Disease Trajectories of a Large French Cohort of 142 Congenital Myopathy Patients in Adult Age

Abstract

Background: Congenital myopathies (CMyo) are a group of rare inherited muscle disorders classified to date according to myopathological features on muscle biopsy. They usually present with an early onset, with a slow or non-progressive muscle weakness. The phenotypic spectrum is wide, ranging from severe early onset forms to milder and later onset conditions. Data regarding the disease trajectory of CMyo in adult patients are lacking. Here, we describe the clinical, myopathological, and genetic features of a large cohort of adult CMyo patients to facilitate their management in adulthood.

Methods: Global data of a cohort of 142 myopathologically and genetically defined adult patients, 76 women and 66 men, followed at Institute of Myology of the Pitié-Salpêtrière Hospital, were retrospectively analyzed focusing on muscular phenotype, cardiac, and respiratory assessment.

Results: RYR1-related CMyo was the most represented entity (N = 65, 45%), followed by DNM2-related CMyo (N = 26, 18%). Eighty-two percent of patients presented with a prenatal, infancy or childhood onset, including delayed motor milestones. An adult onset, defined as > 18 years (median age 43 years), was identified in 15% of patients (N = 18). Fifteen percent of patients were wheelchair-bound. The poorest respiratory outcome was found in SELENON-related CMyo patients.

Conclusions: This observational study provides long-term data on disease progression in CMyo. Adult CMyo patients generally presented mild motor disability at follow-up. Nevertheless, a subset of patients experienced loss of gait and severe respiratory failure. CMyo should be considered in the differential diagnosis of adult-onset myopathies due to the rare but possible late-onset forms.

Keywords: adult‐onset myopathy; congenital myopathy; disease trajectory; genotype–phenotype correlations.

FIGURE 1

Myopathological features. HE: Hematoxylin and Eosin; NADH: Nicotinamide adenine dinucleotide tetrazolium reductase; TG: Gömöri Trichrome. ATPases pH 4.6. Centronuclear myopathy and core myopathy represent together more than half of the cohort, followed by core and rods myopathy, nemaline myopathy, multi‐minicore myopathy, congenital fiber type disproportion, and hyalin body myopathy. (Figure legend: MmD = Multi‐minicore Disease, CFTD = Congenital Fiber Type Disproportion, NM = Nemaline Myopathy, CCD = Central Core Disease, CNM = Centronuclear Myopathy, C&R = Cores and Rods myopathy), HBM = Hyalin Body Myopathy.

FIGURE 2

Genetic analysis. Single gene frequency in our cohort.

FIGURE 3

Age at onset according to genotype. Clinical onset distribution according to genotype; y: Years. The progressively darker color tone indicates a higher gene frequency for each group.

FIGURE 4

Selective patterns of muscle weakness distribution according to genotype. (A) Axial involvement (blue); (B) Proximal involvement (green); (C) Distal involvement (red) with associated mutated genes.

FIGURE 5

Facial muscle involvement. Facial muscle weakness according to genotype.

FIGURE 6

Respiratory involvement according to genotype and age. Respiratory function, ranging from tracheostomy to FVC > 60%, is graphically displayed by the dark pink area compared to the lungs’ total volume. N = number of patients.

FIGURE 7

Motor performance status. Motor performance at last follow‐up evaluation according to genotype. (A) fully ambulatory patients; (B) minimal walking aids; (C) unilateral or bilateral supports; (D) wheelchair bound. The progressive darker color tone indicates a higher gene frequency for each group.

FIGURE 8

Pathogenic variants localizations and severe phenotype. Schematic representation of the RYR1 and DNM2 genes with the localization of variants leading to a severe phenotype. RYR1 monoallelic variants are displayed in red and biallelic in green. Wheelchair symbol: Loss of ambulation; lungs symbol: Respiratory involvement FVC < 60%; thermometer symbol: Variant associated with malignant hyperthermia.