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The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.jpainsymman.2018.03.023. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these two disorders. In Fabry disease, gastrointestinal symptoms occur in approximately 70% of male patients, but the frequency ranges from 19% to 69% in different series. In some patients, colonic dysmotility due glycolipid deposition in autonomic plexus and ganglia can lead to the pseudo-obstruction syndrome, simulating intestinal necrosis. That is why up to this date colostomy has been performed in some cases, even for children with FD without cardiac, renal or cerebrovascular compromise. Early treatment with enzyme replacement therapy in asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression. Several studies have demonstrated that enzyme replacement therapy alleviates GI manifestations. Because of the non-specific nature of the gastrointestinal symptoms, diagnosis of Fabry disease is often delayed for several years. Gastrointestinal involvement is often misdiagnosed or under-reported. It is therefore very important to consider Fabry disease in the differential diagnosis of chronic intestinal pseudo-obstruction.
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BACKGROUND: Certain glomerulopathies are associated with increased levels of CD80 (B7-1). We measured the urinary excretion of CD80, podocyturia and proteinuria in controls and in subjects with Fabry disease either untreated or on enzyme replacement therapy (ERT). METHODS: Cross-sectional study including 65 individuals: controls (n = 20) and Fabry patients (n = 45, 23 of them not on ERT and 22 on ERT). Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), urinary uCD80/creatinine ratio (uCD80) and podocyturia. CD80 mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes. RESULTS: Controls and Fabry patients did not differ in age, eGFR and gender. However, UPCR, uCD80 and podocyturia were significantly higher in Fabry patients than in controls. As expected, Fabry patients not on ERT were younger and a higher percentage were females. Non-ERT Fabry patients had less advanced kidney disease than ERT Fabry patients: UPCR was lower and eGFR higher, but uCD80 and podocyturia did not differ between non-ERT or ERT Fabry patients. There was a significant correlation between uCD80 and UPCR in the whole population (r 0.44, p 0.0005) and in Fabry patients (r 0.42, p 0.0046). Lyso-Gb3 at concentrations found in the circulation of Fabry patients increased uCD80 expression in cultured podocytes. CONCLUSIONS: Fabry disease is characterized by early occurrence of increased uCD80 excretion that appears to be a consequence of glycolipid accumulation. The potential for uCD80 excretion to reflect early, subclinical renal Fabry involvement should be further studied.
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Antígeno B7-1/urina , Doença de Fabry/patologia , Doença de Fabry/urina , Podócitos/metabolismo , Podócitos/patologia , Adolescente , Adulto , Idoso , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Criança , Doença de Fabry/metabolismo , Feminino , Glicolipídeos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esfingolipídeos/metabolismo , Adulto JovemRESUMO
Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.
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Doença de Fabry/diagnóstico , Doença de Fabry/metabolismo , Gastroenteropatias/diagnóstico , Gastroenteropatias/metabolismo , Trato Gastrointestinal/metabolismo , Adolescente , Adulto , Animais , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Comorbidade , Diagnóstico Diferencial , Doença de Fabry/etiologia , Feminino , Gastroenteropatias/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta.
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Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Mutação , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêutico , Adolescente , Encéfalo/metabolismo , Encéfalo/patologia , Química Farmacêutica , Criança , Códon , Éxons , Doença de Fabry/diagnóstico , Feminino , Taxa de Filtração Glomerular , Humanos , Imageamento por Ressonância Magnética , Masculino , Medição da Dor , Resultado do Tratamento , Adulto Jovem , alfa-Galactosidase/químicaRESUMO
BACKGROUND: Screening for Fabry disease (FD) in high risk populations yields a significant number of individuals with novel, ultra rare genetic variants in the GLA gene, largely without classic manifestations of FD. These variants often have significant residual α-galactosidase A activity. The establishment of the pathogenic character of previously unknown or rare variants is challenging but necessary to guide therapeutic decisions. OBJECTIVES: To present 2 cases of non-classical presentations of FD with renal involvement as well as to discuss the importance of high risk population screenings for FD. RESULTS: Our patients with non-classical variants were diagnosed through FD screenings in dialysis units. However, organ damage was not limited to kidneys, since LVH, vertebrobasilar dolichoectasia and cornea verticillata were also present. Lyso-Gb3 concentrations in plasma were in the pathologic range, compatible with late onset FD. Structural studies and in silico analysis of p.(Cys174Gly) and p.(Arg363His), employing different tools, suggest that enzyme destabilization and possibly aggregation could play a role in organ damage. CONCLUSIONS: Screening programs for FD in high risk populations are important as FD is a treatable multisystemic disease which is frequently overlooked in patients who present without classical manifestations.
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AIMS: Fabry disease (FD) is an X-linked inborn error of metabolism caused by alpha-galactosidase A deficiency. The Fabry Registry is an ongoing, global observational database that compiles clinical data from patients with FD. METHODS: Demographic and baseline clinical characteristics of Fabry Registry patients enrolled in Argentina were analysed and compared with patients enrolled in the rest of the world (ROW). Baseline clinical parameters included chronic kidney disease (CKD) stage, urine protein-to-creatinine ratio and left ventricular posterior wall thickness. Only data from untreated patients were included. RESULTS: As of 1 October 2010, 3752 patients were enrolled in the Registry, 70 patients from Argentina and 3682 from the ROW. Argentinean male subjects were younger than Fabry Registry male subjects enrolled in ROW: mean current age 32.5 years vs. 39.0 years for men (p = 0.0257 by t-test). The current age (mean ± standard deviation) of female subjects enrolled in Argentina was not significantly different from that of female subjects enrolled in the ROW: 40.1 ± 17.28 vs. 43.2 ±17.95 years respectively (p = 0.2967). Overall, a smaller percentage of patients from Argentina received ERT compared with patients in the ROW (54% vs. 58% respectively). When evaluated by gender, more men and fewer women in Argentina received ERT compared with ROW (85% vs. 79% for men and 27% vs. 38% for women). A larger proportion of patients in ROW had severe CKD (stage 4 or 5) compared with Argentina (9.8% vs. 0%), most likely because of the older age of the ROW population. CONCLUSIONS: The enrolment of Argentinean patients into the Fabry Registry has steadily increased, as has the inclusion of female and paediatric patients with FD. The medical community in Argentina should be aware of FD in these populations, as awareness will facilitate prompt diagnosis and initiation of treatment, thus leading to improved outcomes.
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Doença de Fabry/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Idoso , Argentina/epidemiologia , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/estatística & dados numéricos , Doença de Fabry/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos , Distribuição por Sexo , Adulto JovemRESUMO
UNLABELLED: Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of alpha-galactosidase A, which results in the progressive accumulation of globotriaosylceramide and other neutral glycolipids in a range of cells and tissues. In association with the renal and cardiac insufficiency, cerebrovascular complications can result in the death of the patients. Several mechanisms causing vascular damage that leads to the development of deep-white matter lesions have been described. Recent clinical trials strongly suggest that statins protect against stroke by neuroprotective properties or pleiotropic effects. AIM: To evaluate evidence and potential beneficial effects of statins in the vasculopathy of Fabry disease.
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Doença de Fabry/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Formação de Conceito , Doença de Fabry/complicações , Fibrinolíticos/uso terapêutico , Humanos , Doenças Vasculares/etiologia , Doenças Vasculares/prevenção & controleRESUMO
AIMS: The purpose of this study was to review the peripheral neurological aspects of Anderson-Fabry disease (AFD). DEVELOPMENT: AFD is a disease caused by lysosomal deposits that was first reported in 1898. This entity has begun to attract renewed interest in recent years because of the progress made in diagnostic techniques and the appearance of enzyme replacement therapy. This pathological condition is transmitted by recessive inheritance linked to the X chromosome and results from a deficiency of the enzyme alpha-galactosidase A, which leads to the accumulation of glycosphingolipids in endothelial and perithelial cells, as well as those of the smooth muscles in blood vessels, the dorsal root ganglia and other structures in the central and peripheral nervous systems. Symptoms during childhood include: neuropathic pain that is predominantly distal in the four limbs (and expresses itself as severe attacks that are often linked to changes in temperature and exercise that interfere with daily activities), hypohidrosis and angiokeratomas. The most serious complications appear during adulthood and include: kidney failure, heart failure and strokes. CONCLUSION: The arrival of enzyme replacement therapy is the first part of a chain in the treatment of AFD, where gene therapy and substrate inhibition therapy are beginning to emerge as real therapeutic alternatives. In spite of all this, at present, the management of painful symptoms is not at all satisfactory for patients and therefore further study and a deeper understanding of the mechanisms involved will allow more specific and effective therapeutic measures to be developed with which to provide patients with greater relief.
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Doença de Fabry/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Diagnóstico Diferencial , Doença de Fabry/genética , Doença de Fabry/terapia , Terapia Genética , Humanos , Doenças do Sistema Nervoso Periférico/terapiaRESUMO
INTRODUCTION: Sensory motor multifocal acquired demyelinating neuropathy (SMMADN) is a variant of the chronic multifocal neuropathies. Several reports have been published about the clinical and electrophysiological progression in motor multifocal neuropathy (MMN) prior to and following immunoglobulin (Ig) therapy, but we have found no reports that deal with SMMADN. AIMS: We describe a case of SMMADN in which we conducted a clinical and electrophysiological evaluation before and after therapy with Ig UNC Hemoderivados. CASE REPORT: Female, 40 years of age, who presented asymmetrical weakness in all four limbs which she had been suffering for 12 years. We observed distal muscular atrophies, notable weakness and paresthesias in the four limbs. Electrophysiological studies revealed demyelinating neuropathy with secondary axonal involvement. Intravenous Ig was indicated. We observed a clear improvement in muscular strength, and changes in motor and sensory conduction speeds, but not in the amplitudes of the respective potentials. CONCLUSION: SMMADN is a chronic sensory motor multiple mononeuropathy that begins in the upper limbs and progresses asymmetrically down towards the lower members. The most usual sensory disorders are distal paresthesias. Electrophysiology presents conduction blockages, temporal dispersion, prolongation of the distal latencies, diminished conduction speeds, absence or prolongation of the F wave in one or more motor nerves, and abnormal sensory conduction speed. Accepted treatment is with Ig and, in some cases, with corticoids. In our case, the variations that were obtained could be explained by myelin reconstitution following the immunomodulatory effect of Ig and the axonal involvement that existed due to the secondary sequelae of the inflammatory process.