Selenoprotein N-related myopathy: a retrospective natural history study to guide clinical trials

Abstract

Objective: To describe clinical features and disease progression of Selenoprotein N-related myopathy in a large multicenter cohort of patients.

Methods: Cross-sectional multicenter data analysis of 60 patients (53 families) with Selenoprotein N-related myopathy and single-center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years.

Results: The majority of patients (46/60, 77%) presented before age 2 years with hypotonia, poor head/neck control, and developmental delay. At last assessment (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no ambulation. Ventilatory support was initiated in 50/60 patients at a mean Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty-five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scoliosis surgery at a median age of 13.6 years. Five children needed nasogastric feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed progressive decline of Hammersmith functional motor scores (estimated annual change -0.55 point), time to walk 10 meter, time standing from sitting, and from lying. Sixteen patients had weights < 2nd centile. The estimated change in FVC % per year was -2.04, with a 95% CI (-2.94, -1.14).

Conclusions: This comprehensive analysis of patients with Selenoprotein N-related myopathy further describes the clinical course of this rare condition. The observed functional motor and respiratory data provide evidence of the slow decline patients experience over time which is useful when considering therapeutic intervention.

Figure 1

Patients’ data availability in cross‐sectional and longitudinal analysis. Flow diagram showing the number of patients for whom cross‐sectional and longitudinal data is available for different investigations and assessment. Sites are indicated on the top. n: number; EMG electromyography; MRI muscle magnetic resonance imaging; NIV noninvasive ventilation; FVC Forced vital capacity; FVC% forced vital capacity percentage predicted; HFMS Hammersmith Functional motor score.

Figure 2

Cross‐sectional data analysis for ambulation, scoliosis, and ventilation in SELENON‐RM patients. Kaplan–Meier estimates for minimal/noambulation (A), scoliosis onset (Cobbs Angle> 10°) (B), and initiation of ventilation (C) from birth.

Figure 3

Longitudinal analysis of functional motor score, respiratory function, and feeding in SELENON‐RM patients. (A) population average model for the relationship between Hammersmith functional motor score and age along with 95% confidence intervals. Dots represent multiple visits per patient (n = 19). (B) Population average model for the relationship between Force Vital Capacity (FVC)% and age along with 95% confidence intervals. Dots represent multiple visits per patient (n = 23). (C) Kaplan–Meier estimates for time to FVC < 40%. (D) Line charts representing the progression of weight Z‐Scores. Dots represent multiple visits per each patient (n = 21).

Figure 4

Estimated statistical power and sample sizes to detect restoration in decline of Forced Vital Capacity % predicted in SELENON‐RM cohort.

Figure 5

Time to event analysis for scoliosis and ventilation need according to onset. Survival curves for scoliosis (A) and ventilation free probability (B) of patients with onset of symptoms ≤ 2 years (early symptom onset, blue line) and> 2 years (late symptom onset, red line).