Trial readiness and fitness for congenital myopathies: A 2-year prospective natural history study including a cross-sectional study on muscle fatigability

Congenital myopathies comprise a clinical, histopathological, and genetic
heterogeneous group of early-onset muscle diseases. Several preclinical studies
are moving towards clinical trials and for CNM the first trials are taking
place. In parallel, many patients report severe muscle fatigability and
positive effects of drugs improving the function of the NMJ. However, this has
only been studied in small case series.[1,2]

Part 1: Assess the natural disease course of three congenital myopathies during
24 months. This will enable us to obtain a detailed assessment of the phenotype
and genotype, evaluate and optimize the current care, determine the rate of
disease progression and select the most sensitive outcome measures.

Part 2: Assess the severity of muscle fatigability in four congenital
myopathies.

Part 1: A 2-year prospective natural history study with internationally set
clinical outcome measures and biomarkers in core myopathies, nemaline
myopathies en centronuclear myopathies, with bi-annual follow-up (five visits;
n=45). We will assess muscle strength and function, physical activity,
experienced fatigue and sleep, pain, quality of life, daily functioning and
social participation. Biomarkers will include laboratory tests, muscle
ultrasound, muscle MRI, and bone densitometry.

Part 2: A cross-sectional study on muscle fatigability consisting of clinical
and electrophysiological endurance tests in CCD/MmD, NEM, CNM (one visit;
n=75). Muscle fatigability will be assessed during standardized functional
endurance tasks and isolated muscle endurance tests using isokinetic
dynamometry combined with surface EMG. Neuromuscular transmission (NMJ
function) will be assessed with repetitive nerve stimulation. This will be
combined with one a the visits from part 1. Everyone from part 1 that adheres
to the inclusion criteria of part 2 will be able to participate in part 2.

Non therapeutical intervention

The measurement days will be burdensome due to the long duration and it can
cause sore muscles the next day. However, since we use all functional test
using movements to which most patients are familiar (i.e. walking, transfers,
etc.) the patient will be able to estimate his/her own risk. We don*t include
tests in which we push patients to their physical limits.We will be gathering a
lot of beneficial data in order to get a clear overview of this group of
patients en the outcomes can be used in future research towards treatment
options. Therefore we see it fit to conduct this research in minors.