RARE DISEASE
Dysferlin-related limb-girdle muscular dystrophy R2
Dysferlin-related limb-girdle muscular dystrophy R2
Dysferlin-related limb-girdle muscular dystrophy R2
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2B, Dysferlin-related LGMD R2, LGMD due to dysferlin deficiency, LGMD type 2B, LGMD2B, Limb-girdle muscular dystrophy due to dysferlin deficiency, Limb-girdle muscular dystrophy type 2B
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2B, Dysferlin-related LGMD R2, LGMD due to dysferlin deficiency, LGMD type 2B, LGMD2B, Limb-girdle muscular dystrophy due to dysferlin deficiency, Limb-girdle muscular dystrophy type 2B
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2B, Dysferlin-related LGMD R2, LGMD due to dysferlin deficiency, LGMD type 2B, LGMD2B, Limb-girdle muscular dystrophy due to dysferlin deficiency, Limb-girdle muscular dystrophy type 2B
Drug discovery
1
drug
With orphan designation
Overview
Dysferlin-related limb-girdle muscular dystrophy R2 (LGMDR2) is an autosomal recessive disorder caused by DYSF gene mutations, resulting in dysferlin deficiency. This impairs sarcolemma repair, vesicle fusion, and Ca²⁺ signaling. Clinical features include progressive proximal pelvic/shoulder girdle weakness (onset: 15-30 years), calf atrophy/hypertrophy, elevated CK (50x normal), and preserved cardiac function in most cases. Diagnosis combines genetic testing, muscle MRI/biopsy showing fat infiltration, and immunohistochemical dysferlin deficiency [1][2][6][14].
Burden
Loss of ambulation occurs ~21 years post-onset (typically 40s) [1]; 30% develop restrictive respiratory patterns [4]
Delayed diagnosis common (mimics polymyositis/neuropathies); no disease-modifying therapies approved [1][6]
High psychosocial impact: 58% report reduced quality of life due to disability and care needs [4][8]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
238 drug discovery papers about Dysferlin-related limb-girdle muscular dystrophy R2, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
238 drug discovery papers about Dysferlin-related limb-girdle muscular dystrophy R2, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-14 | PPMO therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.
The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF) gene. Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated limb-girdle muscular dystrophy type 2R or LGMDR2 (formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified in two independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that disrupt protein expression. In this study, we generated and characterized a novel mouse model for one of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaces the normal homologous mouse DNA. These mice exhibit aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this new model, we identified antisense oligonucleotides and then a PPMO that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle histology and function.
2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle
Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.
2026-05-01 | Myoblast-seeded alginate tubes exacerbate dystrophic features in a mouse model of dysferlinopathy
Introduction: Physical therapy (PT) alone is insufficient to restore lost skeletal muscle tissue in individuals with genetic muscle diseases, such as limb-girdle muscular dystrophy type 2B (LGMD2B). However, PT delivered within a regenerative rehabilitation framework -- one that combines cellular therapies with movement-based interventions has the potential to change the status quo in the field. Therefore, we developed a novel muscle regeneration strategy, which could be augmented by targeted, dosage-adjusted progressive resistance training. This study examined if alginate tubes containing myogenic cells could support in vivo muscle regeneration in a mouse model of LGMD2B. Methods: The technology to generate and implant myogenic alginate tubes was first developed and validated through in vitro experimentation. Using this workflow, we produced 21-gauge alginate tubes composed of 10% sodium alginate and healthy donor myogenic cells. Our laboratory has previously developed a technique known as minimally-invasive muscle embedding (MIME), which is effective in generating donor-cell-derived myogenesis in the mouse tibialis anterior (TA) muscle. In this study, we implanted cellularized alginate tubes into the left TA muscle of four female mice from a mouse model of LGMD2B (dysferlin-deficient) using MIME. Histological evaluation was performed 28 days post-implantation. No statistical analyses were performed due to the exploratory nature and small sample size. Results: Cellularized alginate tubes did not dissolve within host muscle even 28 days post-implantation – we had predicted that the alginate tubes would dissolve within a few days. Furthermore, there was no evidence of donor-cell-derived myogenesis. Unexpectedly, we found that MIME-treated muscles exhibited aggravated dystrophic features, including increased fibrosis, lipid deposition, and muscle fiber size heterogeneity, relative to contralateral control limbs. Discussion: The persistence of alginate constructs and absence of donor myogenesis suggest that delivery systems requiring faster degradation or better host-cell integration may be needed. Despite the unexpected outcome, the model revealed a more severe phenotype than typical LGMD2B mice, offering potential utility in future preclinical testing. Conclusions: Engineered myogenic constructs using alginate tubes failed to promote donor-cell-derived regeneration but may enhance modeling of LGMD2B for basic and preclinical studies. Improvements in construct design and additional testing in healthy and dystrophic mice are warranted. Acknowledgments: Supported by NIH R03HD091648, NIH P2CHD086843 (AR3T Pitch Award), NIH R01AR079884 (subcontract), Wayne State Warrior Funder, and the Jain Foundation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-04-09 | Dysferlinopathies: phenotypic study of a Moroccan series of 28 cases.
Dysferlinopathies are a spectrum of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene (DYSF), leading to heterogeneous phenotypes, mainly limb-girdle muscular dystrophy type 2R (LGMDR2) and Miyoshi distal myopathy (MMD1). In Morocco, dysferlinopathies accounted for 18% of all limb-girdle muscular dystrophies, ranking second after sarcoglycanopathies. We retrospectively analyzed 28 confirmed cases, diagnosed either by dysferlin deficiency or DYSF mutation. The median age at examination was 25,5 years (21-33). Twelve patients (43%) were female, and 19 (68%) had consanguineous parents. The proximodistal phenotype was predominant (50%), followed by LGMDR2 (39%) and MMD1 (11%). Selective biceps brachii involvement was observed in 68% of patients. Seven patients (25%) showed hypertrophy of the extensor digitorum brevis muscle, and two (7%) presented with severe genu recurvatum. In addition to dystrophic lesions, muscle biopsy revealed inflammatory infiltrates in 15 cases (58%), leading to an initial misdiagnosis of inflammatory myopathy in two cases. Dysferlin deficiency confirmed the diagnosis in 26 cases, while two others had homozygous DYSF variants. Four patients received corticosteroids, with clear improvement in only one. Overall, disease progression was slow, although two patients lost ambulation at the ages of 26 and 32. Regular physical activity appeared to have a beneficial effect in most patients.
2026-03-23 | DAB2 in LGMD R2: a molecular link between disease progression and lipid dysregulation.
Limb-girdle muscular dystrophy R2 (LGMD R2) is an autosomal recessive disorder caused by dysferlin deficiency, leading to progressive muscle weakness and wasting. The lack of reliable clinical biomarkers has limited disease monitoring and therapeutic evaluation. Here, we identified Disabled-2 (DAB2) as a molecular and clinical indicator of disease state in LGMD R2. Transcriptomic profiling revealed a significant upregulation of DAB2 in induced pluripotent stem cell-derived (iPSC-derived) myotubes from patients, a finding validated in muscle biopsies from 14 dysferlin-deficient individuals and in dysferlin-deficient Bla/J mice, where DAB2 levels increased with disease progression. Importantly, AAV-mediated expression of full-length dysferlin restored DAB2 levels, supporting its value as a dynamic readout of disease activity for both disease monitoring and therapeutic response. Given the established role of DAB2 in clathrin-mediated endocytosis, particularly in LDL receptor internalization and cholesterol homeostasis, and the pathological lipid accumulation reported in LGMD R2, we investigated its contribution to lipid dysregulation. High DAB2 expression paralleled lipid deposition in patient muscles, iPSC-derived myotubes, and mouse tissue, whereas siRNA-mediated DAB2 knockdown reduced lipid accumulation in LGMD R2 myotubes. Collectively, these findings suggest that DAB2 functions as a mechanistic link between dysferlin deficiency, altered lipid handling, and disease severity, and they highlight its potential as a prognostic marker and therapeutic response measure for LGMD R2.
2026-07-14 | PPMO therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.
The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF) gene. Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated limb-girdle muscular dystrophy type 2R or LGMDR2 (formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified in two independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that disrupt protein expression. In this study, we generated and characterized a novel mouse model for one of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaces the normal homologous mouse DNA. These mice exhibit aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this new model, we identified antisense oligonucleotides and then a PPMO that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle histology and function.
2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle
Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.
2026-05-01 | Myoblast-seeded alginate tubes exacerbate dystrophic features in a mouse model of dysferlinopathy
Introduction: Physical therapy (PT) alone is insufficient to restore lost skeletal muscle tissue in individuals with genetic muscle diseases, such as limb-girdle muscular dystrophy type 2B (LGMD2B). However, PT delivered within a regenerative rehabilitation framework -- one that combines cellular therapies with movement-based interventions has the potential to change the status quo in the field. Therefore, we developed a novel muscle regeneration strategy, which could be augmented by targeted, dosage-adjusted progressive resistance training. This study examined if alginate tubes containing myogenic cells could support in vivo muscle regeneration in a mouse model of LGMD2B. Methods: The technology to generate and implant myogenic alginate tubes was first developed and validated through in vitro experimentation. Using this workflow, we produced 21-gauge alginate tubes composed of 10% sodium alginate and healthy donor myogenic cells. Our laboratory has previously developed a technique known as minimally-invasive muscle embedding (MIME), which is effective in generating donor-cell-derived myogenesis in the mouse tibialis anterior (TA) muscle. In this study, we implanted cellularized alginate tubes into the left TA muscle of four female mice from a mouse model of LGMD2B (dysferlin-deficient) using MIME. Histological evaluation was performed 28 days post-implantation. No statistical analyses were performed due to the exploratory nature and small sample size. Results: Cellularized alginate tubes did not dissolve within host muscle even 28 days post-implantation – we had predicted that the alginate tubes would dissolve within a few days. Furthermore, there was no evidence of donor-cell-derived myogenesis. Unexpectedly, we found that MIME-treated muscles exhibited aggravated dystrophic features, including increased fibrosis, lipid deposition, and muscle fiber size heterogeneity, relative to contralateral control limbs. Discussion: The persistence of alginate constructs and absence of donor myogenesis suggest that delivery systems requiring faster degradation or better host-cell integration may be needed. Despite the unexpected outcome, the model revealed a more severe phenotype than typical LGMD2B mice, offering potential utility in future preclinical testing. Conclusions: Engineered myogenic constructs using alginate tubes failed to promote donor-cell-derived regeneration but may enhance modeling of LGMD2B for basic and preclinical studies. Improvements in construct design and additional testing in healthy and dystrophic mice are warranted. Acknowledgments: Supported by NIH R03HD091648, NIH P2CHD086843 (AR3T Pitch Award), NIH R01AR079884 (subcontract), Wayne State Warrior Funder, and the Jain Foundation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-04-09 | Dysferlinopathies: phenotypic study of a Moroccan series of 28 cases.
Dysferlinopathies are a spectrum of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene (DYSF), leading to heterogeneous phenotypes, mainly limb-girdle muscular dystrophy type 2R (LGMDR2) and Miyoshi distal myopathy (MMD1). In Morocco, dysferlinopathies accounted for 18% of all limb-girdle muscular dystrophies, ranking second after sarcoglycanopathies. We retrospectively analyzed 28 confirmed cases, diagnosed either by dysferlin deficiency or DYSF mutation. The median age at examination was 25,5 years (21-33). Twelve patients (43%) were female, and 19 (68%) had consanguineous parents. The proximodistal phenotype was predominant (50%), followed by LGMDR2 (39%) and MMD1 (11%). Selective biceps brachii involvement was observed in 68% of patients. Seven patients (25%) showed hypertrophy of the extensor digitorum brevis muscle, and two (7%) presented with severe genu recurvatum. In addition to dystrophic lesions, muscle biopsy revealed inflammatory infiltrates in 15 cases (58%), leading to an initial misdiagnosis of inflammatory myopathy in two cases. Dysferlin deficiency confirmed the diagnosis in 26 cases, while two others had homozygous DYSF variants. Four patients received corticosteroids, with clear improvement in only one. Overall, disease progression was slow, although two patients lost ambulation at the ages of 26 and 32. Regular physical activity appeared to have a beneficial effect in most patients.
2026-03-23 | DAB2 in LGMD R2: a molecular link between disease progression and lipid dysregulation.
Limb-girdle muscular dystrophy R2 (LGMD R2) is an autosomal recessive disorder caused by dysferlin deficiency, leading to progressive muscle weakness and wasting. The lack of reliable clinical biomarkers has limited disease monitoring and therapeutic evaluation. Here, we identified Disabled-2 (DAB2) as a molecular and clinical indicator of disease state in LGMD R2. Transcriptomic profiling revealed a significant upregulation of DAB2 in induced pluripotent stem cell-derived (iPSC-derived) myotubes from patients, a finding validated in muscle biopsies from 14 dysferlin-deficient individuals and in dysferlin-deficient Bla/J mice, where DAB2 levels increased with disease progression. Importantly, AAV-mediated expression of full-length dysferlin restored DAB2 levels, supporting its value as a dynamic readout of disease activity for both disease monitoring and therapeutic response. Given the established role of DAB2 in clathrin-mediated endocytosis, particularly in LDL receptor internalization and cholesterol homeostasis, and the pathological lipid accumulation reported in LGMD R2, we investigated its contribution to lipid dysregulation. High DAB2 expression paralleled lipid deposition in patient muscles, iPSC-derived myotubes, and mouse tissue, whereas siRNA-mediated DAB2 knockdown reduced lipid accumulation in LGMD R2 myotubes. Collectively, these findings suggest that DAB2 functions as a mechanistic link between dysferlin deficiency, altered lipid handling, and disease severity, and they highlight its potential as a prognostic marker and therapeutic response measure for LGMD R2.
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Drug Discovery Landscape
1 orphan drug designation for Dysferlin-related limb-girdle muscular dystrophy R2.
1 orphan drug designation for Dysferlin-related limb-girdle muscular dystrophy R2.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant adeno-associated virus serotype rhesus 74 expressing the human dysferin gene (AAVrh74.MHCK7.DYSF.DV) | gene therapies | FDA | 2016-09-19 | — | Sarepta Therapeutics |
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