Clinical utility gene card for: Proximal spinal muscular atrophy (SMA) - update 2015.
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ABSTRACT:
SUBMITTER: Rudnik-Schoneborn S
PROVIDER: S-EPMC4613485 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
Publications
Clinical utility gene card for: Proximal spinal muscular atrophy (SMA) - update 2015.
Rudnik-Schöneborn Sabine S Eggermann Thomas T Kress Wolfram W Lemmink Henny H HH Cobben Jan-Maarten JM Zerres Klaus K
European journal of human genetics : EJHG 20150520 11
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Project description:BackgroundSpinal muscular atrophy (SMA) is a progressive neuromuscular disorder that has a substantial impact on health-related quality of life for patients with SMA and their caregivers. Utility values ('utilities') are used in health economic analyses to incorporate individual or societal perspectives regarding the desirability of health outcomes such as a certain health state or change in health states over time.ObjectivesThe primary objective of this systematic literature review (SLR) was to identify published utilities associated with patients with SMA and their caregivers and to determine the extent to which Health Technology Assessment (HTA) requirements of methods used to generate utilities are met. A secondary objective was to broaden the scope to identify utilities associated with other (non-SMA) neuromuscular disorders.MethodsA comprehensive search to capture published utilities associated with patients with SMA and their caregivers was performed in 2019 and updated in 2021 using several electronic databases in addition to supplementary sources. As we anticipated that few published utilities associated with SMA would be identified, the search also captured utilities for other (non-SMA) neuromuscular disorders that may serve as useful surrogate values for studies of SMA and other rare diseases. Electronic searches were performed in Embase, MEDLINE, Evidence-Based Medicine Reviews, and EconLit via the Ovid platform and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites, and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators, and outcomes (PICO) framework. The quality of the full-text publications was assessed using a checklist based on UK National Institute for Health and Care Excellence technical support documents.ResultsIn total, 14 publications that reported SMA-related patient or caregiver utilities or disutilities met the eligibility criteria to be included in the SLR; the included studies demonstrate the substantial health-related quality-of-life burden of SMA on both patients with SMA and their caregivers. A variety of preference-based measures were used to derive utilities for patients with SMA and their caregivers. Different methods for collecting utility data included patient and proxy assessment of health states using questionnaires, vignette methodologies, structured forms of expert elicitation, and mapped data from results of clinical trials. A range of utilities was reported from both patient- and proxy-reported data, which reflects the degree of disability associated with early- and later-onset SMA. Methods for deriving utilities were assessed with respect to three reference cases from HTA bodies in the UK, the USA, and Canada. None of the 14 publications met the requirements of all three HTA bodies because of differing tariff requirements between countries; one study met the requirements of HTA bodies in Canada and the UK. Also, six studies did not report the method of valuation, which precluded analysis with respect to the HTA reference cases.ConclusionsThis SLR provides a comprehensive repository of the currently available utilities relevant to patients with SMA and their caregivers. This SLR provides recommendations for establishing consensus on the approach to generating utility values for the SMA patient population and their caregivers for health economic decisions.
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Project description:Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.
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Project description:ObjectivesSpinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).MethodsBforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.Results12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.ConclusionsDiscovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.
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Project description:Study of gene expression profiles of muscular and neuronal mouse mutant of spinal muscular atrophy(SMA). Pre and post symptomatic stage disease have been analyzed.
2005-05-20 | E-MEXP-131 | biostudies-arrayexpress
Project description:Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.
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