Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study
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Repeated Measurement of Respiratory Muscle Activity and Ventilation in Mouse Models of Neuromuscular Disease
Published on: April 17, 2017
Karlijn Bouman1, Jeroen L M van Doorn2, Jan T Groothuis3
1Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Amalia Children's Hospital, Radboud university medical center, Nijmegen, the Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.
Insights
SELENON-related myopathy (SELENON-RM) patients exhibit more severe respiratory impairment and diaphragm dysfunction than LAMA2-related muscular dystrophy (LAMA2-MD) patients. Spirometry and respiratory muscle strength tests are valuable for managing these rare neuromuscular diseases.
Area of Science:
- Neurology
- Pulmonology
- Genetics
Background:
- LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases.
- Both conditions cause significant respiratory impairment from a young age.
- Natural history studies are crucial for understanding disease progression, prevalence, and optimizing clinical trial readiness.
Purpose of the Study:
- To conduct a prospective natural history study of LAMA2-MD and SELENON-RM.
- To characterize respiratory function and diaphragm involvement in these rare neuromuscular diseases.
- To evaluate the utility of spirometry and respiratory muscle strength tests for clinical care and trial outcomes.
Main Methods:
- A 1.5-year prospective natural history study.
- Included spirometry (forced vital capacity (FVC), difference between upright and supine vital capacity (dVC)).
- Respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) and diaphragm ultrasound were performed.
Main Results:
- 26 LAMA2-MD and 11 SELENON-RM patients were included.
- All SELENON-RM patients and 85% of LAMA2-MD patients had impaired respiratory function at baseline.
- SELENON-RM patients demonstrated more severe diaphragm atrophy and dysfunction, progressive respiratory decline, and higher rates of mechanical ventilation compared to LAMA2-MD patients.
Conclusions:
- The majority of LAMA2-MD and all SELENON-RM patients experience respiratory impairment.
- SELENON-RM is associated with more severe, progressive respiratory compromise and diaphragm dysfunction.
- Spirometry (FVC%, dVC) and SNIP are effective measures for clinical management and clinical trials in these conditions.
Introduction:
LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases with respiratory impairment from a young age. Prospective natural history studies are needed for prevalence estimations, respiratory characterization, optimizing clinical care and selecting outcome measures for trial readiness.
Methods:
Our prospective 1.5-year natural history study included spirometry (forced vital capacity (FVC); difference between upright and supine vital capacity (dVC)), respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) (age≥5 years), and diaphragm ultrasound (thickness; thickening; echogenicity; all ages).
Results:
Twenty-six LAMA2-MD patients (M = 8, median 21 [9; 31] years) and 11 SELENON-RM patients (M = 8, 20 [10; 33] years) were included. At baseline, 17 (85 %) LAMA2-MD (FVC%: 59 % [33; 68]) and all SELENON-RM patients (FVC%: 34 % [31; 46]) had an impaired respiratory function (FVC%<80 %). Nine (35 %) LAMA2-MD and eight (73 %) SELENON-RM patients received mechanical ventilation at baseline, and two additional SELENON-RM patients started during follow-up. Contrarily to LAMA2-MD, SELENON-RM patients had severe diaphragm atrophy (diaphragm thickness z-score: 2.5 [-3.1; -2.1]) and dysfunction (diaphragm thickness ratio: 1.2 [1.0; 1.7]; dVC: 30 % [7.7; 41]). SNIP was low in both neuromuscular diseases and correlated with motor function. In SELENON-RM, respiratory function decreased during follow-up.
Conclusion:
The majority of LAMA2-MD and all SELENON-RM patients had respiratory impairment. SELENON-RM patients showed lower respiratory function which was progressive, more prevalent mechanical ventilation, and more severe diaphragm atrophy and dysfunction than LAMA2-MD patients. Spirometry (FVC%, dVC) and respiratory muscle strength tests (SNIP) are useful in clinical care and as outcome measure in clinical trials.
Clinical Trial Number:
NCT04478981.
