A 5-year Natural History Study in LAMA2-related Muscular Dystrophy and SELENON-related Myopathy: the Extended LAST STRONG Study

Overview

Journal BMC Neurol

Publisher Biomed Central

Specialty Neurology

Date 2024 Oct 24

PMID 39443859

Authors

E C M de Laat

S L S Houwen-van Opstal

K Bouman

J L M van Doorn

D Cameron

N van Alfen

A T M Dittrich

E J Kamsteeg

H J M Smeets

J T Groothuis

C E Erasmus

Nicol C Voermans

Affiliations

Soon will be listed here.

Abstract

Background: SELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG).

Methods: The Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient's age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed.

Discussion: This study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines.

Trial Registration: This study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee ('METC Oost-Nederland'; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland , file number: 2023-16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).

Citing Articles

Correction: A 5-year natural history study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the Extended LAST STRONG study.

de Laat E, Houwen-van Opstal S, Bouman K, van Doorn J, Cameron D, van Alfen N BMC Neurol. 2024; 24(1):477.

PMID: 39681838 PMC: 11648288. DOI: 10.1186/s12883-024-03994-5.

References

Witting N, Werlauff U, Duno M, Vissing J . Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark. Neurol Genet. 2017; 3(2):e140. PMC: 5362145. DOI: 10.1212/NXG.0000000000000140. View

Villar-Quiles R, von der Hagen M, Metay C, Gonzalez V, Donkervoort S, Bertini E . The clinical, histologic, and genotypic spectrum of -related myopathy: A case series. Neurology. 2020; 95(11):e1512-e1527. PMC: 7713742. DOI: 10.1212/WNL.0000000000010327. View

Lake N, Phua J, Liu W, Moors T, Axon S, Lek M . Estimating the Prevalence of LAMA2 Congenital Muscular Dystrophy using Population Genetic Databases. J Neuromuscul Dis. 2023; 10(3):381-387. DOI: 10.3233/JND-221552. View

Geranmayeh F, Clement E, Feng L, Sewry C, Pagan J, Mein R . Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations. Neuromuscul Disord. 2010; 20(4):241-50. DOI: 10.1016/j.nmd.2010.02.001. View

Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bonnemann C . Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet. 2002; 71(4):739-49. PMC: 378532. DOI: 10.1086/342719. View

Clarke N, Kidson W, Quijano-Roy S, Estournet B, Ferreiro A, Guicheney P . SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol. 2005; 59(3):546-52. DOI: 10.1002/ana.20761. View

Ferreiro A, Ceuterick-de Groote C, Marks J, Goemans N, Schreiber G, Hanefeld F . Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol. 2004; 55(5):676-86. DOI: 10.1002/ana.20077. View

Moghadaszadeh B, Petit N, Jaillard C, Brockington M, Roy S, Merlini L . Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet. 2001; 29(1):17-8. DOI: 10.1038/ng713. View

Sarkozy A, Foley A, Zambon A, Bonnemann C, Muntoni F . LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness. Front Mol Neurosci. 2020; 13:123. PMC: 7419697. DOI: 10.3389/fnmol.2020.00123. View

10.

Bouman K, Groothuis J, Doorduin J, van Alfen N, Udink Ten Cate F, van den Heuvel F . -Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study. Neurol Genet. 2023; 9(5):e200089. PMC: 10356133. DOI: 10.1212/NXG.0000000000200089. View

11.

Bouman K, Groothuis J, Doorduin J, van Alfen N, Udink Ten Cate F, van den Heuvel F . SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness. J Neuromuscul Dis. 2023; 10(6):1055-1074. PMC: 10657684. DOI: 10.3233/JND-221673. View

12.

Smeitink J, van Maanen R, de Boer L, Ruiterkamp G, Renkema H . A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms ("KHENERGYC"). BMC Neurol. 2022; 22(1):158. PMC: 9044835. DOI: 10.1186/s12883-022-02685-3. View

13.

Janssen M, Koene S, de Laat P, Hemelaar P, Pickkers P, Spaans E . The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders. Clin Pharmacol Ther. 2018; 105(1):101-111. PMC: 6704357. DOI: 10.1002/cpt.1197. View

14.

Boyer O, Butler-Browne G, Chinoy H, Cossu G, Galli F, Lilleker J . Myogenic Cell Transplantation in Genetic and Acquired Diseases of Skeletal Muscle. Front Genet. 2021; 12:702547. PMC: 8365145. DOI: 10.3389/fgene.2021.702547. View

15.

van Tienen F, Zelissen R, Timmer E, van Gisbergen M, Lindsey P, Quattrocelli M . Healthy, mtDNA-mutation free mesoangioblasts from mtDNA patients qualify for autologous therapy. Stem Cell Res Ther. 2019; 10(1):405. PMC: 6925445. DOI: 10.1186/s13287-019-1510-8. View

16.

Yurchenco P, McKee K . Linker Protein Repair of LAMA2 Dystrophic Neuromuscular Basement Membranes. Front Mol Neurosci. 2020; 12:305. PMC: 6923227. DOI: 10.3389/fnmol.2019.00305. View

17.

Kemaladewi D, Bassi P, Erwood S, Al-Basha D, Gawlik K, Lindsay K . A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene. Nature. 2019; 572(7767):125-130. DOI: 10.1038/s41586-019-1430-x. View

18.

Rooney J, Knapp J, Hodges B, Wuebbles R, Burkin D . Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy. Am J Pathol. 2012; 180(4):1593-602. PMC: 3349899. DOI: 10.1016/j.ajpath.2011.12.019. View

19.

Bouman K, Groothuis J, Doorduin J, van Alfen N, Udink Ten Cate F, van den Heuvel F . 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. BMC Neurol. 2021; 21(1):313. PMC: 8357962. DOI: 10.1186/s12883-021-02336-z. View

20.

Bouman K, Dittrich A, Groothuis J, van Engelen B, Zweers-van Essen H, de Baaij-Daalmeyer A . Bone quality in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a one-year prospective natural history study. Neuromuscul Disord. 2023; 34:105-113. DOI: 10.1016/j.nmd.2023.11.008. View