Clinical trial NCT05394506: Modifying Factors in Striated Muscle Laminopathies
Official title: Identification of Genetic Modifying Factors in Striated Muscle Laminopathies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Laminopathies
Emery Dreifuss Muscular Dystrophy 2
LMNA-Related Congenital Muscular Dystrophy
Dilated Cardiomyopathy-1A
Keywords: A-type lamins
LMNA
muscular dystrophy
modifier factor
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
First posted: 2022-05-27
Enrollment: 40
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: * To collect biological material (muscle and/or skin biopsies) and the phenotype of patients with mutations in the LMNA gene (within large families with variable clinical presentation or within cohorts of patients with recurrent mutations in the LMNA gene.
* To grade the severity of the muscle phenotype of these patients (severe, moderate, mild).
* Perform "omics" analysis on their biological material.
Primary purpose: BASIC_SCIENCE

Brief summary: Mutations in the LMNA gene, which codes for lamins A and C, proteins of the nuclear lamina, are responsible for a wide spectrum of pathologies, including a group specifically affecting striated skeletal and cardiac muscles, with cardiac involvement being life-threatening. At the skeletal muscle level, a wide phenotypic spectrum has been described, ranging from severe forms of congenital muscular dystrophy to less severe forms of limb-girdle muscular dystrophy. The great clinical variability of striated muscle laminopathies, both inter- and intra-familial, can be observed in the age of onset, severity of signs and progression of muscle and heart involvement. To date, more than 400 LMNA mutations have been associated with striated muscle laminopathies (www.umd.be/LMNA/), highlighting strong clinical and genetic heterogeneity. A few recurrent mutations linked to a difference in severity have been identified. However, these genotype-phenotype relationships and the rare cases of digenism reported do not explain all the clinical variability of laminopathies. Therefore, there are probably other factors of severity than the causative mutation, called "modifier genes".

Identification of such modifier genes has been initiated by studying a large family with significant clinical variability in the age of onset of muscle signs. A segregation analysis within this family identified 2 potential modifier loci. High-throughput sequencing restricted to these 2 regions according to phenotypic subgroups did not led to meaningful results so far. In addition, an international retrospective study of the natural history of early muscle laminopathies has allowed the investigators to highlight a strong inter-family clinical variability in patients carrying recurrent mutations. The investigators thus have strong preliminary data that could allow them to identify modifying genetic factors in a cohort of patients carrying a mutation in the LMNA gene.

In order to identify these factors that modulate the clinical severity of laminopathies, the investigators wish to collect biological material (muscle and/or skin biopsies) from patients carrying a mutation in the LMNA gene. The study of this biological material using multi OMICs technics will allow the investigators to identify and functionally validate the action of these modifying genes.

OMIICs is a set of techniques for characterising biological molecules using high-throughput approaches such as DNA sequencing, RNA sequencing and/or chromatin conformation (ATACseq...), proteins.


Eligibility criteria: Inclusion Criteria:

* Patient with an LMNA mutation that has led to the diagnosis of laminopathy affecting striated muscle
* Presenting the symptoms of the disease, whether they are index cases or related to this index case (muscle weakness, tendon retractions with or without respiratory or cardiac involvement)
* Have no contraindication to muscle or skin biopsy, i.e., 1) presence of a history of allergy to latex, antiseptics, local anesthetics and adhesive dressings, 2) Current oral or parenteral anticoagulant therapy (anti-vitamin K, heparins, anti-platelet agents, anti-factor X, anti-thrombin), 3) History of inherited (haemophilias, platelet diseases) or acquired (vitamin K deficiency, liver failure) coagulation disorders.
* Patients (adult participant) or both holders of parental authority (minor participant) must sign a free and informed consent. If a minor has only 1 legal representative, the latter must attest to this on the consent form.
* Patients affiliated to the general French social security system, to the French Universal Medical Coverage (CMU) or to any French equivalent scheme.

Exclusion Criteria:

* Pregnant or breastfeeding women
* Adult subject to legal protection measures (safeguard of justice, curatorship and guardianship).

Primary outcomes:
measure: Skeletal muscle severity outcome
timeFrame: 5 years
measure: Cardiac muscle severity outcome
timeFrame: 5 years
measure: Protective structural variant outcome
timeFrame: 5 years
measure: Protective differential gene expression outcome
timeFrame: 5 years
measure: Protective 3D chromatin conformation outcome
timeFrame: 5 years
measure: Aggravating structural variant outcome
timeFrame: 5 years
measure: Aggravating differential gene expression outcome
timeFrame: 5 years
measure: Aggravating 3D chromatin conformation outcome outcome
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Bron
country: France
facility: Centre de référence maladies neuromusculaires, Hôpital Femme Mère Enfant, CHU Lyon
state: Auvergne-Rhône-Alpes
city: Montpellier
country: France
facility: Service de Neuropédiatrie, Centre de Référence Maladies Neuromusculaires, CHU de Montpellier
state: Hérault
city: Garches
country: France
facility: Service de Neurologie, Réanimation Pédiatriques, Hôpital Raymond Poincaré, Hôpitaux Universitaires, Paris-Ile-de-France-Ouest
state: Ile De France
city: Rennes
country: France
facility: Service de Génétique médicale, CHU Rennes
state: Ille-et-Vilaine
city: Nantes
country: France
facility: Laboratoire d'Explorations Fonctionnelles - Centre de Référence Maladies Neuromusculaires Rares, CHU Nantes
state: Loire-Atlantique
city: Rouen
country: France
facility: Service de cardiologie & Service de Neurophysiologie - CHU de Rouen
state: Normandie
city: Paris
country: France
facility: Centre de référence maladies neuromusculaires, Institut de myologie, Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: Centre de référence pour les maladies cardiaques héréditaires
Study officials:
References:
citation: Granger B, Gueneau L, Drouin-Garraud V, Pedergnana V, Gagnon F, Ben Yaou R, Tezenas du Montcel S, Bonne G. Modifier locus of the skeletal muscle involvement in Emery-Dreifuss muscular dystrophy. Hum Genet. 2011 Feb;129(2):149-59. doi: 10.1007/s00439-010-0909-1. Epub 2010 Nov 10.
citation: Ben Yaou R, Yun P, Dabaj I, Norato G, Donkervoort S, Xiong H, Nascimento A, Maggi L, Sarkozy A, Monges S, Bertoli M, Komaki H, Mayer M, Mercuri E, Zanoteli E, Castiglioni C, Marini-Bettolo C, D'Amico A, Deconinck N, Desguerre I, Erazo-Torricelli R, Gurgel-Giannetti J, Ishiyama A, Kleinsteuber KS, Lagrue E, Laugel V, Mercier S, Messina S, Politano L, Ryan MM, Sabouraud P, Schara U, Siciliano G, Vercelli L, Voit T, Yoon G, Alvarez R, Muntoni F, Pierson TM, Gomez-Andres D, Reghan Foley A, Quijano-Roy S, Bonnemann CG, Bonne G. International retrospective natural history study of LMNA-related congenital muscular dystrophy. Brain Commun. 2021 Apr 11;3(3):fcab075. doi: 10.1093/braincomms/fcab075. eCollection 2021 Jul.