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      Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives

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          Abstract

          Recent advances in the treatment of spinal muscular atrophy (SMA) have dramatically altered prognosis. Rather than a rapidly lethal disease, SMA type 1, the most severe form with the earliest onset of SMA, has become a disease in which long-term event-free survival with the acquisition of important motor milestones is likely. Prognosis for patients with SMA type 2 has shifted from slow and progressive deterioration to long-term stability. Nevertheless, there is a large heterogeneity in terms of clinical response to currently available treatments, ranging from absence of response to impressive improvement. The only factor identified that is predictive of treatment success is the age of the patient at the initiation of treatment, which is closely related to disease duration. The aim of this paper is to review available evidence that support early intervention using currently available treatment approaches.

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          Most cited references 21

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          How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches.

          Both complex disorders and monogenetic diseases are often modulated in their phenotype by further genetic, epigenetic or extrinsic factors. This gives rise to extensive phenotypic variability and potentially protection from disease manifestations, known as incomplete penetrance. Approaches including whole transcriptome, exome, genome, methylome or proteome analyses of highly discordant phenotypes in a few individuals harboring mutations at the same locus can help to identify these modifiers. This review describes the complexity of modifying factors of one of the most frequent autosomal recessively inherited disorders in humans, spinal muscular atrophy (SMA). We will outline how this knowledge contributes to understanding of the regulatory networks and molecular pathology of SMA and how this knowledge will influence future approaches to therapies. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Disease burden of spinal muscular atrophy in Germany

            Background This study aimed at analyzing the economic burden and disease-specific health-related quality of life (HRQOL) of patients with spinal muscular atrophy (SMA) in Germany. SMA is a so far non-curable neuromuscular disease of the anterior nerve cells that causes high rates of morbidity and mortality. Methods In a cross-sectional study we analyzed the cost of illness (COI) and factors that influence the direct, indirect and informal care costs of affected patients and their families by using standardized, self-developed questionnaires. We used the PedsQL™© Measurement Model to analyze the disease-specific HRQOL of patients. Results One hundred eighty nine patients with SMA types I to III aged <1 to 73 years were enrolled. The average annual COI was estimated at €70,566 per patient in 2013. The highest cost resulted in SMA I with significant lower costs for the milder phenotypes. Inversely, the self-estimated HRQOL increased from SMA I to SMA III. Major cost drivers were informal care cost and indirect cost incurred by patients and their caregivers. Conclusions Although SMA requires high standards of care, there has been a distinct lack of health services research on SMA. Accordingly, our results significantly contribute to a more comprehensive insight into the current burden of SMA and quality of life status as related to SMA health services in Germany. In the light of innovative therapeutic interventions, our results suggest a notable potential for a reduction in overall COI and improvement of HRQOL if the therapeutic intervention leads to a less severe course of the disease.
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              Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

              Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                TCRM
                tcriskman
                Therapeutics and Clinical Risk Management
                Dove
                1176-6336
                1178-203X
                02 October 2019
                2019
                : 15
                : 1153-1161
                Affiliations
                [1 ]Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, Department of Pediatrics, University Hospital Liège & University of Liège , Liège, Belgium
                [2 ]MDUK Neuromuscular Center, Department of Paediatrics, University of Oxford , Oxford, UK
                Author notes
                Correspondence: Laurent Servais CRMN, CHU Liège , Boulevard du Douzième de Ligne, 1, Liège4000, BelgiumTel +33 6 22 59 22 43Fax +32 4 321 83 28 Email lservais@chuliege.be
                Article
                172291
                10.2147/TCRM.S172291
                6778729
                © 2019 Dangouloff and Servais.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                References: 46, Pages: 9
                Categories
                Review

                Medicine

                newborn screening, branaplam, risdiplam, zolgensma, nusinersen, spinal muscular atrophy

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