SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness

Abstract

Background: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness.

Objective: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care.

Methods: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry.

Results: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures.

Conclusions: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Keywords: Muscular diseases; bone density; cardiomyopathies; respiratory insufficiency.

Fig. 1

Facial muscle weakness and dysmorphic features in SELENON-RM patients. (A) neutral position, showing mild bilateral ptosis. (B) m. frontalis weakness. (C) m. orbicularis oculi weakness. (D) m. risorius weakness. (E) inadequate puckering movements, indicating m. orbicularis ori weakness. (F) inability of neck flexion and lumbar flexion, indicating rigid spine. (G) pseudohypertrophy of the calve musculature. (H) general muscle hypotrophy, most pronounced in the calves and upper legs, and spinal deformity (status after osteosynthesis). (I) scapular winging. Permission for publication of the photographs from all identifiable patients was granted.

Fig.2

Median muscle strength according to the MRC grading scale. Median muscle strength (MRC) in neck flexor, neck extensor, deltoid, biceps brachii, triceps brachii, wrist flexor, wrist extensor, finger flexor, finger extensor, iliopsoas, gluteus, quadriceps, hamstrings, foot flexor and foot extensor muscles.

Fig. 3

Overview on percentage of MFM-20/32 total score, MiniBEST, PBS and HFMS; the percentage of distance predicted at the 6MWT; the percentage of predicted strength (N) of several muscles; the percentage of sedentary, light, moderate and vigorous activity and the number of counts per day as measured through accelerometry (mean±SD); and the correlation between the MFM-20/32 total score and percentage of sedentary activity. (A) Percentage of MFM-20/32 total score, MiniBEST, PBS and HFMS; and the percentage of distance predicted at the 6MWT. MFM-20/32 was performed by all patients participating in this study. The MiniBEST and PBS were performed by ambulant patients, while the HFMS was only performed by patients who were not able to perform either of the two balance tests (MiniBEST or PBS) due to physical limitations (n = 3). 6MWT included all ambulant patients of 5 years and older that were seen in the hospital (n = 8). (B) Percentage of predicted strength (N) of the neck extensor, biceps brachii, triceps brachii, quadriceps, foot dorsiflexor and foot flexor muscles and the pinch grip. n = the number of patients (each patient having two muscles examined, i.e. left and right side); (C) Percentage of sedentary, light, moderate and vigorous activity and the number of counts per day as measured through accelerometry. (D) Percentage sedentary activity as measured through accelerometry was negatively correlated to the MFM-20/32 total score (Pearson’s correlation, –0.682, p < 0.05). MFM-20/32 = motor function measurement 20/32; MiniBEST = Mini Balance Evaluation Systems Test; PBS = Pediatric Balance Scale; HFMS = Hammersmith Functional Motor Scale; 6MWT = 6-minute walk test. All values are mean±SD.

Fig. 4

Overview on echogenicity (z-score and Heckmatt score) per muscle. The z-score of the echogenicity (A) and the Heckmatt score (B) in the temporalis, sternocleidomastoid, biceps brachii, flexor carpi radialis, rectus abdominis, rectus femoris, vastus lateralis, tibialis anterior, biceps femoris, gastrocnemius medial head and soleus muscles are shown.

Fig. 5

Correlation between MFM-20/32 total score and muscle ultrasound (echogenicity and Heckmatt score). (A) Correlation between the z-score of echogenicity of flexor carpi radialis muscles and the total MFM-20/32 score (Pearson’s correlation, –0.750, p < 0.01). (B) Correlation between Heckmatt score of flexor carpi radialis muscles and the total MFM-20/32 score (Pearson’s correlation, –0.874, p < 0.01). (C) Correlation between Heckmatt score of biceps brachii muscles and the total MFM-20/32 score (Pearson’s correlation, –0.576, p < 0.01). MFM-20/32 = Motor Function Measurement 20/32.