Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies

Meilleur, K.; Jain, Minal; Hynan, Linda S.; Shieh, Ching Yi; Kim, Eunice; Waite, Mitchell; McGuire, Michelle; Fiorini, Courtney; Glanzman, Allan M.; Main, Marion; Rose, Kristy; Duong, Tina; Bendixen, Roxanna; Linton, Melody M.; Arveson, I.; Nichols, Carmel; Yang, Kelly; Fischbeck, Kenneth H.; Wagner, Kathryn R.; North, Klaus; Mankodi, Ami; Grunseich, Christopher; Hartnett, Elizabeth; Smith, M. I.; Donkervoort, Sandra; Schindler, Alice B.; Kokkinis, Angela; Leach, M.; Foley, A. Reghan; Collins, James J.; Muntoni, Francesco; Rutkowski, Anne; Bönnemann, Carsten G.

doi:10.1016/j.nmd.2014.09.010

Cited by 36 publications

(47 citation statements)

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“…This cross-sectional study is a component of a larger longitudinal study focusing on the natural history and outcome measure validation in two subtypes of CMD, as well as assessing the feasibility, reliability, and validity of a battery of muscle strength, motor function, and patient reported outcome measures for this patient population [6]. The study received approval from the National Institute of Neurological Disorders and Stroke (NINDS) Institutional Review Board (IRB).…”

Section: Methodsmentioning

confidence: 99%

“…All upper extremity measures used in this study were correlated with the Motor Function Measure 32 (MFM32). The MFM32 evaluates head, trunk, upper and lower limb function in both ambulatory and non-ambulatory individuals, is reliable, and has been validated in individuals with CMD [6,7,10]. In addition to the Jebsen, the battery of upper extremity assessments included the Quality of Upper Extremity Skills Test (QUEST), hand held dynamometry, goniometry, and MyoSet Tools.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the Jebsen, the battery of upper extremity assessments included the Quality of Upper Extremity Skills Test (QUEST), hand held dynamometry, goniometry, and MyoSet Tools. The order of the testing was randomized due to the number of assessments completed in the larger longitudinal study, including gross motor tests, pulmonary function test, and quality of life measures [6]. In an attempt to limit fatigue, we did not schedule back to back active testing.…”

Section: Methodsmentioning

confidence: 99%

“…In order to determine the effectiveness of new therapeutic strategies in clinical trials, measures of skeletal muscle structure and function that can quantify disease progression and are validated for patients with CMD are needed [6]. Traditional measures of strength and function in various neuromuscular disorders, including CMD, have incorporated muscle strength testing (myometry), motor performance (6-minute walk test, timed 10-m walk/run and ascend/descend stairs), range of motion (goniometry), forced vital capacity, and anthropometric measures [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy

Bendixen

Butrum

Jain³

et al. 2017

Neuromuscular Disorders

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Purpose Congenital muscular dystrophy (CMD) comprises a rare group of genetic muscle diseases that present at birth or early during infancy. Two common subtypes of CMD are collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). Traditional outcome measures in CMD include gross motor and mobility assessments, yet significant motor declines underscore the need for valid upper extremity (UE) motor assessments as a clinical endpoint. This study validated a battery of UE measures in these two CMD subtypes for future clinical trials. Methods For this cross-sectional study, 42 participants were assessed over the same 2–5 day period at the National Institutes of Health Clinical Center (CC). All UE measures were correlated with the Motor Function Measure 32 (MFM32). The battery of UE assessments included the Jebsen Taylor Hand Function Test, Quality of Upper Extremity Skills Test (QUEST), hand held dynamometry, goniometry, and MyoSet Tools. Spearman Rho was used for correlations to the MFM32. Pearson was performed to correlate the Jebsen, QUEST, hand-held dynamometry, goniometry and the MyoSet Tools. Correlations were considered significant at the 0.01 level (2-tailed). Results Significant correlations were found between both the MFM32 and MFM Dimension 3 only (Distal Motor function) and the Jebsen, QUEST, MyoGrip and MyoPinch, elbow flexion/extension ROM and myometry. Additional correlations between the assessments are reported. Conclusions The Jebsen, the Grasp and Dissociated Movements domains of the QUEST, the MyoGrip and the MyoPinch tools, as well as elbow ROM and myometry were determined to be valid and feasible in this population, provided variation in test items, and assessed a range of difficulty in CMD. To move forward, it will be of utmost importance to determine whether these UE measures are reproducible and sensitive to change over time.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy

Bendixen

Butrum

Jain³

et al. 2017

Neuromuscular Disorders

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“…Focus was addressed by integrating an existing collection of questionnaires for measuring different aspects of wellness developed by the Promis® organisation. These items have been validated in existing medical research (Cella et al, 2007) and applied across a range of fields including pain management (Cook, Buckenmaier, & Gershon, 2014), oncology (Mesa et al, 2013), and neuromuscular disorders (Meilleur et al, 2015), to name but a few (see http:// www.nihpromis.org/science/PublicationsYears for an extensive list).…”

Section: Building An Artefactmentioning

confidence: 99%

Designing an artefact to help users make intervention decisions about their wellness

Gleasure

Grace

2016

Journal of Decision Systems

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Healthcare systems have been evolving towards more decentralised, patient-empowered, and holistic approaches. This places a greater expectation on patients to monitor and report changes in their general wellness so they can make decisions as to when to seek clinical interventions. However, findings from this study suggest individuals find it challenging to detect deteriorations in wellness, due to the vast and multifaceted nature of the concept, the gradual onset of symptoms, and the difficulty in articulating change. Thus a mobile application is developed to help users with these issues. The design of this mobile application draws upon existing cognitive neuroscience research on change detection, both for external stimuli and internal 'interoceptive' sensations. This highlights several key factors to be considered, if wellness-related decision-making is to be supported. In particular, this identifies the role of patients' top-down (attentional) and bottom-up (less-voluntary) processes for detecting wellness deteriorations.

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Dominant collagen XII mutations cause a distal myopathy

Mohassel

Liewluck

et al. 2019

Ann Clin Transl Neurol

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ObjectiveTo characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. MethodsPatients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII.ResultsFour independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns.InterpretationThis study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele.

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Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies

Cited by 36 publications

References 35 publications

Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy

Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy

Designing an artefact to help users make intervention decisions about their wellness

Dominant collagen XII mutations cause a distal myopathy

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