Publications by authors named "Hernan Amartino"

32 Publications

[Idursulfase desensitization in a child with Hunter syndrome (mucopolysaccharidosis II)].

Arch Argent Pediatr 2021 02;119(1):e41-e44

Sección Alergia Pediátrica, Servicio de Clínica Pediátrica, Hospital Italiano de Buenos Aires. Buenos Aires, Argentina.

Enzyme replacement therapy with idursulfase decreases morbidity and improves quality of life of patients with mucopolysaccharidosis ii. Immediate hypersensitivity reactions to this drug have been described. Desensitization is a treatment that induces temporary tolerance to a culprit drug, allowing the allergic patient to receive the medication. We present the case of a 7-year-old patient diagnosed with Hunter syndrome who presented, after 4 years of treatment, two episodes of anaphylaxis during the infusion of idursulfase. Detection of specific immunoglobulin E was carried out using skin tests, with intradermal reaction at a 1/10 dilution (0.2 mg/ml) being positive. A 12-step desensitization protocol was performed without presenting adverse events. The allergological evaluation and the possibility of desensitization were useful tools in the management of our patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5546/aap.2021.e41DOI Listing
February 2021

The odyssey of complex neurogenetic disorders: From undetermined to positive.

Am J Med Genet C Semin Med Genet 2020 12 20;184(4):876-884. Epub 2020 Oct 20.

Neurogenetics Unit, Hospital JM Ramos Mejía, Buenos Aires, Argentina.

The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31848DOI Listing
December 2020

Enzyme replacement therapy interruption in patients with Mucopolysaccharidoses: Recommendations for distinct scenarios in Latin America.

Mol Genet Metab Rep 2020 Jun 27;23:100572. Epub 2020 Feb 27.

Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, Brazil.

Background: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, leading to the progressive accumulation of glycosaminoglycans (GAGs) and the subsequent compromising of tissues and organ malfunction. Although incurable, most types of MPS can be treated with enzyme replacement therapy (ERT), an approach that has had positive effects on the natural clinical evolution and which impact has been extensively investigated. Unfortunately, to date, there is relatively little data regarding the effects of ERT interruption, especially in Latin America, where such interruption may be frequent due to a variety of issues (for instance, difficulties involving logistics, reimbursement and/or payment withdrawal).

Method: A group of medical professionals from Latin America with experience in Genetics, Pediatrics and Neurology held an Advisory Board Meeting in the city of São Paulo, in October 2018, to discuss the issue of ERT interruptions in the region and recommendations health care professionals on how to deal with these interruptions and better assess the therapeutic effects of ERT.

Conclusion: Recommendations provided by the experts may support physicians in dealing with the most common reasons for ERT interruptions in Latin America. Most importantly, recommendations for data collection at specific timepoints (at baseline, throughout the treatment and during the interruption period of ERT and after its resumption) can significantly improve the collection of real world evidence on the effects of ERT and its interruptions, supporting health care professionals and policy makers in the decision making regarding the provision of these therapies for MPS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2020.100572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047015PMC
June 2020

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years.

Ann Hum Genet 2020 01 16;84(1):11-28. Epub 2019 Aug 16.

Neurogenetic Section, Neurology Department, Hospital J.M. Ramos Mejía, CABA, Centro Universitario de Neurología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

Introduction And Objectives: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques.

Materials And Methods: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones.

Results: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease.

Conclusions: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12345DOI Listing
January 2020

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

Orphanet J Rare Dis 2019 06 13;14(1):137. Epub 2019 Jun 13.

Center for Rare Diseases at Host Schmidt Kliniken, Wiesbaden, Germany and Department of Paediatrics University of Padova, Padova, Italy.

Introduction: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.

Methods: Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.

Results: A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).

Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1074-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567385PMC
June 2019

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

Orphanet J Rare Dis 2019 05 29;14(1):118. Epub 2019 May 29.

Center for Rare Diseases at Host Schmidt Kliniken, Wiesbaden, Germany and Department of Paediatrics, University of Padova, Padova, Italy.

Introduction: Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI.

Methods: 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.

Results: A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).

Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1080-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541999PMC
May 2019

Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach.

PLoS One 2018 1;13(2):e0191228. Epub 2018 Feb 1.

Consultorio de Neurogenética, Centro Universitario de Neurologia y Division Neurologia, Hospital J.M.Ramos Mejia, Facultad de Medicina, UBA, Buenos Aires, Argentina.

Background: Diagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called "diagnostic odysseys". Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country-are rare.

Objectives: To assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital.

Methods: This is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated.

Results: We demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3-70). The mean time elapsed from symptom onset to WES was 11 years (range 3-42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center.

Conclusions: WES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794057PMC
March 2018

Epilepsy in mucopolysaccharidosis disorders.

Mol Genet Metab 2017 12 16;122S:55-61. Epub 2017 Oct 16.

Department of Child Neurology, Hospital Universitario Austral, Buenos Aires, Argentina.

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes involved in the catabolism of glycosaminoglycans (GAGs). The resulting GAG accumulation in cells and tissues throughout the body leads to progressive multi-organ dysfunction. MPS patients present with several somatic manifestations, including short stature, musculoskeletal abnormalities, and cardiorespiratory dysfunction, and several primary and secondary neurological signs and symptoms. Epileptic seizures are neurological signs of MPS thought to develop due to accumulation of GAGs in the brain, triggering alterations in neuronal connectivity and signaling, and release of inflammatory mediators. The amount of literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited. This review discusses current knowledge on this topic, as well as two case examples, presented and discussed during a closed meeting on MPS and the brain among an international group of experts with extensive experience in managing and treating MPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2017.10.006DOI Listing
December 2017

Practical management of behavioral problems in mucopolysaccharidoses disorders.

Mol Genet Metab 2017 12 27;122S:35-40. Epub 2017 Sep 27.

Department of Child Neurology, Hospital Universitario Austral, Buenos Aires, Argentina.

The mucopolysaccharidosis (MPS) disorders are caused by deficiencies of specific lysosomal enzymes, resulting in progressive glycosaminoglycan (GAG) accumulation in cells and tissues throughout the body. Excessive GAG storage can lead to a variety of somatic manifestations as well as primary and secondary neurological symptoms. Behavioral problems (like hyperactivity, attention difficulties, and severe frustration) and sleeping problems are typical primary neurological symptoms of MPS caused by GAG accumulation in neurons, and are frequently observed in patients with MPS I, II, III, and VII. As these problems often place a significant burden on the family, proper management is important. This review summarizes current insights into behavioral and sleeping problems in MPS disorders and the most optimal management approaches, as presented and discussed during a meeting of an international group of experts with extensive experience in managing and treating MPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2017.09.010DOI Listing
December 2017

Surgical management of neurological manifestations of mucopolysaccharidosis disorders.

Mol Genet Metab 2017 12 28;122S:41-48. Epub 2017 Sep 28.

Department of Neuroradiology, DASA Group, São Paulo, Brazil.

The mucopolysaccharidosis (MPS) disorders are ultra-rare lysosomal storage disorders associated with progressive accumulation of glycosaminoglycans (GAGs) in cells and tissues throughout the body. Clinical manifestations and progression rates vary widely across and within the different types of MPS. Neurological symptoms occur frequently, and may result directly from brain damage caused by infiltration of GAGs, or develop secondary to somatic manifestations such as spinal cord compression, hydrocephalus, and peripheral nerve entrapment. Management of secondary neurological manifestations often requires surgical correction of the underlying somatic cause. The present review discusses the surgical management of neurological disease in patients with MPS, including diagnostic imaging. Background information is derived from presentations and discussions during a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2017.09.011DOI Listing
December 2017

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

N Engl J Med 2017 10 4;377(17):1630-1638. Epub 2017 Oct 4.

From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).

Background: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.

Methods: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.

Results: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.

Conclusions: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1700554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708849PMC
October 2017

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.

Mol Genet Metab 2017 09 20;122(1-2):18-32. Epub 2017 Aug 20.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Translational Science, Children's National Medical Center, Washington, DC, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2017.08.006DOI Listing
September 2017

Switch from agalsidase beta to agalsidase alfa in the enzyme replacement therapy of patients with Fabry disease in Latin America.

Medicina (B Aires) 2017 ;77(3):173-179

Centro de Estudio de Enfermedades Lisosomales, Hospital Nacional Prof. Dr. Alejandro Posadas, Haedo, Argentina. E-mail:

There are currently two available enzyme replacement therapies for Fabry disease and little information regarding efficacy and safety of switching therapies. Between 2009 and 2012 there was a worldwide shortage of agalsidase beta and patients on that enzyme were switched to agalsidase alfa. This retrospective observational study assessed a 2-year period of efficacy and safety in a population of Fabry patients, in Argentina (30 patients) and Venezuela (3 patients), who switched therapies from algasidase beta to agalsidase alfa. Thirty-three patients completed 24-months follow-up after the switch (age 32.4 ± 2.0, range 10.0-55.9 years; male: female 23:10). Measures of renal function such as estimated glomerular filtration rate remained almost unchanged in 31 patients without end stage renal disease over the 2 years after switching and urine protein excretion continued stable. Cardiac functional parameters: left ventricular mass index, interventricular septum, left ventricular posterior wall showed no significant change from baseline in the 33 patients. Quality of life, pain and disease severity scores were mostly unchanged after 24-months and agalsidase alfa was generally well tolerated. Our findings showed there is no significant change in the efficacy measured through the renal or cardiac function, quality of life, pain, disease severity scoring and safety for at least 2 years after switching from agalsidase beta to agalsidase alfa.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2018

Effectiveness of enzyme replacement therapy in Fabry disease: Long term experience in Argentina.

Mol Genet Metab Rep 2017 Jun 4;11:65-68. Epub 2017 May 4.

GADYTEF (Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Fabry), Argentina.

Evidence regarding long term effectiveness of enzyme replacement therapy (ERT) in Fabry disease (FD) is needed. The aim of this study was to analyze in a cohort of FD patients in Argentina, the long term effectiveness of ERT on renal, cardiac and cerebrovascular parameters.

Methods: Patients with genetically proven FD were included from GADYTEF (Argentinean group for the treatment of FD) between 2001 and 2014. Renal, cardiac, and cerebral outcomes were prospectively studied in patients treated with ERT. Additionally, the occurrence of major cardiac complications, stroke, end-stage renal disease and death was analyzed during follow up.

Results: During the follow-up 8 major complications occurred in 5 patients ( = 2 deaths,  = 4 cases of end stage renal disease and  = 1 atrial fibrillation), 4 of them males and only 1 female who suffered an atrial fibrillation. Sudden death or stroke did not occur. Four (40%) of 10 males with baseline left ventricular hypertrophy (LVH) reduced left ventricular mass index (LVMI) from 163.1 ± 64.7 to 123.4 ± 49.8 g/m, 2 stabilized LVMI and 4 increased LVMI from157.9 ± 32.3 to 261.6 ± 48.6 g/m. Estimated glomerular filtration was stable in 30 patients (17 males and 13 females).

Conclusions: We observed a few major complications during the follow up. Future studies are necessary to show the effectiveness of ERT in affected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2017.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423300PMC
June 2017

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

N Engl J Med 2016 Aug;375(6):545-55

From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal NHS Foundation Trust, Salford (A.J.), and University of Sunderland, Sunderland (S.W.) - all in the United Kingdom; the Department of Nephrology, Royal Melbourne Hospital, Parkville, VIC (K. Nicholls), and the Metabolic Clinic, Women's and Children's Hospital, Adelaide, SA (D.B.) - both in Australia; the Clinical Research Division, Hôpital du Sacré-Coeur, Montreal (D.G.B.); Medical Genetics Service, Clinic Hospital of Porto Alegre, Porto Alegre (R.G.), and Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo-Ribeirão Preto, Ribeirão Preto (C.M.L.) - both in Brazil; the Departments of Human Genetics (W.R.W., S.P.S.) and Ophthalmology (S.P.S.), Emory University School of Medicine, Atlanta; the Dermatology Unit, University of Parma, Parma, Italy (C.F.); the Faculty of Medicine, Department and Laboratory of Pediatric Metabolic Disorders, Gazi University, Ankara, Turkey (F.E.); the Department of Pediatrics, Hospital Alemán, Buenos Aires (H.A.); the Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen (U.F.-R.); Infusion Associates, Grand Rapids, MI (K. Nedd); the Faculty of Medicine, Kasr El Ainy Hospital, Cairo (U.S.E.D.); New York Presbyterian Hospital, New York (M.B.); the Division of Genetics, Ann & Robert H. Lurie Children's Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago (J. Charrow); the Department of Urology, University of Kansas Medical Center, Kansas City (M.D., A.T.); Children's Hospital of Pittsburgh, Pittsburgh (D.F.); Hospital Miguel Servet, Zaragoza (P.G.), and Fundacio Puigvert, Universidad Autónoma de Barcelona, Barcelona (R.T.) - both in Spain; O & O Alpa

Background: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes.

Methods: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes.

Results: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased.

Conclusions: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1510198DOI Listing
August 2016

Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.

J Inherit Metab Dis 2016 Mar 16;39(2):243-52. Epub 2015 Oct 16.

Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.

Patients And Results: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38% of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14% of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69% of SUCLA2 and 80% of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found.

Conclusions: To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10545-015-9894-9DOI Listing
March 2016

Methods of diagnosis of patients with Pompe disease: Data from the Pompe Registry.

Mol Genet Metab 2014 Sep-Oct;113(1-2):84-91. Epub 2014 Jul 16.

Genzyme, a Sanofi company, 500 Kendall Street, Cambridge, MA 02142, USA.

Pompe disease is a rare, autosomal recessive disorder characterized by deficiency of lysosomal acid alpha-glucosidase and accumulation of lysosomal glycogen in many tissues. The variable clinical manifestations, broad phenotypic spectrum, and overlap of signs and symptoms with other neuromuscular diseases make diagnosis challenging. In the past, the diagnosis of Pompe disease was based on enzyme activity assay in skin fibroblasts or muscle tissue. In 2004, methods for measuring acid alpha-glucosidase activity in blood were published. To compare how diagnostic methods changed over time and whether they differed by geographic region and clinical phenotype, we examined diagnostic methods used for 1059 patients enrolled in the Pompe Registry in three onset categories (Group A: onset of signs/symptoms ≤ 12 months of age with cardiomyopathy; Group B: onset ≤ 12 months without cardiomyopathy and onset >1 year to ≤ 12 years; Group C: onset >12 years). Enzyme activity-based assays were used more frequently than other diagnostic methods. Measuring acid alpha-glucosidase activity in blood (leukocytes, lymphocytes, or dried-blood spot) increased over time; use of muscle biopsy decreased. The increased use of blood-based assays for diagnosis may result in a more timely diagnosis in patients across the clinical spectrum of Pompe disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2014.07.014DOI Listing
June 2015

Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America.

Genet Mol Biol 2014 Jun;37(2):315-29

Hospital Universitario Austral , Buenos Aires , Argentina .

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase(®), Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients' responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094607PMC
http://dx.doi.org/10.1590/s1415-47572014000300003DOI Listing
June 2014

Fabry disease: multidisciplinary evaluation after 10 years of treatment with agalsidase Beta.

JIMD Rep 2014 22;16:7-14. Epub 2014 May 22.

Laboratorio Neuroquímica Dr Chamoles (FESEN), Buenos Aires, Argentina,

Unlabelled: Fabry disease is an X linked disorder of metabolism due to deficient α-galactosidase A activity. Enzyme replacement therapy (ERT) with agalsidase Beta was approved by EMA in 2001 and FDA in 2003.

Patients And Methods: Six patients were enrolled. Baseline data was measured for renal, cardiac, and cerebrovascular functioning. We compared baseline quality of life scales with the current results. These parameters were assessed during the 10 years of follow-up period.

Results: Before ERT four patients showed normal eGFR, one stage 2 of CKD, and one hyperfiltration stage. All presented microalbuminuria and just two cases showed proteinuria. After 10 years of ERT, no patient showed decrease in renal functioning. One patient decreased from proteinuria to microalbuminuria range. Before treatment one case showed left ventricular (LV) hypertrophy and LV Mass Index was abnormal in two female patients. After 10 years echocardiographic values did not present progression to LVH and one female showed regression to normal values of LV posterior wall and interventricular septum. Brain MRI showed ischemic lesions in one female and vertebrobasilar dolichoectasia in one male. From baseline and during the follow-up period MRI did not progress to new ischemic lesions and there were no clinical signs of cerebrovascular damage. After 10 years quality of life showed improvement in all domains measured.

Conclusion: Early treatment of agalsidase Beta is related to a better outcome regarding stability and regression of signs and symptoms in Fabry disease. Our results in patients with mild organ involvement showed good outcomes and support an early and continuous ERT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/8904_2014_310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221298PMC
November 2014

[Guidelines for diagnosis, monitoring and treatment of Fabry disease].

Medicina (B Aires) 2013 ;73(5):482-94

Hospital Italiano de La Plata. E-mail:

Fabry disease is an X-linked hereditary lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Knowledge about this disease, and its medical management, has made remarkable progress in the last decade, including the development of its specific treatment. This guide was developed by medical professionals from various specialties involved in the care of patients with Fabry disease. The discussion and analysis of the available scientific evidence, coupled with the experience of each of the participants, has allowed us to develop the concepts included in this guide in order to provide a useful tool for all professionals who care for patients with Fabry disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2014

Timing of diagnosis of patients with Pompe disease: data from the Pompe registry.

Am J Med Genet A 2013 Oct 30;161A(10):2431-43. Epub 2013 Aug 30.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.

Diagnostic delays in Pompe disease are common. The diagnostic gap (the time from the onset of symptoms to the diagnosis of Pompe disease) and factors associated with diagnostic delays were examined among Pompe Registry patients in three onset categories: Group A, onset ≤12 months of age with cardiomyopathy; Group B, onset ≤12 months without cardiomyopathy and onset >12 months to ≤12 years; and Group C, onset >12 years. Of 1,003 patients, 647 were available for analysis. In all groups, musculoskeletal signs and symptoms were among the most frequent presenting signs and symptoms, in addition to cardiomyopathy in Group A, which was part of the group's definition. Diagnostic gaps existed in all three groups. Patients presenting with respiratory and musculoskeletal signs and symptoms concurrently had the shortest diagnostic gap, while those presenting with neither respiratory nor musculoskeletal signs and symptoms had the longest. Independent factors influencing the probability of a long diagnostic gap included presenting signs and symptoms (all three groups) and year of diagnosis and age at symptom onset (Groups B and C). Group B, which represents the infantile patients without cardiomyopathy and juvenile Pompe cases, had the longest median gap (12.6 years). Diagnostic testing methods used also were reviewed. Despite the availability of blood-based assays that can be used to quickly and accurately diagnose Pompe disease, diagnostic gaps in Pompe patients across the disease spectrum continue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36110DOI Listing
October 2013

[Alrternating hemiplegia of childhood: a case report and literature review].

Arch Argent Pediatr 2012 Oct;110(5):e86-90

Departamento de Pediatría, Hospital Alemán.

Alternating hemiplegia of childhood is an entity of uncertain etiology, with an incidence of about one case per million. This paroxysmal disease with progressive course is characterized by repeated episodes of hemiplegia that alternates its location and that may last from a few minutes to several days. These episodes are usually aborted during sleep. Paroxysmal eye movements, cognitive impairment and autonomic disorders, can also be seen. Due to its progressive course and bad prognosis, it turns out to be important for the generalist physician to be aware of this entity, thus facilitating an early diagnosis and avoiding empiric pharmacologic ineffective treatments. We present the case of a ten year-old girl with alternating hemiplegia of childhood, show imaging of this disease and make a brief review of the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5546/aap.2012.e86DOI Listing
October 2012

[Enzyme replacement therapy in the infantile form of Pompe disease: Argentinean experience in a seven-year follow up case].

Arch Argent Pediatr 2012 Aug;110(4):323-7

Departamento de Pediatría, Hospital Alemán, Ciudad Autónoma de Buenos Aires, Argentina.

The infantile form of Pompe disease drives children to death before the first year of life due to cardiomyopathy and respiratory insufficiency. We present the seven-year follow-up experience with enzyme replacement therapy on a child with Pompe disease, being the longest follow-up in the country. The treatment was well tolerated without adverse reactions. The echocardiographic and electrocardiographic parameters clearly improved during the first year and remain stable. Motor milestones (like rolling over or sitting down without support) were initially achieved, but, after the third year were getting lost. The average age of ventilator dependence was also delayed (16 months). The 7-year old patient remains alive with severe generalized muscle weakness. The child notably overcame the average age of survival and onset of ventilator dependence. Although the cardiovascular improvement was clear, enzyme replacement therapy efficacy on skeletal muscle was limited in this patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5546/aap.2012.323DOI Listing
August 2012

Biomarkers for the mucopolysaccharidoses: discovery and clinical utility.

Mol Genet Metab 2012 Aug 14;106(4):395-402. Epub 2012 May 14.

Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.

The mucopolysaccharidoses (MPSs), a group of inherited lysosomal storage diseases, are complex, progressive, multisystem disorders with extreme clinical heterogeneity. The introduction of therapies that target the underlying enzyme deficiency in a number of the MPSs has brought to light the need for biomarkers that would aid in the evaluation of disease burden and as a means to objectively measure therapeutic response in individual patients. It is increasingly recognized that due to the extraordinarily complex pathogenesis of the MPSs, achieving these goals with a single analyte, such as urinary glycosaminoglycans, is unlikely. This recognition has created an impetus for the search for clinically useful biomarkers that reflect the disease pathogenesis and that are stage- or organ-specific. In this review, the current state of MPS biomarker research is discussed, with a focus on clinical utility in the MPSs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2012.05.003DOI Listing
August 2012

Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES).

Epilepsia 2012 Jul 17;53(7):1156-61. Epub 2012 Apr 17.

Department of Neurology, Juan P. Garrahan Pediatric Hospital, Buenos Aires, Argentina.

Purpose: In children with symptomatic or idiopathic focal epilepsies, their disease may evolve into an epileptic encephalopathy related to continuous spike and wave during slow sleep (CSWS) or electrical status epilepticus during slow sleep (ESES). ESES syndrome implies serious risks of neuropsychologic impairment, and its treatment has frequently been disappointing. The aim of this study is to present our experience using sulthiame as add-on treatment in 53 patients with ESES syndrome that was refractory to other antiepileptic drugs (AEDs).

Methods: Neurologic examinations, cerebral magnetic resonance imaging (MRI), and repeated prolonged sleep electroencephalography (EEG) studies were performed in all cases. Data about school achievements and or neuropsychological evaluations were obtained repeatedly during the follow-up of 1.5-16 years. Sulthiame was added in doses ranging between 5 and 30 mg/kg/day.

Key Findings: Since add-on of sulthiame, 10 of 28 patients in the symptomatic group became seizure free: 4 patients with normal EEG studies and 6 with residual spikes. Nine of 28 patients showed a significant reduction in number of seizures and presented spikes but no ESES on EEG. The other nine cases showed neither clinical nor EEG improvement. A striking result was that 3 of 11 children with unilateral polymicrogyria and ESES syndrome became seizure free, and in another six a significant improvement in frequency of seizures and in EEG abnormalities seemed to be related to the add-on of sulthiame. Twenty-one of the 25 patients in the idiopathic group became seizure free and without ESES in <3 months after add on of sulthiame. In two of the patients the changes were seen in a few days.

Significance: We understand that sulthiame may be effective as add-on treatment in children with ESES syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2012.03458.xDOI Listing
July 2012

Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.

Gene 2012 May 13;499(2):262-5. Epub 2012 Mar 13.

Regional Coordinator Centre for Rare Disease, University Hospital Santa Maria della Misericordia, Udine, Italy.

Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2012.03.022DOI Listing
May 2012

Utility of rare disease registries in latin america.

JIMD Rep 2011 25;1:111-5. Epub 2011 Jun 25.

Fabry Registry Brazil, Latin America Fabry, Gaucher, MPS I and Pompe Registries, Universidade Federal de São Paulo, São Paulo, Brazil,

There are many registries in Latin America as dialysis and kidney transplantation, breast cancer, primary immunodeficiency, acute coronary syndromes, but the focus here are the registries of lysosomal storage diseases (LSD) because is our experience. Registry of Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis type I are comprehensive observational voluntary programs that aim to collect clinical and laboratory data of initiation, progression, and evolution of those diseases, with and without treatment, using questionnaires of quality of life and/or skills and functions. There are two more programs of LSD: Hunter outcome survey and Fabry outcome survey. The registries are a kind of phase IV clinical trials, postmarketing studies delineate additional information including the drug's risks, benefits, and optimal use, and in addition we have data from natural history. The demographics of the Gaucher, Fabry, MPS I, and Pompe Registries show that a total of patients, being 16%, 8%, 15%, and 7%, respectively, of this population, and 19%, 19%, 18%, and 13%, respectively, of all physicians participating in the program are from Latin America. In the Gaucher Registry, we can observe that the percentage of children in Latin America (29%) is bigger than the rest of the world (20%), what can mean more severe disease in this population. These diseases are rare, and a database of clinical data from a larger number of patients gives us the opportunity to know about the natural history of these diseases, their phenotypic variability, and the response to specific enzyme replacement therapy in our population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/8904_2011_25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509820PMC
February 2013

p.[G576S; E689K]: pathogenic combination or polymorphism in Pompe disease?

Eur J Hum Genet 2008 Aug 27;16(8):875-9. Epub 2008 Feb 27.

Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.

We discuss four cases of acid alpha-glucosidase deficiency (EC, 3.2.1.3/20) without evident symptoms of Pompe disease (OMIM No 232300) in individuals of Asian descent. In three cases, the deficiency was associated with homozygosity for the sequence variant c.[1726G>A; 2065G>A] in the acid alpha-glucosidase gene (GAA) translating into p.[G576S; E689K]. One of these cases was a patient with profound muscular atrophy, another had cardio-myopathy and the third had no symptoms. The fourth case, the mother of a child with Pompe disease, was compound heterozygote for the GAA sequence variants c.[1726G>A; 2065G>A]/c.2338G>A (p.W746X) and had no symptoms either. Further investigations revealed that c.[1726A; 2065A] is a common GAA allele in the Japanese and Chinese populations. Our limited study predicts that approximately 4% of individuals in these populations are homozygote c.[1726A; 2065A]. The height of this figure in contrast to the rarity of Pompe disease in Asian populations and the clinical history of the cases described in this paper virtually exclude that homozygosity for c.[1726A; 2065A] causes Pompe disease. As c.[1726A; 2065A] homozygotes have been observed with similarly low acid alpha-glucosidase activity as some patients with Pompe disease, we caution they may present as false positives in newborn screening programs especially in Asian populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2008.34DOI Listing
August 2008

Genetic and clinical heterogeneity in eIF2B-related disorder.

J Child Neurol 2008 Feb;23(2):205-15

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC 20010, USA.

Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073807308705DOI Listing
February 2008

Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations.

Neuromuscul Disord 2007 Jan 23;17(1):16-22. Epub 2006 Oct 23.

Molecular Genetic Analysis Group, Genzyme Corporation, Framingham, MA 01701, USA.

Pompe disease is an autosomal recessive disorder caused by a deficiency in 1,4-alpha-glucosidase (EC.3.2.1.3), the enzyme required to hydrolyze lysosomal glycogen to glucose. While previous studies have focused on Pompe patients from Europe, the United States, and Taiwan, we have analyzed a group of South American Pompe patients to better understand the molecular basis of their disease. From 14 Argentinean patients diagnosed with either infantile or late-onset disease, we identified 14 distinct mutations in the acid alpha-glucosidase (GAA) gene including nine novel variants (c.236_246del, c.377G>A, c.1099T>C, c.1397T>G, c.1755-1G>A, c.1802C>G, c.1978C>T, c.2281delGinsAT, and c.2608C>T). Three different families displayed the c.377G>A allelic variant, suggesting a higher frequency among a subset of Argentineans. Comparison of patients with similar or identical variations in the GAA gene highlights the phenotypic diversity of late-onset disease and supports a role for other genetic and environmental factors in disease presentation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2006.09.004DOI Listing
January 2007