha-galactosidase A gene sequence analysis revealed a heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4 in this woman, leading to the p.Tyr184Asn amino acid substitution.
Assuntos
Doença de Fabry/diagnóstico , Acidente Vascular Cerebral/diagnóstico , alfa-Galactosidase/genética , Sequência de Aminoácidos , Sequência de Bases , Doença de Fabry/genética , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Recidiva , Análise de Sequência de DNA , Acidente Vascular Cerebral/genética , alfa-Galactosidase/sangueRESUMO
Calciphylaxis is a severe "vascular ossification-calcification," associated with a very high mortality rate that involves arterial wall, venular wall, and nerves resulting in ischemia and necrosis of skin, subcutaneous fat, visceral organs, and skeletal muscles. Sodium thiosulfate has recently been used as a novel treatment option for calciphylaxis because of its dual role as an antioxidant and a chelator. Multiple case reports demonstrated that such therapy has resulted in pain relief and healing of skin ulceration. We report a case of calciphylaxis of large severity that had an ambiguous response to sodium thiosulfate treatment (improvement of symptomatology and skin lesions, improvement of blood parameters, worsening of general conditions, and consciousness until death).