Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy in the RF

• Conditions: Miyoshi Myopathy; LGMDR2; Dysferlinopathy; DMAT

• Registration Number: NCT04824040
• Lead Sponsor: Human Stem Cell Institute, Russia

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.

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 Timeline

• Study Start: 2020-01-15
• Study First Submitted: 2021-02-16
• Study First Submitted QC: 2021-03-26
• Study First Posted: 2021-04-01
• Status Verified: 2022-07
• Last Update Submitted: 2022-07-25
• Last Update Posted: 2022-07-27
• Primary Completion: 2024-02-25
• Study Completion: 2024-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

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).

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Сlinical status of patients with dysferlinopathy (MMT score)	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.
Сlinical status of patients with dysferlinopathy (Hand Held Dynamometry).	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.
Сlinical status of patients with dysferlinopathy (6-minute walk test)	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.
Clinical blood test. Level of RBC	Through study completion at 24 months.	Level of RBC is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test.	Through study completion at 24 months	Levels of potassium (mmol/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of creatinine	Through study completion at 24 months.	Level of creatinine (μmol/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of ALT	Through study completion at 24 months.	Level of ALT (U/l) is planned to be assessed in patients with dysferlinopathy.
Blood cytokine levels in subjects with dysferlinopathy and healthy volunteers.	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.
Subpopulation compositions of T-lymphocytes in subjects with dysferlinopathy.	Through study completion at 24 months	• To characterize changes in subpopulation compositions of T-lymphocytes in %.
Subpopulation compositions of phagocytic activity of leukocytes (a phagocytic index) in subjects with dysferlinopathy.	Through study completion at 24 months	• To characterize changes in phagocytic activity of leukocytes (a phagocytic index).
Clinical blood test. Level of hematocrit	Through study completion at 24 months.	Level of hematocrit (%) is planned to be assessed in patients with dysferlinopathy.
Clinical blood test. Level of platelets	Through study completion at 24 months.	Level of platelets is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of sodium	Through study completion at 24 months.	Level of sodium (mmol/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of glucose	Through study completion at 24 months.	Level of glucose (mmol/l) is planned to be assessed in patients with dysferlinopathy.
Clinical blood test (level of hemoglobin)	Through study completion at 24 months.	Level of hemoglobin is planned to be assessed in patients with dysferlinopathy.
Clinical blood test. Levels of ESR	Through study completion at 24 months.	Levels of ESR (mm/h) is planned to be assessed in patients with dysferlinopathy.
Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (NBT test)	Through study completion at 24 months	• To characterize changes in phagocytic activity of leukocytes (NBT test in CU).
Cardiac function (assessed by Electrocardiography). Outcome 13	Through study completion at 24 months.	To assess rhythm characteristic, P-wave, QRS, T-wave duration; PR, RR, QT intervals; PR, ST segments.
Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of EF	Through study completion at 24 months.	Volumetric evaluation of EF by manual tracing will be performed.
Muscle MRI in patients with dysferlinopathy.	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;
Сlinical status of patients with dysferlinopathy ( North Star Assessment for dysferlinopathy)	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).
Biochemical blood test. Level of calcium	Through study completion at 24 months.	Level of calcium (mmol/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of uric acid	Through study completion at 24 months.	Level of uric acid (μmol/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of CRP	Through study completion at 24 months.	Level of CRP (mg/l) is planned to be assessed in patients with dysferlinopathy.
Clinical blood test. Level of WBC	Through study completion at 24 months.	Level of WBC is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of urea	Through study completion at 24 months.	Level of urea (mmol/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of AST	Through study completion at 24 months.	Level of AST (U/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of total protein	Through study completion at 24 months.	Level of total protein (g/l) is planned to be assessed in patients with dysferlinopathy.
Biochemical blood test. Level of CPK	Through study completion at 24 months.	Level of CPK (U/l) is planned to be assessed in patients with dysferlinopathy.
Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (lysosomal-cation test).	Through study completion at 24 months	• To characterize changes in phagocytic activity of leukocytes (lysosomal-cation test in CU).
Cardiac function (assessed by Echocardiography). Myocardium mass	Through study completion at 24 months.	The absolute and relative sizes of the myocardium mass index will be determined.
Cardiac function (assessed by Echocardiography). LA	Through study completion at 24 months.	The absolute and relative sizes of the left atrium (LA) index will be determined
Subpopulation compositions of B-lymphocytes in subjects with dysferlinopathy.	Through study completion at 24 months	• To characterize changes in subpopulation compositions of B-lymphocytes in %.
Biochemical blood test. Level of triglycerides	Through study completion at 24 months.	Level of triglycerides (mmol/l) is planned to be assessed in patients with dysferlinopathy.
Autoantibodies in patients with dysferlinopathy.	Through study completion at 24 months	Assessment of antibodу level against skeletal muscle antigens; an antinuclear factor (ANA), an extractable nuclear antigen.
Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy.	Through study completion at 24 months	• To characterize changes in phagocytic activity of leukocytes (a phagocyte number in CU).
Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent).	Through study completion at 24 months.	Volumetric evaluation of volume by manual tracing will be performed.
Gait pattern and balance characteristics in patients with limb-girdle muscular dystrophy R2.	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").
Cardiac function (assessed by Echocardiography). LV	Through study completion at 24 months.	The absolute and relative sizes of the left ventricle (LV) index will be determined.
Cardiac function (assessed by Echocardiography). LV mass	Through study completion at 24 months.	The absolute and relative sizes of the LV mass index will be determined.
Cardiac function (assessed by Echocardiography). RV	Through study completion at 24 months.	The absolute and relative sizes of the right ventricle (RV) index will be determined.
Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of LV mass	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.
Morphological muscle study	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.

Trial Locations

Locations (1)

Human Stem Cells Institute; 🇷🇺 Moscow, Russian Federation