Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies
Introduction
Congenital muscular dystrophy (CMD) comprises a clinically diverse and genetically heterogeneous group of early-onset muscle disorders with characteristic dystrophic features on muscle biopsy. Core groups within the CMDs include collagen VI-related muscular dystrophies (COL6-RD) (Ullrich congenital muscular dystrophy, intermediate collagen VI-related muscular dystrophy and Bethlem myopathy), laminin alpha 2-related muscular dystrophy (LAMA2-RD) (merosin deficiency), the α-dystroglycan-related muscular dystrophies (dystroglycanopathies), lamin A/C-related muscular dystrophy (L-CMD), and selenoprotein N 1-related myopathy (rigid spine CMD) [1]. COL6-RD and LAMA2-RD together are the most common subtypes, with some clinical similarities but also differences. Both are chronically progressive pediatric disorders that present with hypotonia at birth and lead to increasing muscle weakness, respiratory insufficiency, and joint contractures within the first two decades of life [1], [2]. However, both types include early- and late-onset presentations, as well as a severity spectrum [1], [2]. Given this broad phenotypic spectrum, the 173rd European Neuromuscular Centre (ENMC) International Workshop on CMD outcome measures recommended evaluating performance using a battery of outcomes such as forced vital capacity (FVC) percent predicted, motor scales, quality of life measures, caregiver assessments, goniometry, and myometry [3]. Because therapeutic interventions are currently under development for these two CMD subtypes, the establishment of validated clinical outcome measures becomes a clinical priority [3].
In COL6-RD, the phenotypic spectrum ranges from an early-onset, severe presentation with inability to achieve ambulation or loss of ambulation at a mean age of 10 years (Ullrich CMD) [4] to a milder form in which individuals can achieve and maintain ambulation through adulthood (Bethlem myopathy) [5]Intermediate COL6-RD individuals achieve ambulation, but do not run nor hop, lose ambulation at a mean age of 19 years, and may develop respiratory insufficiency while ambulant [6]. Individuals with complete deficiency of laminin alpha 2 (laminin alpha 2-related dystrophy [LAMA2-RD] or complete merosin deficiency) typically do not achieve ambulation [7], [8], [9]. Individuals with partial deficiency of LAMA2 have a more variable phenotype in regard to pattern of weakness and may achieve ambulation [10].
The lack of validated clinical outcome measures in these two CMD subtypes led us to implement a novel study design to validate several outcome measures simultaneously in preparation for clinical trials. The prospective cohort design involved administering 17 outcome measures, specified below, which have been validated in other neuromuscular diseases and were thus predicted to show validity in our population [11], [12], [13], [14], [15], [16], [17], [18]. The battery of measures was administered in one weekend (two years in a row) to a cohort of 22 (year 1) and 32 (year 2) participants by 15 experts (neuromuscular physicians, physical therapists, and psychologists). The administration of outcome measures also served as the basis for an ongoing, 5-year, prospective, natural history study in these two CMD subtypes, which uses outcome measures shown to be feasible, reliable, and valid in this initial two-year pilot study.
We specifically chose assessments that would allow examination of changes within the domains of the international classification of functioning, disability, and health of the World Health Organization (WHO) (Table 1). Although the WHO international classification was originally developed as a tool to aid in the development of interventions, community programs, and public policy, it can be used as an appropriate framework to identify and understand outcome measures [19]. The WHO approach places an emphasis on quantifying impairments of body structure and function, activity limitations, and participation restrictions in the context of one's personal and environmental factors. This approach defines the factors that impact how people with a particular muscle disorder feel and function over time and the various influences that might come to bear on the measurement of disability in the context of a clinical trial. Defining outcome measures within this framework allows prioritization of outcomes that are important for affected individuals and caregivers and creates an awareness of potential intervening variables related to measurement of function that might not be immediately apparent. The ability of an outcome measure to establish efficacy in clinical trials is established through the reliability of measurement and its ability to reflect the domain targeted for measurement [19].
In CMD, common tools for clinical evaluation and thus potential candidates for outcome measures include tests of: muscle power (Medical Research Council [MRC] scale, myometry), joint passive range of motion (goniometry), and motor performance (timed, 10-meter walk/run, rise from floor, ascend/descend 4 stairs) [13], [20], [21], [22]. Although these domains can be measured over time, it is unclear as to whether better scores in impairment-based measurements (e.g., range of motion or strength) translate into an improvement in function and ultimately in the child's quality of life.
Motor function scales, such as the Hammersmith Functional Motor Scale (HFMS), the North Star Ambulatory Assessment (NSAA), and more recently, the Motor Function Measure (MFM32), which have been validated in other neuromuscular disorders, may provide information regarding the global ability of the child to perform common motor tasks. The HFMS is validated in children with spinal muscular atrophy (SMA) and functional impairments [12]; the NSAA is validated in ambulatory children with Duchenne muscular dystrophy (DMD) and SMA type III [14], [23]. The MFM32, validated in individuals with various neuromuscular disorders, is a scale that spans the spectrum of abilities from non-ambulatory to ambulatory [11], [24], [25]. Other scales gather information about different aspects of function. For example, the Egen Klassification Scale Version 2 (EK2) provides a picture of overall function in non-ambulatory individuals with DMD and SMA [17], and ACTIVLIM is a self-reported questionnaire of limitations in daily activities in children and adults with various NM disorders [18], [26]. The Quality of Upper Extremity Skills Test (QUEST) measures several domains of upper extremity function and has been validated in children with cerebral palsy [27]. The Pediatric Quality of Life Inventory (Generic and Neuromuscular modules) has been validated in healthy individuals and individuals with SMA [16], [28], [29]. Finally, FVC has been shown to be a reliable outcome measure in SMA [29] and, recently, in COL6-RD, with the latter showing predicted rates of decline specific to the severity of disease [6].
The main goal of this study was to validate the use of several of these measurements in these two subtypes of CMD given the urgent need to accurately test the efficacy of potential therapies, which are currently under development for clinical trials. To address the ENMC's recommendation, we implemented a 2-year pilot study in individuals with COL6-RD and LAMA2-MD to test the feasibility, reliability, and validity of several motor scales (primarily the MFM32), myometry and goniometry measurements, affected individual and caregiver assessments, and quality of life measurements. As mentioned above, the pilot study serves as the basis of an ongoing, 5-year, longitudinal study, which will evaluate the validated measures' sensitivity to change over the 5-year natural history of COL6-RD and LAMA2-RD in the enrolled individuals. FVC percent predicted has now been demonstrated to be a viable outcome measure [6] and was used as the initial standard in the current study.
Section snippets
Subjects and methods
We obtained approval from the National Institute of Neurological Disorders and Stroke (NINDS) Institutional Review Board for this study. Subjects (and/or parents) who agreed to participate provided informed consent (and assent if a minor under the age of 18 years). Parents or caregivers of minors, heretofore referred to as parents, signed informed consent forms.
Year 1
Descriptive statistics for all outcome measures performed in year 1 are provided in Table 3. Note that goniometry measurements display a wide range.
Discussion
Until recently, natural history studies in CMD have been limited to small, retrospective studies of key medical care issues [10]. A universal finding highlighted in these previous studies is that the rate of change in FVC percent predicted was indicative of the progressive respiratory insufficiency in CMD [4], [10]. A more recent, larger, retrospective study of pulmonary function in 145 individuals with COL6-RD confirmed this finding, and showed predicted rates of decline based on disease
Acknowledgments
We would like to thank the following people without which this study would not have been possible: the participants and their families for their time, flexibility, and commitment during the two years of this study; the nurses and staff of the NIH Clinical Center's outpatient neurology clinic (year 1) and pediatric outpatient clinic (year 2); the National Heart Lung and Blood Institute's Pulmonary Function Lab physicians, therapists, and staff; Mrs. Livija Medne for her assistance with the study
References (39)
- et al.
Congenital muscular dystrophies: new aspects of an expanding group of disorders
Biochim Biophys Acta
(2007) - et al.
CMD outcomes consortium. 173rd ENMC international workshop: congenital muscular dystrophy outcome measures 5–7 March 2010, Naarden, The Netherlands
Neuromuscul Disord
(2011) - et al.
Genotype–phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations
Neuromuscul Disord
(2010) - et al.
The Peds QL in pediatric patients with spinal muscular atrophy; feasibility, reliability, and validity of the pediatric Quality of Life Inventory Generic Core Scales and Neuromuscular Module
Neuromuscul Disord
(2009) - et al.
ACTIVLIM: a Rasch-built measure of activity limitations in children and adults with neuromuscular disorders
Neuromuscul Disord
(2007) - et al.
Responsiveness of the motor function measure in patients with spinal muscular atrophy
Arch Phys Med Rehabil
(2013) - et al.
Reference values of maximum isometric muscle force obtained in 270 children aged 4–16 years by hand-held dynamometry
Neuromuscul Disord
(2001) - et al.
Hammersmith functional motor scale and motor function measure-20 in non ambulant SMA patients
Neuromuscul Disord
(2014) - et al.
Informant agreement in behavior ratings for children with epilepsy
Epilepsy Behav
(2000) The collagen VI-related myopathies: muscle meets its matrix
Nat Rev Neurol
(2011)
Natural history of Ullrich congenital muscular dystrophy
Neurology
Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures
Brain
Natural history of pulmonary function in collagen VI-related myopathies
Brain
Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI
Proc Natl Acad Sci USA
Consensus statement on standard of care for congenital muscular dystrophies
J Child Neurol
Respiratory involvement in inherited primary muscle conditions
J Neurol Neurosurg Psychiatry
Responsiveness of the motor function measure in neuromuscular diseases
Arch Phys Med Rehabil
Validation of the expanded hammersmith functional motor scale in spinal muscular atrophy type II and III
J Child Neurol
Reliable surrogate outcome measures in multicenter clinical trials of Duchenne muscular dystrophy
Muscle Nerve
Cited by (28)
Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study
2024, European Journal of Paediatric NeurologyResponsiveness and Minimal Clinically Important Difference of the Motor Function Measure in Collagen VI-Related Dystrophies and Laminin Alpha2-Related Muscular Dystrophy
2021, Archives of Physical Medicine and RehabilitationReliability and validity analyses of the North Star Ambulatory Assessment in Brazilian Portuguese
2017, Neuromuscular DisordersCitation Excerpt :While those times do not influence the score, they can be used to monitor changes over time [6,8]. Although it was developed to assess ambulatory patients, the NSAA has been widely accepted and used to evaluate ambulatory motor performance in children and young adults with DMD, as well as in patients with other neuromuscular diseases [9–12]. As the NSAA was not available in Brazilian Portuguese, the purposes of this study were to perform a cross-cultural adaptation for the Portuguese language spoken in Brazil and to evaluate the reliability and validity of the adapted instrument.
Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy
2017, Neuromuscular DisordersCitation Excerpt :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.
New Clinical and Immunofluoresence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients
2023, International Journal of Molecular Sciences
- †
Authors contributed equally to this work.