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

Study Overview
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Brief Summary
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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
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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: Subject enrollment - 24 months Data collection and analysis - 12 months Study Report - 30 days.

Official Title
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Evaluation of Clinical, Immunological, Morphological, Molecular and Genetic Characteristics of Patients With Limb-girdle Muscular Dystrophy Type R2 (Type 2B) in the Russian Federation

Conditions
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Dysferlinopathy, Miyoshi Myopathy, LGMDR2, DMAT

Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Study group<br>Patients with a genetically confirmed dysferlinopathy. | |
| Control group<br>Healthy Volunteers | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Сlinical status of patients with dysferlinopathy (MMT score) | Muscle strength will be assessed using MMT and will be expressed in points for each of the muscle groups assessed. | Through study completion at 24 months | 
| Сlinical status of patients with dysferlinopathy ( North Star Assessment for dysferlinopathy) | 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). | Through study completion at 24 months | 
| Сlinical status of patients with dysferlinopathy (Hand Held Dynamometry). | 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. | Through study completion at 24 months | 
| Сlinical status of patients with dysferlinopathy (6-minute walk test) | The participant will be asked to complete maximal distance in 6 minet as quickly as safely possible and the time in seconds is recorded. | Through study completion at 24 months | 
| Clinical blood test (level of hemoglobin) | Level of hemoglobin is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Clinical blood test. Level of hematocrit | Level of hematocrit (%) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Clinical blood test. Level of RBC | Level of RBC is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Clinical blood test. Level of WBC | Level of WBC is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Clinical blood test. Levels of ESR | Levels of ESR (mm/h) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Clinical blood test. Level of platelets | Level of platelets is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. | Levels of potassium (mmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months | 
| Biochemical blood test. Level of sodium | Level of sodium (mmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of calcium | Level of calcium (mmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of creatinine | Level of creatinine (μmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of glucose | Level of glucose (mmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of uric acid | Level of uric acid (μmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of urea | Level of urea (mmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of ALT | Level of ALT (U/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of AST | Level of AST (U/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of total protein | Level of total protein (g/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of CPK | Level of CPK (U/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of triglycerides | Level of triglycerides (mmol/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Biochemical blood test. Level of CRP | Level of CRP (mg/l) is planned to be assessed in patients with dysferlinopathy. | Through study completion at 24 months. | 
| Blood cytokine levels in subjects with dysferlinopathy and healthy volunteers. | 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. | Through study completion at 24 months | 
| Autoantibodies in patients with dysferlinopathy. | Assessment of antibodу level against skeletal muscle antigens; an antinuclear factor (ANA), an extractable nuclear antigen. | Through study completion at 24 months | 
| Muscle MRI in patients with dysferlinopathy. | To characterize muscle involvement based on MRI results; To evaluate the progression of muscle involvement based on repeated MRI once year; | Through study completion at 24 months. | 
| Subpopulation compositions of T-lymphocytes in subjects with dysferlinopathy. | • To characterize changes in subpopulation compositions of T-lymphocytes in %. | Through study completion at 24 months | 
| Subpopulation compositions of B-lymphocytes in subjects with dysferlinopathy. | • To characterize changes in subpopulation compositions of B-lymphocytes in %. | Through study completion at 24 months | 
| Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (NBT test) | • To characterize changes in phagocytic activity of leukocytes (NBT test in CU). | Through study completion at 24 months | 
| Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy. | • To characterize changes in phagocytic activity of leukocytes (a phagocyte number in CU). | Through study completion at 24 months | 
| Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (lysosomal-cation test). | • To characterize changes in phagocytic activity of leukocytes (lysosomal-cation test in CU). | Through study completion at 24 months | 
| Subpopulation compositions of phagocytic activity of leukocytes (a phagocytic index) in subjects with dysferlinopathy. | • To characterize changes in phagocytic activity of leukocytes (a phagocytic index). | Through study completion at 24 months | 
| Gait pattern and balance characteristics in patients with limb-girdle muscular dystrophy R2. | To determine a gait pattern characteristics in patients with limb-girdle muscular dystrophy R2 using electrophysiological techniques (Neurosoft Gait Assessment System STEDIS). | Through study completion at 24 months. | 
| Cardiac function (assessed by Echocardiography). LV | The absolute and relative sizes of the left ventricle (LV) index will be determined. | Through study completion at 24 months. | 
| Cardiac function (assessed by Echocardiography). LV mass | The absolute and relative sizes of the LV mass index will be determined. | Through study completion at 24 months. | 
| Cardiac function (assessed by Echocardiography). Myocardium mass | The absolute and relative sizes of the myocardium mass index will be determined. | Through study completion at 24 months. | 
| Cardiac function (assessed by Echocardiography). RV | The absolute and relative sizes of the right ventricle (RV) index will be determined. | Through study completion at 24 months. | 
| Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of LV mass | Volumetric evaluation of LV mass by manual tracing will be perform. An MRI of the heart will assess fibrosis. | Through study completion at 24 months. | 
| Cardiac function (assessed by Echocardiography). LA | The absolute and relative sizes of the left atrium (LA) index will be determined | Through study completion at 24 months. | 
| Cardiac function (assessed by Electrocardiography). Outcome 13 | To assess rhythm characteristic, P-wave, QRS, T-wave duration; PR, RR, QT intervals; PR, ST segments. | Through study completion at 24 months. | 
| Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of EF | Volumetric evaluation of EF by manual tracing will be performed. | Through study completion at 24 months. | 
| Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). | Volumetric evaluation of volume by manual tracing will be performed. | Through study completion at 24 months. | 
| Morphological muscle study | 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. | Through study completion at 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LGMDR2, Miyoshi Myopathy, Dysferlinopathy, DYSF, DMAT