The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.

Trial Readiness and Trial Fitness for Congenital Myopathies: a 2-year Prospective Natural History Study Including a Cross-sectional Study on Muscle Fatigability

Core myopathies (CCD/MmD), nemaline myopathies (NEM) and centronuclear myopathies (CNM) are three types of rare congenital myopathies. Not much is known about the natural history and no curative treatment is available for these groups. Also patients report fatigability as one of their symptoms. The goal of this observational study is to study the natural history during 24 months to achieve trial readiness and to study the muscle fatigability in CCD/MmD, NEM and CNM.

Rationale: Patients with CCD/MmD, NEM and CNM report symptoms of weakness in the arms and legs. Other symptoms include weakness of the respiratory, facial and swallowing muscles. No treatments are available for congenital myopathies (CM) to slow down or cure the disease. A few type I-II trials have taken place and more are expected. Therefore it is important to reach trial readiness. To create trial readiness, there is a need for natural history study to create a detailed report of the disease course and a selection of the most sensitive clinical and functional outcome measures and biomarkers. Besides muscle weakness, several patients report muscle fatigability. This has not been investigated systematically in CM. The lack of evidence calls for a cross-sectional study assessing muscle fatigability and neuromuscular transmission in CM.

Objectives: i) To assess the natural disease course of CCD/MmD, NEM and CNM during 24 months. ii) To select relevant and sensitive clinical and functional outcome measures and biomarkers. iii) To assess the severity of muscle fatigability in CCD/MmD, NEM and CNM.

Study design: Patients with a genetically confirmed CCD/MmD, NEM or CNM will be able to participate in this study. The study consist of 2 parts. Part 1: a prospective cohort study with 5 visits every 6 months, for a total of 2 years. 45 patients will be included for this part. Part 2: an observational study with 2 visits. For this part 75 patients will be included. There will be an overlap in patients for the two parts. So a total of approximately 100 patients will be included. A large set of tests will be performed to assess the full capabilities of the patient, e.g. muscle strength/endurance, muscle imaging (MRI/ultrasound), activities, walking ability, quality of life, muscle fatigability and the feeling of fatigue.

Inclusion Criteria for the natural history:

• 2 years or older
• Willing and able to complete the measurement protocol
• Willing and able to travel to Nijmegen and Utrecht
• Dutch-speaking
• Genetically-confirmed congenital myopathy (CCD/MmD, NEM, and CNM)

Inclusion Criteria for the fatigability study:

• 8-60 years old
• Willing and able to complete the measurement protocol
• Willing and able to travel to Nijmegen and Utrecht
• Dutch-speaking
• Genetically-confirmed congenital myopathy (CCD/MmD, NEM, and CNM)
• Willing to stop taking pyridostigmine and/or salbutamol 24 hours before the visit.

Exclusion Criteria for both parts:

Other neuromuscular, psychiatric or neurological disorders.