Fundacion Para El Estudio de Las Enfermedades Neurometabolicas FESEN

Buenos Aires, Argentina

Fundacion Para El Estudio de Las Enfermedades Neurometabolicas FESEN

Buenos Aires, Argentina

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Wood T.,Greenwood Genetic Center | Bodamer O.A.,University of Miami | Burin M.G.,Hospital Of Clinicas Of Porto Alegre | D'Almeida V.,University of Sao Paulo | And 15 more authors.
Molecular Genetics and Metabolism | Year: 2012

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). This enzyme is required for the degradation of dermatan sulfate. In its absence, dermatan sulfate accumulates in cells and is excreted in large quantities in urine. Specific therapeutic intervention is available; however, accurate and timely diagnosis is crucial for maximal benefit. To better understand the current practices for diagnosis and to establish diagnostic guidelines, an international MPS VI laboratory diagnostics scientific summit was held in February of 2011 in Miami, Florida.The various steps in the diagnosis of MPS VI were discussed including urinary glycosaminoglycan (uGAG) analysis, enzyme activity analysis, and molecular analysis. The following conclusions were reached. Dilute urine samples pose a significant problem for uGAG analysis and MPS VI patients can be missed by quantitative uGAG testing alone as dermatan sulfate may not always be excreted in large quantities. Enzyme activity analysis is universally acknowledged as a key component of diagnosis; however, several caveats must be considered and the appropriate use of reference enzymes is essential. Molecular analysis supports enzyme activity test results and is essential for carrier testing, subsequent genetic counseling, and prenatal testing.Overall the expert panel recommends caution in the use of uGAG screening alone to rule out or confirm the diagnosis of MPS VI and acknowledges enzyme activity analysis as a critical component of diagnosis. Measurement of another sulfatase enzyme to exclude multiple sulfatase deficiency was recommended prior to the initiation of therapy. When feasible, the use of molecular testing as part of the diagnosis is encouraged. A diagnostic algorithm for MPS VI is provided. © 2012 Elsevier Inc.


Serebrinsky G.,Labgen | Calvo M.,Hospital Zonal General Of Agudos Evita | Fernandez S.,Centro Medico CIPERCA | Saito S.,Hokkaido Information University | And 5 more authors.
Molecular Genetics and Metabolism Reports | Year: 2015

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. © 2015 Published by Elsevier Inc.


Politei J.,Fundacion para el Estudio de las Enfermedades Neurometabolicas FESEN | Thurberg B.L.,Genzyme | Wallace E.,University of Alabama at Birmingham | Warnock D.,University of Alabama at Birmingham | And 3 more authors.
Clinical Genetics | Year: 2016

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. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Politei J.M.,Fundacion para el Estudio de las Enfermedades Neurometabolicas FESEN | Bouhassira D.,French Institute of Health and Medical Research | Germain D.P.,University of Versailles | Goizet C.,Bordeaux University Hospital Center | And 9 more authors.
CNS Neuroscience and Therapeutics | Year: 2016

Aims: Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed. Methods: In 2014, experts met to discuss recent advances on this topic and update clinical guidance. Results: Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Würzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs. Conclusion: To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications. © 2016 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.


PubMed | Genzyme, Fundacion para el Estudio de las Enfermedades Neurometabolicas FESEN, University of Alabama at Birmingham and LABGEN
Type: Case Reports | Journal: Clinical genetics | Year: 2016

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.


Rost N.S.,Massachusetts General Hospital | Cloonan L.,Massachusetts General Hospital | Kanakis A.S.,Massachusetts General Hospital | Fitzpatrick K.M.,Massachusetts General Hospital | And 9 more authors.
Neurology | Year: 2016

Objective: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). Methods: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses. Results: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm 3 (interquartile range 1.8-4.0). Age (β 0.02, p 0.008) and history of stroke (β 1.13, p 0.02) were independently associated with lnWMHV. However, WMH burden - as well as WMHV predictors - varied by decade of life in this cohort of patients with FD (p < 0.0001). Conclusions: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed. © 2016 American Academy of Neurology.


PubMed | University of Würzburg, Massachusetts General Hospital, The Alfred Hospital, University of Versailles and 8 more.
Type: Journal Article | Journal: CNS neuroscience & therapeutics | Year: 2016

Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed.In 2014, experts met to discuss recent advances on this topic and update clinical guidance.Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Wrzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs.To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications.


Tondel C.,University of Bergen | Kanai T.,Jichi Medical University | Larsen K.K.,University of Bergen | Ito S.,National Center for Child Health and Development | And 3 more authors.
Nephron | Year: 2015

In Fabry disease, globotriaocylceramid (GL3) starts to accumulate in kidney cells in utero, and continues to accumulate throughout childhood and adulthood with progressive tissue damage, which may lead to renal failure. Material and Methods: Eight children with classical Fabry disease, median age 12 (range 4-16 years) had a renal biopsy performed before the initiation of enzyme replacement therapy (ERT). All patients were normalbuminuric and had normal GFR. Three patients were re-biopsied after three or five years. Results: In all patients, significant GL3-accumulation was found in several types of kidney cells with high amounts of GL3 in the podocytes. Segmental podocyte foot process effacement was shown in all but two patients; no effacement was seen neither in the youngest male patient at 4 years of age nor in a male aged 12. A 12-year-old female patient had normal podocyte foot processes before the start of ERT, but de novo foot process flattening and unchanged high score of podo-cyte GL3 accumulation were seen in the re-biopsy after three years of ERT (agalsidase alpha 0.2 mg/kg/every other week). Two boys showed worsening of podocyte effacement in kidney biopsy after five years of agalsidase alpha 0.2 mg/kg/eow. Conclusions: Podocyte foot process effacement was found in the majority of eight young classical Fabry patients of both genders after the age of 11 years, without clinical signs of Fabry nephropathy. Kidney biopsies are essential in the early diagnosis of nephropathy and in the evaluation of the response to enzyme replacement therapy of early Fabry nephropathy. © 2014 S. Karger AG, Basel.

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