An international team of clinicians, including experts from the Institute of Myology (Paris), published in September 2020 a retrospective study of 132 people with SELENON-related myopathy (ex-SEPN1), aged 2 to 58 years with a follow-up of 8 months to 25 years, 69 were diagnosed in France. This is the largest case series of this uncommon disease described so far.
The onset occurred before the age of 15 and in 84.8% of cases in the first two years of life: neonatal hypotonia in one-third of the cases, delayed motor development, poor head control, acquisition of walking on average around the age of 18 months, muscle weakness, frequent falls, difficulty climbing stairs, running, early scoliosis, hyperlordosis or stiff spine …
A severe axial deficit, and a newly identified oculomotor deficit
- The face presents mild to moderate muscle weakness with an arched palate and a shrill nasal voice.
- The weakness of the neck and trunk flexors is important, while the extensors are relatively spared. That of the limbs is proximal and not very marked, with an almost normal quadriceps. In the most severe forms, there is also distal weakness.
- Spinal stiffness is present in 87.8% of cases, most often before the age of 10. The retractions of the extensor muscles of the neck and paravertebral muscles lead to cervico-dorsal stiffness, compensated by lumbar mobility that is retained for a long time to lean forward.
- The loss of dorsal kyphosis (or even dorsal lordosis) flattens the thorax, the mobility of which is further reduced by the retractions of the intercostal muscles and the pectoralis major.
- The clinical picture is completed over the years with the development of scoliosis, the onset of respiratory failure, a drop in the weight curve and in some cases retractions of the muscles of the limbs.
- Scoliosis is present in 86.1% of cases, and in 93.8% of children over 13 years old. It was contained by a corset until the age of spinal arthrodesis (13.5 +/- 1.9 years in this series), which allowed radiological and clinical stabilization of the spine.
- Respiratory impairment does not correlate with limb muscle involvement: most patients require ventilatory assistance while their walking is preserved. A total of 81.9% of cases had ventilator support from the mean age of 14 (range 3 to 49), with the majority needing non-invasive nighttime ventilation and 12 people needing a tracheostomy.
- While the birth weight is usually normal, there is significant weight loss around puberty with melting of subcutaneous cellular tissue and a pseudo cachectic appearance. The four overweight patients, two of whom were obese from childhood, all had severe disease with severe respiratory failure and early loss of walking.
- Systematic examination of ocular motor skills frequently reveals weakness in the upward gaze. Three severely affected patients presented with undeniable ophthalmoparesis. With age, moderate ptosis developed in six patients and strabismus in four.
A majority of multi-minicores… but not only
Analysis of the 79 available muscle biopsies showed that:
- multi-minicores were the most frequent histological lesion (59.5% of biopsies) and the main one in 49.4% of cases;
- in 24% of cases, there were predominant dystrophic signs, associated or not with multiminicores;
- a quarter of the biopsies showed only non-specific signs of myopathy. This concerned the youngest patients (mean age 8.5 years) while the more specific signs were present on muscle biopsies from older patients (average 13.89 years).
On an evolutionary level
All the children learned to walk and improved their motor performance in childhood. After spinal arthrodesis and the establishment of assisted ventilation, patients’ condition remained stable for several decades before the disease steadily worsened from the fourth decade. Loss of walking occurred in eight patients at a mean age of 21.5 years (range 8 years to 54 years)
The main life-threatening factor appears to be respiratory failure, with half of patients requiring assisted ventilation within the first thirteen years of life.
Severity criteria
To assess possible evolutionary determinants, the authors defined gravity / severity criteria:
- marked neonatal hypotonia or permanent / persistent loss of head control,
- scoliosis or respiratory failure before the age of 10,
- progressive motor disability leading to loss of walking before adulthood
From these criteria, the authors determined three groups:
- a severe form when patients present two or more severity criteria,
- a form of medium severity if they have only one criterion of severity;
- moderate form if they do not meet any of these criteria. The moderate or mild forms represent the typical picture previously described of myopathy associated with SEPN1.
This study also found a significant correlation between body weight and the severity of the disease in the 47 files containing anthropometric data, with weight gain leading to a decrease in functional performance and an increase in fatigue.
