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

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

doi:10.1016/j.nmd.2014.09.010

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

Neuromuscul Disord. 2015 Jan;25(1):43-54. doi: 10.1016/j.nmd.2014.09.010. Epub 2014 Sep 28.

Authors

Katherine G Meilleur¹, Minal S Jain², Linda S Hynan³, Ching-Yi Shieh⁴, Eunice Kim⁵, Melissa Waite², Michelle McGuire⁶, Courtney Fiorini⁷, Allan M Glanzman⁸, Marion Main⁹, Kristy Rose¹⁰, Tina Duong¹¹, Roxanna Bendixen¹², Melody M Linton¹³, Irene C Arveson¹³, Carmel Nichols², Kelly Yang¹⁴, Kenneth H Fischbeck¹⁴, Kathryn R Wagner⁷, Kathryn North¹⁰, Ami Mankodi¹⁴, Christopher Grunseich¹⁴, Elizabeth J Hartnett¹⁴, Michaele Smith², Sandra Donkervoort¹⁴, Alice Schindler¹⁴, Angela Kokkinis¹⁴, Meganne Leach¹⁵, A Reghan Foley⁹, James Collins⁶, Francesco Muntoni⁹, Anne Rutkowski¹⁶, Carsten G Bönnemann¹⁷

Affiliations

¹ National Institute of Nursing Research, NIH, Bethesda, MD, USA. Electronic address: meilleurk@mail.nih.gov.
² Mark O. Hatfield Clinical Research Center, NIH, Bethesda, MD, USA.
³ Departments of Clinical Sciences (Biostatistics) and Psychiatry, University of Texas Southwestern, Dallas, TX, USA.
⁴ National Institutes of Health, Bethesda, MD, USA.
⁵ CureCMD, Los Angeles, CA, USA.
⁶ Pediatric Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁷ The Kennedy Krieger Institute and the Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.
¹⁰ Institute for Neuroscience and Muscle Research at The Children's Hospital at Westmead, Sydney, Australia.
¹¹ Children's National Medical Center, Washington, DC, USA.
¹² University of Pittsburgh, Pittsburgh, PA, USA.
¹³ National Institute of Nursing Research, NIH, Bethesda, MD, USA.
¹⁴ National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
¹⁵ Children's National Medical Center, Washington, DC, USA; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
¹⁶ CureCMD, Los Angeles, CA, USA; Kaiser SCPMG, Los Angeles, CA, USA.
¹⁷ National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. Electronic address: carsten.bonnemann@nih.gov.

Abstract

Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes.

Keywords: Clinical outcome measures; Collagen VI related muscular dystrophy; Laminin alpha 2 related dystrophy; Motor function scales; Neuromuscular disease.

Published by Elsevier B.V.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Collagen Type VI / genetics*
Exercise Test*
Female
Humans
Laminin / genetics*
Male
Muscular Dystrophies / congenital
Muscular Dystrophies / therapy*
Mutation
Pilot Projects
Quality of Life
Reproducibility of Results
Severity of Illness Index*
Treatment Outcome
Young Adult

Substances

Collagen Type VI
Laminin
laminin alpha 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding