Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Incidental finding of cornea verticillata or lamellar inclusions in kidney biopsy: measurement of lyso-Gb3 in plasma defines between Fabry disease and drug-induced phospholipidosis.

INTRODUCTION: Therapy with cationic amphiphilic drugs (Amiodarone or hydroxychloroquine) may result in biochemically and ultrastructurally similar lipid inclusions in many cells also affected by Fabry disease (FD). In addition, it often results in similar clinical manifestations such as cornea verticillata. This may lead to a FD misdiagnosis, especially when a complete medical history is not available to the ophthalmologist confronted with cornea verticillata or to the pathologist examining a kidney biopsy. When enzymatic/genetic test or pathological studies are not conclusive, a specific biomarker may help clarify this dilemma. The plasma globotriaosylsphingosine (lyso-Gb3) assay has high sensitivity and specificity and is elevated above normal levels in FD. MATERIALS AND METHODS: We measured plasma lyso-Gb3 levels in male patients receiving Amiodarone or hydroxychloroquine and compared it with male patients with classic and late onset variant of FD. RESULTS: In all Fabry patients (classic and late onset variant) α-GalA activity was deficient in dried blood spot and plasma lyso-Gb3 was above normal levels. Patients on treatment with Amiodarone or hydroxychloroquine had normal values for α-GalA activity and lyso-Gb3 in plasma. CONCLUSIONS: Even when Amiodarone or hydroxychloroquine may decrease α-GalA activity in vitro or in cell culture, our results showed that in all patients lyso-Gb3 plasma levels remain normal with no evidence of reduction in α-GalA activity, confirming the specificity of this biomarker for the diagnosis of FD.

WITHDRAWN: Recommendations for evaluation and management of pain in patients with mucopolysaccharidosis in Latin America.

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.

Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

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.

Increased urinary CD80 excretion and podocyturia in Fabry disease.

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.

Gastrointestinal involvement in Fabry disease. So important, yet often neglected.

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.

Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations--different outcome?

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.

Late onset variants in Fabry disease: Results in high risk population screenings in Argentina.

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.

Fabry disease in latin america: data from the fabry registry.

The purpose of these analyses was to characterize demographic and baseline clinical characteristics of Latin American patients with Fabry disease compared to that of patients in the rest of the world. Observational data reported to the Fabry Registry were obtained from untreated patients or prior to treatment with enzyme replacement therapy. As of October 1, 2010, 3,752 patients were enrolled in the Fabry Registry worldwide, including 333 patients within Latin America. Latin American patients tended to be younger than Fabry Registry patients enrolled in the rest of the world: mean current age 35.5 years versus 39.2 years for men (p < 0.05 by t-test), mean age 37.8 years versus 43.6 years for women (p < 0.05 by t-test). A smaller percentage of Latin American patients have received enzyme replacement therapy, compared to patients in the rest of the world: 67% versus 80% for men, and 19% versus 39% of women, respectively. Thirty-one percent of men and 22% of women in Latin America reported experiencing a significant cardiovascular, renal, or cerebrovascular event, at a mean age of 35 ± 12.6 years in men and 44 ± 12.3 years in women. Cardiovascular events were the most common type of initial clinical event among men and women in Latin America. The medical community in Latin America should be aware of Fabry disease as a possible cause of renal or cardiac dysfunction. Increased awareness will facilitate prompt diagnosis and initiation of treatment.

Fabry disease in Argentina: an evaluation of patients enrolled in the Fabry Registry.

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.

Can we use statins to prevent stroke in Fabry disease?

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.

[Peripheral neuropathy in Anderson-Fabry disease: its physiology, evaluation and treatment]. / Neuropatía periférica en la enfermedad de Anderson-Fabry: fisiopatología, evaluación y tratamiento.

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.

[Electrophysiological evaluation of a case of sensory-motor multifocal acquired demyelinating neuropathy. The effects of immunoglobulin therapy]. / Evaluación electrofisiológica en un caso de neuropatía desmielinizante adquirida multifocal sensitivomotora. Efectos del tratamiento con inmunoglobulina.

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.

[Cerebral haematoma in the course of herpes simplex encephalitis]. / Hematoma cerebral en el curso de una encefalitis herpética.

INTRODUCTION: Herpes simplex encephalitis (HSE) is the most common cause of infectious encephalitis at all ages. The usual presentation includes a high temperature, headache and confusion associated with convulsions and signs of a focal neurological deficiency. The typical findings shown by magnetic resonance imaging (MRI) consist of hyperintense lesions, in T2 and FLAIR sequences, especially in the medial and inferior temporal lobe. AIMS. The aim of this paper is to report a case of HSE that associated a cerebral haematoma (CH) in its clinical course. CASE REPORT: A 69 year old female patient who was admitted to hospital because of a syndrome of high temperature, confusion and urinary infection. Studies of the cerebrospinal fluid showed only a slight pleocytosis, and a polymerase chain reaction (PCR) for the herpes simplex virus (HSV) was required. Initial MRI scanning showed an image that was compatible with cerebritis in the left parieto occipital lobe. A later RMI scan revealed a cerebral haematoma in the left parieto occipital lobe, together with new haemorrhagic foci in the bifrontal and in the right temporal lobes. The haematoma was drained surgically and empirical therapy was begun with acyclovir, and later a positive HSV PCR was received. The patient responded favourably to the therapy and was discharged from hospital. DISCUSSION: A variety of atypical presentations in HSE have been reported. Our case presented scant pleocytosis, infrequent lesion topography and coursed with CH. Only a few cases of this last occurrence have been reported in the literature. CONCLUSION: The presence of infrequent features, such as CH, within the framework of the clinical features of encephalopathy cannot exclude the possible existence of HSE.