Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study

K. Bouman*, J.T. Groothuis, J. Doorduin, N. van Alfen, F.E.A.U. ten Cate, F.M.A. van den Heuvel, R. Nijveldt, W.C.M. van Tilburg, S.C.F.M. Buckens, A.T.M. Dittrich, J.M.T. Draaisma, M.C.H. Janssen, E.J. Kamsteeg, E.S.B. van Kleef, S. Koene, J.A.M. Smeitink, B. Kusters, F.H.J. van Tienen, H.J.M. Smeets, B.G.M. van EngelenC.E. Erasmus, N.C. Voermans

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit a2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit a2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness.Methods: LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age >= 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age >= 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age >= 5 years), and accelerometry for 8 days (age >= 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age >= 2 years), spine X-ray (age >= 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age >= 2 years) and full body magnetic resonance imaging (MRI) (age >= 10 years). All examinations are adapted to the patient's age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed.Discussion: Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up.Conclusion: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD.
Original languageEnglish
Article number313
Number of pages14
JournalBMC Neurology
Volume21
Issue number1
DOIs
Publication statusPublished - 12 Aug 2021

Keywords

  • LAMA2
  • Laminin subunit a2 deficiency
  • Merosin-deficient congenital muscular dystrophy type 1A (MDC1A)
  • SELENON
  • SEPN1
  • Natural history
  • Outcome measures
  • Trial readiness
  • All ages
  • SKELETAL-MUSCLE PATHOLOGY
  • SELENOPROTEIN-N
  • OXIDATIVE STRESS
  • REFERENCE VALUES
  • DUCHENNE DYSTROPHY
  • CLINICAL-TRIALS
  • RELIABILITY
  • VALIDATION
  • ULTRASOUND
  • QUESTIONNAIRE

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