Improvement of DIAgnostic and Phenotype-genotype Correlation Studies in Patients With MYOpathy Suspected of TITinopathy

NCT03998540 | Recruiting DMC

• 2 other identifiers: RECHMPL18_00772018-A02287-48
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Due to the widespread use of NGS, TTN is emerging as a major causative gene in neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and mode of inheritance (recessive or dominant) of titinopathies are poorly understood. They involve the primordial structural functions of titin on the formation and stability of the sarcomere, as well as its interactions with other proteins. We identified by NGS, in patients with skeletal myopathy (with or without cardiomyopathy), several potentially disease causing TTN variants. The specific aims of the present project are to implement functional studies (transcripts, protein analyses, in vitro protein-protein interaction studies) to evaluate the effect of TTN variants on the transcripts and protein in order to perform phenotype-genotype correlation studies. We participate to the national "titin network" and to international efforts for the understanding of the molecular bases of titinopathies. Genomic characterisation opens the way to develop cellular models of titinopathy, derived from patient biopsies. This is also a mandatory first step for the design of novel therapeutic approaches.

Conditions

Myopathy; Phenotypic Abnormality; Genetic Disease

Keywords

titine; western blot

Outcome Measures

Primary Outcomes (2)

• Measurement of the relative quantity of titin protein

  Evaluated by Western blot: normal or not, characterization of anomalies if any

  enrollment

• Measurement of the relative size of titin protein

  Evaluated by Western blot: normal or not, characterization of anomalies if any

  enrollment

Secondary Outcomes (9)

• Measurement of consequences on interacting proteins

  during 2 years

• Measurement of the consequences of TTN variants on titin transcripts

  2 years

• Phenotype-genotype correlation studies

  2.5 years

• Analyses of molecular bases of the different mode of inheritance of the disease

  2.5 years

• Mesurement of the level of interactions by in-vitro studies

  during 2 years

Study Arms (1)

Patients with myopathy suspected of titinopathy

Patients with myopathy in which one or more potentially pathogenic TTN variants have been previously identified (index cases and related cases affected). Muscle biopsy performed previously

Diagnostic Test: Western blot; Other: Protein interaction studies; Other: Mass Spectometry; Other: RNA seq

Interventions

Western blot DIAGNOSTIC_TEST

Western-blot analysis of a giant protein, with specific antibodies directed against C-ter and N-Ter of the protein

Patients with myopathy suspected of titinopathy

Protein interaction studies OTHER

Analyses of several interacting proteins by specific Western-blot and in-vitro tests.

Patients with myopathy suspected of titinopathy

Mass Spectometry OTHER

samples previously used for western blotting will be subjected to mass spectrometry analysis

Patients with myopathy suspected of titinopathy

RNA seq OTHER

analyze muscle gene expression in patients with titinopathies in our cohort by RNAseq

Patients with myopathy suspected of titinopathy

Eligibility Criteria

• 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 suspected titinopathy

You may qualify if:

• Patient followed by a neurologist or a pediatric neurologist.
• Child or adult with congenital or progressive, proximal or distal myopathy
• Identification by NGS analysis of variant(s) in the potentially pathogenic TTN gene(s)
• Muscle biopsy performed previously
• Collection of the patient's (or one of his legal representatives if minor) non-opposition to participate in the present study and for the collection of the necessary biological material (muscle)
• Patient affiliated to or benefiting from a social security scheme

You may not qualify if:

• Absence of muscle sampling

Sponsors & Collaborators

• University Hospital, Montpellier: lead

Study Sites (1)

CHU Montpellier

Montpellier, 34090, France

RECRUITING

MeSH Terms

Conditions

Muscular Diseases; Genetic Diseases, Inborn

Interventions

Base Sequence

Condition Hierarchy (Ancestors)

Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Molecular Structure; Biochemical Phenomena; Chemical Phenomena; Genetic Structures; Genetic Phenomena

Central Study Contacts

Mireille COSSEE, MCU PH

CONTACT

04 11 75 98 63; mireille.cossee@inserm.fr

Fanny CARDON

CONTACT

fanny-cardon@chu-montpellier.fr

Study Design

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

Study Record Dates

• First Submitted: June 20, 2019
• First Posted: June 26, 2019
• Study Start: December 5, 2019
• Primary Completion: December 5, 2024
• Study Completion: May 5, 2025
• Last Updated: February 28, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)