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      Consensus clinical management guidelines for Alström syndrome

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          Abstract

          Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.

          These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.

          These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

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          State of the art: using natriuretic peptide levels in clinical practice.

          Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians: 1) NP levels are quantitative plasma biomarkers of heart failure (HF). 2) NP levels are accurate in the diagnosis of HF. 3) NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge. 4) NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea. 5) NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients. 6) NP levels at discharge aid in risk stratification of the HF patient. 7) NP-guided therapy may improve morbidity and/or mortality in chronic HF. 8) The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF. 9) NP levels can accelerate accurate diagnosis of heart failure presenting in primary care. 10) NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.
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            Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome.

            Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.
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              New Alström syndrome phenotypes based on the evaluation of 182 cases.

              Alström syndrome is a recessively inherited genetic disorder characterized by congenital retinal dystrophy that leads to blindness, hearing impairment, childhood obesity, insulin resistance, and type 2 diabetes mellitus. We provide new details on cardiologic, hepatic, gastrointestinal, urologic, pulmonary, and neurobehavioral phenotypes in Alström syndrome and describe the histopathologic findings in 5 individuals. We obtained data on 182 patients from clinical examinations, medical record reviews, standardized questionnaires, and personal interviews with physicians and parents. Dilated cardiomyopathy occurred in 60% of patients. Age at onset was either during infancy, often before vision disturbances were noted, or in adolescence or adulthood. There is a risk of recurrence of infantile cardiomyopathy. Hyperinsulinemia (92%) developed in early childhood and progressed to type 2 diabetes mellitus in 82% of those older than 16 years. Hypertriglyceridemia (54%) precipitated pancreatitis in 8 patients. Urologic dysfunction and gastrointestinal disturbances occurred in 48% and 35% of patients, respectively. Fifty-three percent of patients had persistent pulmonary symptoms. Neurologic symptoms in 20% of patients included clonic tic and absence seizures. Developmental motor or language delays were observed in 46% of patients. Fibrotic infiltrations of multiple organs, that is, kidney, heart, liver, lung, urinary bladder, gonads, and pancreas, were observed. The wide-ranging and complex spectrum of phenotypes reported herein broadens those previously described for Alström syndrome. These findings will aid physicians in making an early and accurate diagnosis and will help effect appropriate monitoring and treatment.
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                Author and article information

                Contributors
                Tarekegn.Geberhiwot@uhb.nhs.uk
                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                1750-1172
                21 September 2020
                21 September 2020
                2020
                : 15
                : 253
                Affiliations
                [1 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, Department of Diabetes, Endocrinology and Metabolism, University Hospitals Birmingham NHS Foundation Trust, , Queen Elizabeth Hospital, ; Birmingham, B15 2TH UK
                [2 ]GRID grid.411474.3, ISNI 0000 0004 1760 2630, Department of Medicine (DIMED), , Padua University Hospital, ; Padua, Italy
                [3 ]GRID grid.411474.3, ISNI 0000 0004 1760 2630, Adult MTG3 Chair of ENDO-ERN, Azienda Ospedaliera Padova, ; Padua, Italy
                [4 ]GRID grid.412220.7, ISNI 0000 0001 2177 138X, Centre de référence pour les affections rares ophtalmologiques CARGO, FSMR SENSGENE, ERN-EYE, , Hôpitaux Universitaires de Strasbourg, ; Strasbourg, France
                [5 ]GRID grid.11843.3f, ISNI 0000 0001 2157 9291, Laboratoire de Génétique Médicale, UMRS_1112, Institut de Génétique Médicale d’Alsace, , Université de Strasbourg, ; Strasbourg, France
                [6 ]GRID grid.439442.c, ISNI 0000 0004 0474 1025, Diabetes Research Unit, Torbay and South Devon NHS Foundation Trust, ; Torquay, UK
                [7 ]GRID grid.6312.6, ISNI 0000 0001 2097 6738, CINBIO (Centro de Investigacion Biomedica), Universidad de Vigo, ; Vigo, Spain
                [8 ]GRID grid.413728.b, ISNI 0000 0004 0383 6997, Departments of Pediatrics and Physiology, College of Medicine, University of Tennessee Health Science Center and Pediatric Obesity Program, Children’s Foundation Research Institute, , Le Bonheur Children’s Hospital, ; Memphis, TN USA
                [9 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, Department of Respiratory Medicine, University Hospital Birmingham NHS Foundation Trust, , Queen Elizabeth Hospital, ; Birmingham, UK
                [10 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, Liver and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, , Queen Elizabeth Hospital, ; Birmingham, UK
                [11 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, , Queen Elizabeth Hospital, ; Birmingham, UK
                [12 ]GRID grid.411082.e, ISNI 0000 0001 0720 3140, Department of Medical Genetics, , Abant İzzet Baysal University, ; Bolu, Turkey
                [13 ]GRID grid.257413.6, ISNI 0000 0001 2287 3919, Department of Medical and Molecular Genetics, , Indiana University School of Medicine, ; Indianapolis, IN USA
                [14 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Departments of Genetic Medicine and Pediatrics, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [15 ]Italian Association Alström Syndrome, Padua, Italy
                [16 ]ENDO-ERN ePAG representative in MTG3, Padua, Italy
                [17 ]Alström Syndrome UK, Torquay, Devon UK
                [18 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, Department of Cardiology, University Hospitals Birmingham NHS Foundation Trust, , Queen Elizabeth Hospital, ; Birmingham, UK
                [19 ]Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK
                [20 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Metabolism and System Research, , University of Birmingham, ; Birmingham, UK
                Author information
                http://orcid.org/0000-0002-3629-2338
                Article
                1468
                10.1186/s13023-020-01468-8
                7504843
                32958032
                2279ec38-51af-41cc-8831-7c8b17d65b70
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 1 May 2020
                : 21 July 2020
                Categories
                Position Statement
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                © The Author(s) 2020

                Infectious disease & Microbiology
                alström syndrome,guidelines,rare disease,blindness,deafness,cardiomyopathy,insulin resistance,obesity,non-alcoholic fatty liver disease

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