Association of Initial Maximal Motor Ability With Long-term Functional Outcome in Patients With COL6-Related Dystrophies

Abstract

Objective: To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness.

Methods: This retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD.

Results: We studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation.

Conclusion: This work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts.

Figure 1. Motor Function in Patients with COL6-RD by Phenotype

Highly significant direct correlation is seen between the scores of all the motor function scales assessed: (A) Motor Function Measure (MFM)-32 (including each of its 3 functional domains: [B] D1, [C] D2, and [D] D3), (E) North Star Ambulatory Assessment (NSAA), and (F) 6-minute walk test (6MWT) and collagen VI–related dystrophy (COL6-RD) phenotype (based on the classification proposed here using maximal motor function achieved) (p < 0.001, Kruskal-Wallis test). Box plots show that, regardless of current age, patients whose maximal motor function achieved was climbing 4 steps without holding onto a railing (categorized as Bethlem myopathy [BM]) obtain higher scores in the motor function scales than those whose maximal motor function achieved was rising from the floor unassisted (intermediate COL6-RD) and those who did not achieve either of these 2 milestones (Ullrich congenital muscular dystrophy [UCMD]). Box plots represent medians and quartiles; whiskers signify the 5th and 95th percentiles.

Figure 2. Motor Function and Age

(A–F) An indirect relationship is seen between the scores of all the motor function scales and age, both for the entire collagen VI–related dystrophy (COL6-RD) cohort and for each of the COL6-RD phenotypes. A significantly sharper decline in the Motor Function Measure (MFM) total score in relation to age (A) was detected for those patients within the UCMD subgroup (p = 0.03). BM = Bethlem myopathy; D1 = domain 1; D2 = domain 2; D3 = domain 3; NSAA = North Star Ambulatory Assessment; 6MWT = 6-minute walk test; UCMD = Ullrich congenital muscular dystrophy.

Figure 3. LoA in Patients With COL6-RD by Phenotype

Kaplan-Meier curves depict the probability of loss of ambulation (LoA) by age and collagen VI–related dystrophy (COL6-RD) phenotypic classification BM = Bethlem myopathy; UCMD = Ullrich congenital muscular dystrophy.

Figure 4. Correlation of Motor Function and Pulmonary Function Assessments

Correlation matrix compares different motor function scales and pulmonary function as measured by forced vital capacity (FVC) in our cohort of patients with collagen VI–related dystrophy. Red indicates positive correlation; purple indicates negative correlation. D1 = domain 1; D2 = domain 2; D3 = domain 3; MFM = Motor Function Measure; NSAA = North Star Ambulatory Assessment; 6MWT = 6-minute walk test.

Figure 5. Pulmonary Function and NIV in Patients With Col6-RD by Phenotype

Relationship between pulmonary function and collagen VI–related dystrophy (COL6-RD) phenotype (based on the classification proposed here using maximal motor function achieved) is highly statistically significant (p < 0.001) as demonstrated by (A) box plots (representing medians and quartiles with whiskers signifying the 5th and 95th percentiles) and (B) scatterplots. (C) Kaplan-Meier curves depict the probability of initiation of noninvasive ventilation (NIV) by age and COL6-RD phenotypic classification. BM = Bethlem myopathy; FVC = forced vital capacity; UCMD = Ullrich congenital muscular dystrophy.