The Natural History of Patients With Mutations in SEPN1 (SELENON) or LAMA2

NCT04478981 | Completed

• 1 other identifier: NL64269.091.17
• Study Type: observational
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

SEPN1 (SELENON) is a rare congenital myopathy due to mutations in the SELENON gene. MDC1A is a rare congenital muscle dystrophy due to mutations in the LAMA2 gene. Currently, not much is known about the natural history of these two muscle diseases and no (curative) treatment options exist. The investigators aim to study the natural history of SELENON- and LAMA2-related myopathy/congenital muscular dystrophy patients and prepare for future trials by selection of the most appropriate outcome measures. To this end, a standard medical history, neurological examination, functional measures, questionnaires, cardiac examination, respiratory function tests, radiological examination and accelerometry will be performed over an one and-a-half year period.

Conditions

MDC1A; SELENON-related Myopathy

Keywords

MDC1A; LAMA2-related muscular dystrophy; LAMA2; Laminin2 / genetics; Laminin2 / deficiency; SELENON; SEPN1; Multi-minicore Disease; Rigid Spine Muscular Dystrophy; Selenoproteins / genetics; Natural history study; Outcome measures; Congenital muscular dystrophy; Congenital myopathy; Muscle disease

Outcome Measures

Primary Outcomes (1)

• Change of Motor Function Measure (MFM)-32 (older than 7 years) or MFM-20 (2 to 7 years old)

  Global motor functioning. The items of the MFM are classified in 3 domains: D1: Standing and transfers (13 items, sub score range 0-39) D2: Axial and proximal motor function (12 items, sub score range 0-36) D3: Distal motor function (7 items, sub score range 0-21) Each item is scored on a 0-3 scale. Each sub score will be calculated as the percentage of total possible score achieved. Higher scores indicate a better outcome. The range of the total score is 0-96, again recalculated as the percentage of total possible score achieved. The main point of interest includes the change of MFM score over a period of 1,5 year. Additionally, MFM scores of participants will be compared to reference values.

  Change from baseline at 6 months, 12 months and 18 months

Secondary Outcomes (39)

• Accelerometry (2 years and older) - change of physical activity in daily life

  Change from baseline at 6 months, 12 months and 18 months

• Change of activity limitations - ACTIVLIM (6 years and older)

  Change from baseline at 6 months, 12 months and 18 months

• Change of balance by Pediatric balance scale (2 - 17 years) or Mini Balance Evaluation System Test (miniBEST) (18 years and older)

  Change from baseline at 6 months, 12 months and 18 months

• Change of bone density - DEXA scan (2 years and older)

  Change from baseline at 12 months

• Change of Borg Rating Scale of Perceived Exertion (5 years and older) - physical activity intensity level

  Change from baseline at 6 months, 12 months and 18 months

Study Arms (1)

SELENON- or LAMA2-related muscular dystrophy

Participants diagnosed with congenital myopathy/muscular dystrophy due to mutations in the SEPN1 (SELENON) or LAMA2 gene

Other: No intervention

Interventions

No intervention OTHER

This concerns a natural history study; no interventions will be used

SELENON- or LAMA2-related muscular dystrophy

Eligibility Criteria

• Age: 1 Day - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with a congenital myopathy/muscular dystrophy due to mutations in SELENON- or LAMA2 genes will be identified through contact with genetic diagnostic services, rehabilitation centers, and muscle disease experts in The Netherlands and Dutch-speaking Belgium. Patients with a congenital myopathy/muscular dystrophy due to SELENON (prevalence 0.5:1000,000) or LAMA2 (4 in 500,000) mutations are rare and no Dutch registry exists. Therefore the investigators can only estimate the number of patients.

You may qualify if:

• Willing and able to complete (part of the) measurement protocol
• Willing and able to travel to Nijmegen (The Netherlands)
• Dutch-speaking
• Genetically-confirmed muscle disease caused by mutations in SELENON (SEPN1): congenital muscular dystrophy with early spine rigidity or congenital myopathy (multicore/minicore disease, congenital fiber type size disproportion)
• Genetically confirmed muscular dystrophy caused by mutations in LAMA2: merosin-deficient muscular dystrophy 1A (early-onset LAMA2-related muscular dystrophy) or childhood-onset limb-girdle type muscular dystrophy (late-onset LAMA2-related muscular dystrophy)

You may not qualify if:

• None

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboudumc

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

Related Publications (10)

• Witting N, Werlauff U, Duno M, Vissing J. Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark. Neurol Genet. 2017 Mar 21;3(2):e140. doi: 10.1212/NXG.0000000000000140. eCollection 2017 Apr.

  PMID: 28357410 BACKGROUND

• Scoto M, Cirak S, Mein R, Feng L, Manzur AY, Robb S, Childs AM, Quinlivan RM, Roper H, Jones DH, Longman C, Chow G, Pane M, Main M, Hanna MG, Bushby K, Sewry C, Abbs S, Mercuri E, Muntoni F. SEPN1-related myopathies: clinical course in a large cohort of patients. Neurology. 2011 Jun 14;76(24):2073-8. doi: 10.1212/WNL.0b013e31821f467c.

  PMID: 21670436 BACKGROUND

• Schara U, Kress W, Bonnemann CG, Breitbach-Faller N, Korenke CG, Schreiber G, Stoetter M, Ferreiro A, von der Hagen M. The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy. Eur J Paediatr Neurol. 2008 May;12(3):224-30. doi: 10.1016/j.ejpn.2007.08.011. Epub 2007 Oct 22.

  PMID: 17951086 BACKGROUND

• Oliveira J, Gruber A, Cardoso M, Taipa R, Fineza I, Goncalves A, Laner A, Winder TL, Schroeder J, Rath J, Oliveira ME, Vieira E, Sousa AP, Vieira JP, Lourenco T, Almendra L, Negrao L, Santos M, Melo-Pires M, Coelho T, den Dunnen JT, Santos R, Sousa M. LAMA2 gene mutation update: Toward a more comprehensive picture of the laminin-alpha2 variome and its related phenotypes. Hum Mutat. 2018 Oct;39(10):1314-1337. doi: 10.1002/humu.23599. Epub 2018 Aug 10.

  PMID: 30055037 BACKGROUND

• Nguyen Q, Lim KRQ, Yokota T. Current understanding and treatment of cardiac and skeletal muscle pathology in laminin-alpha2 chain-deficient congenital muscular dystrophy. Appl Clin Genet. 2019 Jul 3;12:113-130. doi: 10.2147/TACG.S187481. eCollection 2019.

  PMID: 31308722 BACKGROUND

• Moulin M, Ferreiro A. Muscle redox disturbances and oxidative stress as pathomechanisms and therapeutic targets in early-onset myopathies. Semin Cell Dev Biol. 2017 Apr;64:213-223. doi: 10.1016/j.semcdb.2016.08.003. Epub 2016 Aug 12.

  PMID: 27531051 BACKGROUND

• de Vries PR, Janssen M, Spaans E, de Groot I, Janssen A, Smeitink J, Koene S. Natural variability of daily physical activity measured by accelerometry in children with a mitochondrial disease. Mitochondrion. 2019 Jul;47:30-37. doi: 10.1016/j.mito.2019.04.005. Epub 2019 Apr 20.

  PMID: 31014978 BACKGROUND

• Bouman K, van Doorn JLM, Groothuis JT, Wijkstra PJ, van Engelen BGM, Erasmus CE, Doorduin J, Voermans NC. Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study. Eur J Paediatr Neurol. 2024 Jan;48:30-39. doi: 10.1016/j.ejpn.2023.11.005. Epub 2023 Nov 22.

  PMID: 38008001 DERIVED

• Bouman K, Groothuis JT, Doorduin J, van Alfen N, Udink Ten Cate FEA, van den Heuvel FMA, Nijveldt R, Kamsteeg EJ, Dittrich ATM, Draaisma JMT, Janssen MCH, van Engelen BGM, Erasmus CE, Voermans NC. LAMA2-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study. Neurol Genet. 2023 Jul 19;9(5):e200089. doi: 10.1212/NXG.0000000000200089. eCollection 2023 Oct.

  PMID: 37476021 DERIVED

• Bouman K, Groothuis JT, Doorduin J, van Alfen N, Udink Ten Cate FEA, van den Heuvel FMA, Nijveldt R, van Tilburg WCM, Buckens SCFM, Dittrich ATM, Draaisma JMT, Janssen MCH, Kamsteeg EJ, van Kleef ESB, Koene S, Smeitink JAM, Kusters B, van Tienen FHJ, Smeets HJM, van Engelen BGM, Erasmus CE, Voermans NC. 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 Aug 12;21(1):313. doi: 10.1186/s12883-021-02336-z.

  PMID: 34384384 DERIVED

MeSH Terms

Conditions

Muscular dystrophy congenital, merosin negative; Rigid spine syndrome; Minicore Myopathy with External Ophthalmoplegia; Myotonia Congenita; Muscular Diseases

Condition Hierarchy (Ancestors)

Myotonic Disorders; Musculoskeletal Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Nicol Voermans

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2020
• First Posted: July 21, 2020
• Study Start: August 26, 2020
• Primary Completion: May 23, 2022
• Study Completion: March 24, 2023
• Last Updated: November 18, 2023

Record last verified: 2022-04

Locations

NL (1)