Inspiratory Muscle Training in Nemaline Myopathy

Nemaline myopathy is a rare congenital myopathy. Respiratory failure is the main cause of death in these patients. The primary objective of this study is to determine the effect of a 8-week inspiratory muscle training program on respiratory muscle function in nemaline myopathy patients. The secondary objective is to determine respiratory muscle function in nemaline myopathy patients and its correlation with clinical severity and general neuromuscular function. The nemaline myopathy patients will be included in the first phase for a clinical characterization. From this phase patients will be selected for the second phase, which is a controlled before-after trial of inspiratory muscle training. The primary outcome is the change in maximal inspiratory pressure (MIP) after active inspiratory muscle training

Rationale: Nemaline myopathy is a group of congenital, hereditary neuromuscular disorders with variable symptoms such as muscle weakness, swallowing dysfunction, and dysarthria. Respiratory failure is the main cause of death in nemaline myopathy and occurs even in ambulant patients who otherwise appear to be only mildly affected; respiratory muscle weakness may even be the presenting feature. Inspiratory muscle training has shown to increase inspiratory muscle strength in patients with other neuromuscular disorders. It is hypothesized that inspiratory muscle training improves respiratory muscle function in nemaline myopathy patients with respiratory muscle weakness.

Objective: The primary objective is to determine the effect of a 8-week inspiratory muscle training program on respiratory muscle function in nemaline myopathy patients. The secondary objective is to determine respiratory muscle function in nemaline myopathy patients and its correlation with clinical severity and general neuromuscular function.

Study design: The study consist of two phases. Phase 1: A screening phase with an open design from which patients will be selected for the second phase. Phase 2: A controlled before-after trial of inspiratory muscle training. The 2 conditions tested are sham IMT and active IMT.

Study population: Nemaline myopathy patients from the local neuromuscular database will be recruited. Furthermore, other centres in the Netherlands will be contacted to expand the database of nemaline myopathy patients. Phase 2 requires 23 patients.

Intervention: Active IMT consists of 15 minutes of IMT, twice a day, 5 days per week for 8 weeks, at a training workload of 30% of MIP using a resistive inspiratory muscle training device. Sham IMT consists of similar training regime using a resistive inspiratory muscle training device where the resistance has been removed.

Main study parameters/endpoints: The primary outcome parameter is the change in maximal inspiratory pressure (MIP) after active inspiratory muscle training.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The intervention of inspiratory muscle training is not associated with any risks, but can be challenging in patients with respiratory muscle weakness to perform. There will be three visits to the hospital in 16 weeks. The first visit has a maximal duration of 6 hours (including breaks) and the other two visits 1.5 hour. During these visits several tests and physical examinations will be performed. Some of the tests may cause some physical discomfort, but none of them carry any risk. Patients may benefit from participating in this study by developing improved respiratory muscle function as a result of the inspiratory muscle training.

Eligibility Criteria:
Inclusion Criteria:

* genetically-confirmed nemaline myopathy (mutations in one of the genes causing nemaline myopathy: TPM3, NEB, ACTA1, TPM2, TNNT1, KBTBD13, CFL2, KLHL40, KHLH41, LMOD3, MYPN, RYR1)
* informed consent from participant or legal representative
* age-range: between the age of 6-80 years

Exclusion Criteria:

* history of another condition that affects respiratory muscle strength or function (e.g. COPD)