title: Natural history of pulmonary function in collagen VI-related myopathies.
abstract: The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.
authors.affiliation: 1 Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, WC1N 1EH, UK.
authors.forename: A Reghan
authors.initials: AR
authors.lastname: Foley
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.forename: James
authors.initials: J
authors.lastname: Collins
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Michelle
authors.initials: M
authors.lastname: McCallum
authors.forename: Nicolas
authors.initials: N
authors.lastname: Deconinck
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Marika
authors.initials: M
authors.lastname: Pane
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Kathryn
authors.initials: K
authors.lastname: North
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Valérie
authors.initials: V
authors.lastname: Allamand
authors.forename: Debbie
authors.initials: D
authors.lastname: Hicks
authors.forename: Shireen
authors.initials: S
authors.lastname: Lamandé
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
authors.forename: Sungyoung
authors.initials: S
authors.lastname: Auh
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D024142:Collagen Type VI / Q000172:deficiency / Q000235:genetics*; D004185:Disability Evaluation; D005060:Europe; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008171:Lung Diseases / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D009135:Muscular Diseases / Q000145:classification / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D012121:Respiration, Artificial; D012189:Retrospective Studies; D014481:United States; D014797:Vital Capacity / Q000235:genetics; D055815:Young Adult
chemical_list: D024142:Collagen Type VI
keywords: collagen VI-related myopathies; forced vital capacity; natural history; optimization of care; outcome measure