Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies

Abstract

ObjectiveTo identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs).MethodsOver the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts.ResultsTotal MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed.ConclusionResults of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.

LAMA2‐related muscular dystrophy: Natural history of a large pediatric cohort

“…12,[19][20][21] Recently, a prospective natural history study was completed on 24 LAMA2-RD patients over an average of 3 years (NIH, Bethesda, USA). 33 This study assessed a range of outcome measures and evaluated their rate of change/year. While this work provides useful information towards trial readiness, detailed knowledge on long-term progression of skeletal and respiratory muscle weakness, occurrence and time of intervention for disease-related complications are still lacking.…”

“…The yearly 6.6˚progression in elbow extension is similar to what reported by Jain et al (4.11˚/year). 33 While such variables might not represent reliable outcome measures for future clinical trials, with the exception of elbow flexion, joint contractures are relevant when assessing the ability to perform activities of daily living and selecting appropriate functional scales. 39 We confirm that severe cardiomyopathy is not common during childhood in LAMA2-RD.…”

LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

“…Longitudinal goniometry measurements were statistically significant in non-ambulatory LAMA2-RD patients in left elbow extension (−4.11° per year; p < 0.01). The annual rate of change in forced vital capacity (FVC) was not found to be significant in LAMA2-RD patients in this longitudinal study; however, one potential reason could be that the non-ambulatory patients with LAMA2-RD in this study may have already reached a nadir in their respiratory insufficiency, resulting in a lack of further decline during this study which took place over 4 years (Jain et al, 2019 ). It is notable that in a separate, retrospective study of pulmonary function in 65 patients with LAMA2-RD, the annual rate of decline of FVC in non-ambulatory LAMA2-RD patients was found to be 1.73% per year ( p < 0.01; Collins et al, personal observation).…”

Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway

“…LAMA2 gene encodes an alpha 2 chain, which constitutes one of the subunits of laminin 2. Loss of LAMA2 can lead into muscular dystrophy 10 – 12 . And decreased expression of LAMA2 caused by promoter hypermethylation has been confirmed in various cancers, including invasive PiNETs, colon, and bladder cancers, which indicate LAMA2 is a suppressor gene 13 , 14 .…”