Long-term Natural History of Pediatric Dominant and Recessive RYR1-Related Myopathy

Abstract

Background and objectives: RYR1-related myopathies are the most common congenital myopathies, but long-term natural history data are still scarce. We aim to describe the natural history of dominant and recessive RYR1-related myopathies.

Methods: A cross-sectional and longitudinal retrospective data analysis of pediatric cases with RYR1-related myopathies seen between 1992-2019 in 2 large UK centers. Patients were identified, and data were collected from individual medical records.

Results: Sixty-nine patients were included in the study, 63 in both cross-sectional and longitudinal studies and 6 in the cross-sectional analysis only. Onset ranged from birth to 7 years. Twenty-nine patients had an autosomal dominant RYR1-related myopathy, 31 recessive, 6 de novo dominant, and 3 uncertain inheritance. Median age at the first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant, and 1 dominant patient) and 7% lost ambulation during follow-up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients, and 57% of those needed gastrostomy or tube feeding. There were no anesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory outcomes, and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients.

Discussion: This clinical study provides long-term data on disease progression in RYR1-related myopathies that may inform management and provide essential milestones for future therapeutic interventions.

Figure 1. Longitudinal Observational Data on Gross Motor Abilities in Patients with RYR1-RM

Each horizontal line indicates single patients. Symbol on lines indicates different assessments in each patient. Patients are distributed according to inheritance, starting from the bottom: patients with autosomal dominant inheritance (AD), autosomal recessive (AR), and apparent de novo dominant (AD*) and uncertain inheritance (Uk). Full circles represent nonambulation; white circle represent ability to walk with support; grey triangle ability to walk independently. The dashed vertical line at 18 months indicates WHO thresholds for attaining independent sitting and walking alone in 99% of children.

Figure 2. Longitudinal Analysis of Motor Ability Tests

(A) Spaghetti plots representing timed rise from sitting and from lying on the floor in AD and AR patients. (B) Spaghetti plots representing individual functional motor scale scores for the entire cohort of patients with RYR1-RM at all available time points.

Figure 3. Weight Z-Scores

Trend lines representing the 2 subgroups of dominant (black circles) and recessive (white circles) patients with RYR1-RM (A). In (B), only pregastrostomy values were included. Z scores are derived from a normative UK population. A Z-Score of 0 corresponds to the 50th centile, a Z-score of −1 corresponds to the 26th centile, a Z-Score of −2 corresponds to the 2.5th centile, and a Z-score of −3 corresponds to the 0.3rd centile.

Figure 4. Respiratory Function

(A) Scatter plots representing absolute values of forced vital capacity for the 2 subgroups of dominant (black circles, continuous trend line) and recessive patients with RYR1-RM (white circles, dotted trend line). (B) Scatter plot representing forced vital capacity % predicted for the 2 subgroups of dominant (black circles, continuous trend line) and recessive patients with RYR1-RM (white circles, dotted trend line).

Figure 5. Clinical Severity

Disease severity progression in selected patients with infantile severity score >3 or Amburgey severity score >5. Each horizontal bar indicates single patients. Patients are grouped according to inheritance pattern. Gross motor function and comorbidities are indicated for each patient as in legend.