Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy (LGMD R2) in the RF (DYSF-RUS)

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: 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 Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 119333
    • Human Stem Cells Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• 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.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Artgen Biotech
• Collaborators: Genotarget
• Investigators: Study Chair: Roman Deev, PhD, HSCI, Russia

Publications and helpful links

General Publications

• Bardakov SN, Deev RV, Tsargush VA, Kaimonov VS, Musatova EV, Blagodatskikh KA, Tveleneva AA, Sofronova YV, Suslov VM, Carlier PG, Kurbatov SA, Yakovlev IA, Umakhanova ZR, Isaev AA. Asymptomatic and oligosymptomatic states of dysferlinopathy. J Neuromuscul Dis. 2024 Nov;11(6):1283-1294. doi: 10.1177/22143602241289227. Epub 2024 Dec 8.
• Bardakov SN, Deev RV, Isaev capital A, Cyrilliccapital A, Cyrillic, Khromov-Borisov NN, Kopylov ED, Savchuk capital EM, CyrillicR, Pushkin MS, Presnyakov EV, Magomedova RM, Achmedova PG, Umakhanova ZR, Kaimonov VS, Musatova EV, Blagodatskikh Kcapital A, Cyrillic, Tveleneva Acapital A, Cyrillic, Sofronova YV, Yakovlev IA. Genetic screening of an endemic mutation in the DYSF gene in an isolated, mountainous population in the Republic of Dagestan. Mol Genet Genomic Med. 2023 Oct;11(10):e2236. doi: 10.1002/mgg3.2236. Epub 2023 Aug 8.
• Umakhanova ZR, Bardakov SN, Mavlikeev MO, Chernova ON, Magomedova RM, Akhmedova PG, Yakovlev IA, Dalgatov GD, Fedotov VP, Isaev AA, Deev RV. Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan. Front Neurol. 2017 Mar 8;8:77. doi: 10.3389/fneur.2017.00077. eCollection 2017.
• Bardakov SN, Titova AA, Nikitin SS, Nikitins V, Sokolova MO, Tsargush VA, Yuhno EA, Vetrovoj OV, Carlier PG, Sofronova YV, Isaev capital A, Cyrilliccapital A, Cyrillic, Deev RV. Miyoshi myopathy associated with spine rigidity and multiple contractures: a case report. BMC Musculoskelet Disord. 2024 Feb 16;25(1):146. doi: 10.1186/s12891-024-07270-y.
• Bardakov SN, Tsargush VA, Carlier PG, Nikitin SS, Kurbatov SA, Titova AA, Umakhanova ZR, Akhmedova PG, Magomedova RM, Zheleznyak IS, Emelyantsev AA, Berezhnaya EN, A Yakovlev I, Isaev AA, Deev RV. Magnetic resonance imaging pattern variability in dysferlinopathy. Acta Myol. 2021 Dec 31;40(4):158-171. doi: 10.36185/2532-1900-059. eCollection 2021 Dec.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2020
• Primary Completion (Estimated): February 25, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: February 16, 2021
• First Submitted That Met QC Criteria: March 26, 2021
• First Posted (Actual): April 1, 2021

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 24, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Miyoshi Myopathy; Dysferlinopathy; DYSF; LGMDR2; DMAT
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Diseases; Muscular Dystrophies, Limb-Girdle
• Other Study ID Numbers: DYSF-Observation (RUS)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No