Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy in the RF (DYSF-RUS)

• ClinicalTrials.gov Identifier: NCT04824040
• Recruitment Status: Enrolling by invitation
• First Posted: April 1, 2021
• Last Update Posted: July 27, 2022
• Sponsor: Human Stem Cell Institute, Russia
• Collaborator: Genotarget
• Information provided by (Responsible Party): Human Stem Cell Institute, Russia

Study Description

Brief Summary:

To evaluate specific characteristics of phenotype, immune status, molecular and genetic as well as morphological characteristics of adult patients with limb-girdle muscular dystrophy R2 in various regions of the Russian Federation.

Condition or disease
Dysferlinopathy; Miyoshi Myopathy; LGMDR2; DMAT

Detailed Description:

A single-center, cohort clinical study. Subjects of both sexes aged 18 to 65 inclusive with genetically confirmed diagnosis of limb-girdle muscular dystrophy type R2, who have signed the written informed consent form for this study.

The control and case groups should be age- and gender-matched.

Study Objectives:

• To evaluate a clinical status of a subject (MMT score; 6-minute walk test; North Star Assessment for dysferlinopathy (NSAD));
• To assess blood biochemistry;
• To characterize muscle involvement based on MRI results;
• To evaluate the progression of muscle involvement based on repeated MRI;
• To assess cardiac function with ECG, EchoCG and MRI;
• To determine a gait pattern and balance characteristics in patients with limb-girdle muscular dystrophy using electrophysiological techniques (Neurosoft Gait Assessment System Steadys; stabilometrics and plantography with "SIDAS");
• To characterize changes in subpopulation compositions of T- and B-lymphocytes, phagocytic activity of leukocytes (a phagocytic index, a phagocyte number, an index of phagocytosis completeness, lysosomal-cation and NBT tests);
• To assess average blood cytokine levels in subjects with limb-girdle muscular dystrophy (type R2) in various regions of the Russian Federation;
• To assess average blood cytokine levels in healthy subjects from various regions of the RF;
• To analyze the relationship between blood cytokine levels and the presence of a mutation in the dysferlin gene;
• To study the expression (immunohistochemistry and western-blotting) and distribution of dysferlin in impaired muscles of subjects with LGMDR2.

The clinical study includes the stages as follows:

1. Subject enrollment - 24 months
2. Data collection and analysis - 12 months
3. Study Report - 30 days.

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 100 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 2 Years
• Official Title: Evaluation of Clinical, Immunological, Morphological, Molecular and Genetic Characteristics of Patients With Limb-girdle Muscular Dystrophy Type R2 (Type 2B) in the Russian Federation
• Actual Study Start Date: January 15, 2020
• Estimated Primary Completion Date: February 25, 2024
• Estimated Study Completion Date: July 2024

Groups and Cohorts

Group/Cohort
Study group; Patients with a genetically confirmed dysferlinopathy.
Control group; Healthy Volunteers

Outcome Measures

Primary Outcome Measures :

1. Сlinical status of patients with dysferlinopathy (MMT score) [ Time Frame: Through study completion at 24 months ]
   Muscle strength will be assessed using MMT and will be expressed in points for each of the muscle groups assessed.
2. Сlinical status of patients with dysferlinopathy ( North Star Assessment for dysferlinopathy) [ Time Frame: Through study completion at 24 months ]
   North Star Assessment for Dysferlinopathy (NSAD) is a functional scale that will be used to measure motor performance in individuals with dysferlinopathy (includes 29 items).
3. Сlinical status of patients with dysferlinopathy (Hand Held Dynamometry). [ Time Frame: Through study completion at 24 months ]
   Hand held dynamometry using the MicroFET2 myometer will be utilized to capture isometric muscle strength. Maximum strength in kilograms will be reported for each muscle group.
4. Сlinical status of patients with dysferlinopathy (6-minute walk test) [ Time Frame: Through study completion at 24 months ]
   The participant will be asked to complete maximal distance in 6 minet as quickly as safely possible and the time in seconds is recorded.
5. Clinical blood test (level of hemoglobin) [ Time Frame: Through study completion at 24 months. ]
   Level of hemoglobin is planned to be assessed in patients with dysferlinopathy.
6. Clinical blood test. Level of hematocrit [ Time Frame: Through study completion at 24 months. ]
   Level of hematocrit (%) is planned to be assessed in patients with dysferlinopathy.
7. Clinical blood test. Level of RBC [ Time Frame: Through study completion at 24 months. ]
   Level of RBC is planned to be assessed in patients with dysferlinopathy.
8. Clinical blood test. Level of WBC [ Time Frame: Through study completion at 24 months. ]
   Level of WBC is planned to be assessed in patients with dysferlinopathy.
9. Clinical blood test. Levels of ESR [ Time Frame: Through study completion at 24 months. ]
   Levels of ESR (mm/h) is planned to be assessed in patients with dysferlinopathy.
10. Clinical blood test. Level of platelets [ Time Frame: Through study completion at 24 months. ]
    Level of platelets is planned to be assessed in patients with dysferlinopathy.
11. Biochemical blood test. [ Time Frame: Through study completion at 24 months ]
    Levels of potassium (mmol/l) is planned to be assessed in patients with dysferlinopathy.
12. Biochemical blood test. Level of sodium [ Time Frame: Through study completion at 24 months. ]
    Level of sodium (mmol/l) is planned to be assessed in patients with dysferlinopathy.
13. Biochemical blood test. Level of calcium [ Time Frame: Through study completion at 24 months. ]
    Level of calcium (mmol/l) is planned to be assessed in patients with dysferlinopathy.
14. Biochemical blood test. Level of creatinine [ Time Frame: Through study completion at 24 months. ]
    Level of creatinine (μmol/l) is planned to be assessed in patients with dysferlinopathy.
15. Biochemical blood test. Level of glucose [ Time Frame: Through study completion at 24 months. ]
    Level of glucose (mmol/l) is planned to be assessed in patients with dysferlinopathy.
16. Biochemical blood test. Level of uric acid [ Time Frame: Through study completion at 24 months. ]
    Level of uric acid (μmol/l) is planned to be assessed in patients with dysferlinopathy.
17. Biochemical blood test. Level of urea [ Time Frame: Through study completion at 24 months. ]
    Level of urea (mmol/l) is planned to be assessed in patients with dysferlinopathy.
18. Biochemical blood test. Level of ALT [ Time Frame: Through study completion at 24 months. ]
    Level of ALT (U/l) is planned to be assessed in patients with dysferlinopathy.
19. Biochemical blood test. Level of AST [ Time Frame: Through study completion at 24 months. ]
    Level of AST (U/l) is planned to be assessed in patients with dysferlinopathy.
20. Biochemical blood test. Level of total protein [ Time Frame: Through study completion at 24 months. ]
    Level of total protein (g/l) is planned to be assessed in patients with dysferlinopathy.
21. Biochemical blood test. Level of CPK [ Time Frame: Through study completion at 24 months. ]
    Level of CPK (U/l) is planned to be assessed in patients with dysferlinopathy.
22. Biochemical blood test. Level of triglycerides [ Time Frame: Through study completion at 24 months. ]
    Level of triglycerides (mmol/l) is planned to be assessed in patients with dysferlinopathy.
23. Biochemical blood test. Level of CRP [ Time Frame: Through study completion at 24 months. ]
    Level of CRP (mg/l) is planned to be assessed in patients with dysferlinopathy.
24. Blood cytokine levels in subjects with dysferlinopathy and healthy volunteers. [ Time Frame: Through study completion at 24 months ]
    • To assess average blood cytokine levels in subjects with dysferlinopathy in various regions of the Russian Federation;
    • To assess average blood cytokine levels in healthy subjects.

    Blood serum cytokine profiling will be performed with the use of the multiparameter fluorescent diagnostic system Luminex 200 and the Bio-Plex Pro Human 27-Plex Panel (Bio-Rad, Hercules, USA) in accordance with the manufacturer's instructions. The data obtained will be processed with the use of MasterPlex CT control and MasterPlex QT analysis software (Hitachi Software, San Bruno, USA).

    The following cytokine Levels will be assessed in the study:FGF2, Eotaxin,G-CSF, GM-CSF, IFN-γ, IL-1β, 1IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 p70, IL-13, IL-15, IL-17, IP-10, MCP-1/MCAF, MIP-1α, MIP-1β,PDGF-BB, RANTES, TNF-α, VEGF.

25. Autoantibodies in patients with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    Assessment of antibodу level against skeletal muscle antigens; an antinuclear factor (ANA), an extractable nuclear antigen.
26. Muscle MRI in patients with dysferlinopathy. [ Time Frame: Through study completion at 24 months. ]
    • To characterize muscle involvement based on MRI results;
    • To evaluate the progression of muscle involvement based on repeated MRI once year;
27. Subpopulation compositions of T-lymphocytes in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in subpopulation compositions of T-lymphocytes in %.
28. Subpopulation compositions of B-lymphocytes in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in subpopulation compositions of B-lymphocytes in %.
29. Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (NBT test) [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (NBT test in CU).
30. Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (a phagocyte number in CU).
31. Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (lysosomal-cation test). [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (lysosomal-cation test in CU).
32. Subpopulation compositions of phagocytic activity of leukocytes (a phagocytic index) in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (a phagocytic index).
33. Gait pattern and balance characteristics in patients with limb-girdle muscular dystrophy R2. [ Time Frame: Through study completion at 24 months. ]
    To determine a gait pattern characteristics in patients with limb-girdle muscular dystrophy R2 using electrophysiological techniques (Neurosoft Gait Assessment System "STEDIS").
34. Cardiac function (assessed by Echocardiography). LV [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the left ventricle (LV) index will be determined.
35. Cardiac function (assessed by Echocardiography). LV mass [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the LV mass index will be determined.
36. Cardiac function (assessed by Echocardiography). Myocardium mass [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the myocardium mass index will be determined.
37. Cardiac function (assessed by Echocardiography). RV [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the right ventricle (RV) index will be determined.
38. Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of LV mass [ Time Frame: Through study completion at 24 months. ]
    Volumetric evaluation of LV mass by manual tracing will be perform. An MRI of the heart will assess fibrosis.
39. Cardiac function (assessed by Echocardiography). LA [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the left atrium (LA) index will be determined
40. Cardiac function (assessed by Electrocardiography). Outcome 13 [ Time Frame: Through study completion at 24 months. ]
    To assess rhythm characteristic, P-wave, QRS, T-wave duration; PR, RR, QT intervals; PR, ST segments.
41. Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of EF [ Time Frame: Through study completion at 24 months. ]
    Volumetric evaluation of EF by manual tracing will be performed.
42. Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). [ Time Frame: Through study completion at 24 months. ]
    Volumetric evaluation of volume by manual tracing will be performed.
43. Morphological muscle study [ Time Frame: Through study completion at 24 months. ]
    If it was necessary to confirm the causation of mutations in the dysferlin gene, the patients underwent muscle biopsy. To study the expression (immunohistochemistry and western-blotting) and distribution of dysferlin in impaired muscles of subjects with LGMDR2.

Biospecimen Retention:   Samples With DNA

Serum, Plasma, DNA, RNA

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Probability Sample

Study Population

Study participants will be identified through self-selection and direct recruitment options. Participants will be identified from the population of individuals who are followed at the neuromuscular clinics. Participants will also be solicited from the DYSF Russian registry.

Criteria

Inclusion Criteria:

• 18 to 85 (inclusive) years-old subjects of both sexes;
• A signed written informed consent form;
• Genetically confirmed diagnosis of limb-girdle muscular dystrophy (type 2B) (a case group)

Exclusion Criteria:

• A subject who is an investigator, study assistant, study coordinator and a member of the other personnel indirectly or directly associated with the conduct of the study;
• Acute medical conditions associated with visceral dysfunction, life-threatening conditions which occurred less than 6 months prior to enrollment into the study such as acute cardiac, renal, hepatic insufficiency, myocardial infarction or an acute cerebrovascular accident (stroke) as well as infectious diseases;
• Excessive alcohol consumption (> 20 g/day).

Contacts and Locations

Locations

Russian Federation

Human Stem Cells Institute

Moscow, Russian Federation, 119333

Sponsors and Collaborators

Human Stem Cell Institute, Russia

Genotarget

Investigators

• Study Chair: Roman Deev, PhD; HSCI, Russia

More Information

Publications:

Khaiboullina SF, Martynova EV, Bardakov SN, Mavlikeev MO, Yakovlev IA, Isaev AA, Deev RV, Rizvanov AA. Serum Cytokine Profile in a Patient Diagnosed with Dysferlinopathy. Case Rep Med. 2017;2017:3615354. doi: 10.1155/2017/3615354. Epub 2017 Apr 13.

Umakhanova ZR, Bardakov SN, Mavlikeev MO, Chernova ON, Magomedova RM, Akhmedova PG, Yakovlev IA, Dalgatov GD, Fedotov VP, Isaev AA, Deev RV. Corrigendum: Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan. Front Neurol. 2017 Apr 18;8:145. doi: 10.3389/fneur.2017.00145. eCollection 2017.

• Responsible Party: Human Stem Cell Institute, Russia
• ClinicalTrials.gov Identifier: NCT04824040
• Other Study ID Numbers: DYSF-Observation (RUS)
• First Posted: April 1, 2021
• Last Update Posted: July 27, 2022
• Last Verified: July 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Human Stem Cell Institute, Russia:

LGMDR2; Miyoshi Myopathy; Dysferlinopathy; DYSF; DMAT

Additional relevant MeSH terms:

Muscular Diseases; Muscular Dystrophies, Limb-Girdle; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Muscular Dystrophies; Muscular Disorders, Atrophic; Genetic Diseases, Inborn