Autosomal Recessive Limb-Girdle Muscular Dystrophy

Mendelian MONDO:0015152 Pathograph 6 Show in embeddings browser Limb-Girdle Muscular Dystrophy Muscular Dystrophy Neuromuscular Disease

Autosomal recessive limb-girdle muscular dystrophy (LGMD-R, historically LGMD type 2) is a genetically heterogeneous group of progressive muscular dystrophies that preferentially affect the proximal limb-girdle musculature (the pelvic and shoulder girdle). It is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in genes encoding sarcolemmal repair proteins (DYSF), enzymes (CAPN3, ANO5), components of the dystrophin-glycoprotein complex (the sarcoglycans SGCA/SGCB/SGCG/SGCD), and enzymes that glycosylate alpha-dystroglycan (FKRP and other dystroglycanopathy genes). Under the 2017 European Neuromuscular Centre nomenclature, autosomal recessive forms are designated LGMD R with at least 26 recognized subtypes, and account for roughly 80-90% of all LGMD. The shared mechanism is myofiber membrane (sarcolemmal) fragility and failed repair leading to repeated myofiber degeneration, chronic inflammation, fibrofatty replacement, and progressive proximal weakness with markedly elevated serum creatine kinase; some subtypes additionally involve cardiac and respiratory muscle.

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1
Inheritance
3
Pathophys.
10
Phenotypes
6
Pathograph
8
Genes
6
Medical Actions
8
Subtypes
1
Trials
2
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
All LGMD-R subtypes are inherited in an autosomal recessive manner; affected individuals carry biallelic pathogenic variants and each sib of an affected individual has a 25% recurrence risk.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301480 SUPPORT Human Clinical
"Dysferlinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DYSF pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being..."
The Dysferlinopathy GeneReviews documents the autosomal recessive inheritance and 25% recurrence risk that is shared across LGMD-R subtypes.
◆

Subtypes

8
LGMD R1 (calpainopathy, LGMD2A; CAPN3)
CAPN3 hgnc:1480
Calpainopathy, caused by biallelic CAPN3 variants. The most common LGMD-R subtype in many cohorts (~30-40% of LGMD). Characterized by symmetric progressive proximal weakness, scapular winging, tiptoe walking, Achilles tendon shortening, and scoliosis, typically without cardiac involvement.
LGMD R2 (dysferlinopathy, LGMD2B; DYSF)
DYSF hgnc:3097
Dysferlinopathy, caused by biallelic DYSF variants encoding the membrane-repair protein dysferlin. Onset usually in the late teens to thirties, with very high serum CK (50-200x normal) and a phenotypic spectrum that also includes Miyoshi distal myopathy. Cardiac involvement is rare.
LGMD R3 (alpha-sarcoglycanopathy, LGMD2D; SGCA)
SGCA hgnc:10805
Alpha-sarcoglycanopathy, caused by biallelic SGCA variants. Usually childhood onset with proximal weakness, calf hypertrophy, and risk of cardiomyopathy.
LGMD R4 (beta-sarcoglycanopathy, LGMD2E; SGCB)
SGCB hgnc:10806
Beta-sarcoglycanopathy, caused by biallelic SGCB variants. Often a severe childhood-onset sarcoglycanopathy with cardiac and respiratory involvement.
LGMD R5 (gamma-sarcoglycanopathy, LGMD2C; SGCG)
SGCG hgnc:10809
Gamma-sarcoglycanopathy, caused by biallelic SGCG variants. Variable severity including a severe childhood form with early loss of ambulation, calf hypertrophy, and high CK.
LGMD R6 (delta-sarcoglycanopathy, LGMD2F; SGCD)
SGCD hgnc:10807
Delta-sarcoglycanopathy, caused by biallelic SGCD variants. A typically severe childhood-to-adolescence sarcoglycanopathy with risk of cardiomyopathy and respiratory complications.
LGMD R9 (FKRP-related dystroglycanopathy, LGMD2I; FKRP)
FKRP hgnc:17997
FKRP-related dystroglycanopathy, caused by biallelic FKRP variants that impair glycosylation of alpha-dystroglycan. Variable onset; the common founder variant c.826C>A is associated with a later median loss of ambulation; respiratory decline and cardiomyopathy may occur.
LGMD R12 (anoctaminopathy, LGMD2L; ANO5)
ANO5 hgnc:27337
Anoctaminopathy, caused by biallelic ANO5 variants. Typically adult-onset proximal weakness, sometimes asymmetric or with a mixed proximal/distal pattern, with elevated CK and slower progression than the childhood sarcoglycanopathies.
⚙

Pathophysiology

3
Sarcolemmal Instability and Failed Membrane Repair
Across LGMD-R subtypes the proximate defect destabilizes the myofiber plasma membrane (sarcolemma). Sarcoglycanopathies (SGCA-D) and dystroglycanopathies (FKRP) disrupt the dystrophin-glycoprotein complex that links the cytoskeleton to the extracellular matrix, while dysferlin (DYSF) deficiency impairs calcium-triggered resealing of membrane microtears. The result is a fragile sarcolemma that cannot withstand or repair contraction-induced injury.
skeletal muscle fiber CL:0008002
plasma membrane repair GO:0001778 ↓ DECREASED
Downstream
Myofiber Degeneration and Necrosis A fragile, poorly repaired sarcolemma cannot withstand contraction-induced stress, leading to repeated myofiber injury and necrosis.
Show evidence (2 references)
PMID:40422224 SUPPORT Human Clinical
"A specific subgroup of muscular dystrophies is associated with genetic defects in components of the dystrophin-glycoprotein complex (DGC), which plays a crucial role in linking the cytosol to the skeletal muscle basement membrane. In these cases, dystrophin-associated proteins fail to correctly..."
Establishes that DGC defects (e.g., sarcoglycanopathies, dystroglycanopathies) destabilize the sarcolemma, the shared upstream lesion in this node.
PMID:38540676 SUPPORT Human Clinical
"They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes."
Establishes that dysferlin deficiency impairs membrane repair, the complementary mechanism of sarcolemmal instability in LGMDR2.
Myofiber Degeneration and Necrosis
Sarcolemmal instability permits pathological calcium influx and uncontrolled activation of degradative pathways (calpain proteolysis, the ubiquitin-proteasome system, and dysregulated autophagy), driving cycles of myofiber degeneration, necrosis, and regeneration. Centralized nuclei, necrotic fibers, and inflammatory cytokine release are characteristic histological features.
skeletal muscle fiber CL:0008002
muscle cell apoptotic process GO:0010657 ↑ INCREASED calcium ion transport GO:0006816 ⚠ ABNORMAL autophagy GO:0006914 ⚠ ABNORMAL
Downstream
Chronic Inflammation and Fibrofatty Replacement Repeated necrosis releases inflammatory cytokines and eventually exhausts regenerative capacity, leading to chronic inflammation and replacement of muscle with fibrotic and fatty tissue.
Show evidence (1 reference)
PMID:40422224 SUPPORT Human Clinical
"These are characterized by the centralization of skeletal muscle syncytial nuclei, the replacement of muscle fibers with fibrotic tissue, the release of inflammatory cytokines, and the disruption of muscle protein homeostasis, ultimately leading to necrosis and loss of muscle functionality."
Documents myofiber necrosis, disrupted protein homeostasis, and inflammatory cytokine release downstream of sarcolemmal destabilization.
Chronic Inflammation and Fibrofatty Replacement
Sustained injury drives chronic inflammation (with impaired macrophage M1-to-M2 switching) and progressive replacement of contractile muscle by fibrotic and adipose tissue, which is detectable as subtype-specific fatty infiltration patterns on muscle MRI and as fibrosis on biopsy. This is the structural substrate of permanent weakness.
macrophage CL:0000235 fibroblast CL:0000057
inflammatory response GO:0006954 ↑ INCREASED tissue remodeling GO:0048771 ⚠ ABNORMAL
Downstream
Progressive proximal muscle weakness Loss of functional contractile muscle and its replacement by fibrofatty tissue manifests clinically as progressive proximal limb-girdle weakness.
Elevated serum creatine kinase Ongoing myofiber membrane breakdown and necrosis releases intracellular creatine kinase into the circulation, producing markedly elevated serum CK.
Calf muscle hypertrophy In the sarcoglycanopathies, fibrofatty replacement and reactive enlargement of the calf musculature produce calf (pseudo)hypertrophy, a characteristic sign.
Show evidence (1 reference)
PMID:37974208 SUPPORT Human Clinical
"Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B."
Documents fibrofatty (fatty infiltration) replacement of muscle, with subtype-specific MRI patterns, as a downstream consequence of repeated degeneration.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Limb-Girdle Muscular Dystrophy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Cardiovascular 1
Cardiomyopathy Cardiomyopathy HP:0001638
Show evidence (1 reference)
PMID:37974208 SUPPORT Human Clinical
"A total of 22.0% of the patients had cardiac abnormalities"
The Chinese LGMD cohort quantifies cardiac involvement, which is concentrated in the sarcoglycanopathy and dystroglycanopathy subtypes.
Metabolism 1
Elevated serum creatine kinase Elevated circulating creatine kinase concentration HP:0003236
Show evidence (1 reference)
PMID:20301480 SUPPORT Human Clinical
"Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only."
The Dysferlinopathy GeneReviews documents marked serum CK elevation, a feature shared across LGMD-R subtypes.
Musculoskeletal 4
Skeletal muscle atrophy Skeletal muscle atrophy HP:0003202
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:40364688 SUPPORT Human Clinical
"Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of muscle disorders characterized by progressive muscle atrophy and loss of motor function."
Identifies progressive muscle atrophy as a defining feature of LGMD.
Scoliosis Scoliosis HP:0002650
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis."
The Calpainopathy GeneReviews lists scoliosis among the clinical findings.
Flexion contracture Flexion contracture HP:0001371
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis."
The Calpainopathy GeneReviews documents Achilles tendon shortening (a contracture) among the clinical findings.
Respiratory insufficiency due to muscle weakness Respiratory insufficiency due to muscle weakness HP:0002747
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37974208 SUPPORT Human Clinical
"A total of 15.4% of the patients had restrictive respiratory insufficiency."
The Chinese LGMD cohort documents restrictive respiratory insufficiency from respiratory muscle weakness.
Nervous System 1
Waddling gait Waddling gait HP:0002515
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis."
The Calpainopathy GeneReviews lists waddling gait among the clinical findings.
Other 3
Progressive proximal muscle weakness Limb-girdle muscle weakness HP:0003325
Course: PROGRESSIVE
Show evidence (2 references)
PMID:37974208 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis."
Establishes limb-girdle (proximal) muscle weakness as the defining clinical feature.
PMID:20301490 SUPPORT Human Clinical
"Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles."
The Calpainopathy GeneReviews confirms the symmetric, progressive proximal pattern in the most common subtype.
Scapular winging Scapular winging HP:0003691
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis."
The Calpainopathy GeneReviews lists scapular winging among the clinical findings.
Calf muscle hypertrophy Calf muscle hypertrophy HP:0008981
Show evidence (1 reference)
PMID:39174842 SUPPORT Human Clinical
"progressive weakness of pelvic and/or scapular girdle muscles and calf hypertrophy, with a wide range of clinical inter- and intra-familial clinical variability."
Documents calf hypertrophy as a presenting feature of alpha-sarcoglycanopathy (LGMD R3), representative of the sarcoglycanopathy subtypes.
🧬

Genetic Associations

8
CAPN3 (calpainopathy / LGMDR1)
Gene: CAPN3 hgnc:1480
Show evidence (1 reference)
PMID:38045992 SUPPORT Human Clinical
"The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
The US MD STARnet population-based surveillance study identifies CAPN3 among the most common genes associated with LGMD.
DYSF (dysferlinopathy / LGMDR2)
Gene: DYSF hgnc:3097
Show evidence (1 reference)
PMID:38540676 SUPPORT Human Clinical
"They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes."
Identifies DYSF/dysferlin as the cause of dysferlinopathy and its membrane-repair role.
SGCA (alpha-sarcoglycanopathy / LGMDR3)
Gene: SGCA hgnc:10805
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including the sarcoglycanopathies, arise from mutations in multiple distinct genes.
SGCB (beta-sarcoglycanopathy / LGMDR4)
Gene: SGCB hgnc:10806
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including beta-sarcoglycanopathy, arise from mutations in multiple distinct genes.
SGCG (gamma-sarcoglycanopathy / LGMDR5)
Gene: SGCG hgnc:10809
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including gamma-sarcoglycanopathy, arise from mutations in multiple distinct genes.
SGCD (delta-sarcoglycanopathy / LGMDR6)
Gene: SGCD hgnc:10807
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including delta-sarcoglycanopathy, arise from mutations in multiple distinct genes.
FKRP (FKRP-related dystroglycanopathy / LGMDR9)
Gene: FKRP hgnc:17997
Show evidence (1 reference)
PMID:38045992 SUPPORT Human Clinical
"The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
FKRP is the most common LGMD-associated gene in the US MD STARnet surveillance cohort.
ANO5 (anoctaminopathy / LGMDR12)
Gene: ANO5 hgnc:27337
Show evidence (1 reference)
PMID:38045992 SUPPORT Human Clinical
"The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
ANO5 is among the most common LGMD-associated genes in the US MD STARnet cohort.
💊

Medical Actions

6
Physical therapy and rehabilitation
Action: physical therapy MAXO:0000011
No curative therapy is approved; management is supportive. Physical therapy and stretching promote mobility and prevent contractures, with mobility aids as needed.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Physical therapy and stretching exercises to promote mobility and prevent contractures; supervised strengthening and gentle low-impact aerobic exercise"
The Calpainopathy GeneReviews recommends physical therapy and stretching as mainstay supportive management.
Noninvasive ventilation
Action: noninvasive ventilation MAXO:0000506
Nocturnal and chronic noninvasive ventilatory support is used as respiratory muscle weakness progresses to respiratory insufficiency.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"nocturnal ventilator assistance as needed; respiratory aids to treat chronic respiratory insufficiency in late stages of the disease"
The Calpainopathy GeneReviews recommends ventilatory support for respiratory insufficiency in advanced disease.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is essential for carrier identification, recurrence-risk assessment, and reproductive planning given autosomal recessive inheritance.
Show evidence (1 reference)
PMID:20301480 SUPPORT Human Clinical
"Once the DYSF pathogenic variants have been identified in an affected family member, carrier testing for at-risk"
The Dysferlinopathy GeneReviews describes carrier testing and genetic counseling following identification of family pathogenic variants.
AAV gene replacement therapy (investigational)
Action: gene therapy MAXO:0001001
Adeno-associated virus (AAV) gene replacement therapies are in clinical development for the sarcoglycanopathies, including bidridistrogene xeboparvovec (SRP-9003) for beta-sarcoglycanopathy/LGMDR4, which has progressed to a Phase 3 trial.
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"In the last decade, multiple other potential treatments were developed and studied, such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene editing."
The classification/therapy review documents gene delivery (gene replacement) among the molecular therapies in development for LGMD.
Cardiac management for LGMD-associated cardiomyopathy
Action: Pharmacotherapy NCIT:C15986
Agent: ACE inhibitor NCIT:C247 beta-blocker NCIT:C29576
Cardiac surveillance and standard heart-failure pharmacotherapy are indicated in the subtypes with cardiac involvement (sarcoglycanopathies LGMDR3-R6 and FKRP-related LGMDR9). Guideline-directed medical therapy for dilated cardiomyopathy uses angiotensin-converting-enzyme (ACE) inhibitors and beta-adrenergic antagonists (beta-blockers) to reduce afterload and neurohormonal activation.
Show evidence (1 reference)
PMID:20301582 SUPPORT Human Clinical
"monitoring for cardiomyopathy in LGMD types with cardiac involvement"
The Limb-Girdle Muscular Dystrophy Overview GeneReviews recommends monitoring for cardiomyopathy in the LGMD subtypes with cardiac involvement, which underpins the ACE-inhibitor/beta-blocker heart-failure management standard of care.
Agents and circumstances to avoid
Action: avoidance of myotoxic and anesthetic triggers Ontology label: supportive care MAXO:0000950
Because of a malignant-hyperthermia-like anesthetic risk and drug-induced myotoxicity, succinylcholine and halogenated (volatile) anesthetic agents should be avoided when possible, and cholesterol-lowering statins should be avoided when possible in calpainopathy and related LGMD-R subtypes.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Avoid succinylcholine and halogenated anesthetic agents when possible; avoid cholesterol-lowering agents (e.g., statins) when possible."
The Calpainopathy GeneReviews lists succinylcholine, halogenated anesthetics, and statins among the agents/circumstances to avoid.
🔬

Clinical Trials

1
NCT06246513 PHASE_III ACTIVE_NOT_RECRUITING
A Phase 3 multinational, open-label systemic gene-delivery study evaluating the safety and efficacy of a single systemic dose of SRP-9003 (bidridistrogene xeboparvovec), an AAVrh74 beta-sarcoglycan gene-transfer therapy, in ambulatory and non-ambulatory participants with beta-sarcoglycanopathy (LGMD2E/R4).
Target Phenotypes: Limb-girdle muscle weakness HP:0003325
Show evidence (1 reference)
clinicaltrials:NCT06246513 SUPPORT
"This is a multicenter, global study of the effects of a single systemic dose of SRP-9003 on beta-sarcoglycan (β-SG) gene expression in participants with limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4)."
The trial summary confirms SRP-9003 is a systemic beta-sarcoglycan gene therapy in Phase 3 development for LGMD2E/R4 (beta-sarcoglycanopathy).
{ }

Source YAML

click to show 
name: Autosomal Recessive Limb-Girdle Muscular Dystrophy
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
synonyms:
- LGMD type 2
- LGMD-R
- autosomal recessive limb-girdle muscular dystrophy
- limb-girdle muscular dystrophy, autosomal recessive
description: >-
  Autosomal recessive limb-girdle muscular dystrophy (LGMD-R, historically LGMD type 2)
  is a genetically heterogeneous group of progressive muscular dystrophies that
  preferentially affect the proximal limb-girdle musculature (the pelvic and shoulder
  girdle). It is caused by biallelic (homozygous or compound heterozygous) loss-of-function
  variants in genes encoding sarcolemmal repair proteins (DYSF), enzymes (CAPN3, ANO5),
  components of the dystrophin-glycoprotein complex (the sarcoglycans SGCA/SGCB/SGCG/SGCD),
  and enzymes that glycosylate alpha-dystroglycan (FKRP and other dystroglycanopathy genes).
  Under the 2017 European Neuromuscular Centre nomenclature, autosomal recessive forms are
  designated LGMD R with at least 26 recognized subtypes, and account for roughly 80-90%
  of all LGMD. The shared mechanism is myofiber membrane (sarcolemmal) fragility and failed
  repair leading to repeated myofiber degeneration, chronic inflammation, fibrofatty
  replacement, and progressive proximal weakness with markedly elevated serum creatine
  kinase; some subtypes additionally involve cardiac and respiratory muscle.
disease_term:
  preferred_term: autosomal recessive limb-girdle muscular dystrophy
  term:
    id: MONDO:0015152
    label: autosomal recessive limb-girdle muscular dystrophy
parents:
- Limb-Girdle Muscular Dystrophy
- Muscular Dystrophy
- Neuromuscular Disease
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All LGMD-R subtypes are inherited in an autosomal recessive manner; affected
    individuals carry biallelic pathogenic variants and each sib of an affected
    individual has a 25% recurrence risk.
  evidence:
  - reference: PMID:20301480
    reference_title: "Dysferlinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysferlinopathy is inherited in an autosomal recessive manner. If both parents
      are known to be heterozygous for a DYSF pathogenic variant, each sib of an
      affected individual has at conception a 25% chance of being affected, a 50%
      chance of being an asymptomatic carrier, and a 25% chance of being unaffected
      and not a carrier.
    explanation: >-
      The Dysferlinopathy GeneReviews documents the autosomal recessive inheritance
      and 25% recurrence risk that is shared across LGMD-R subtypes.

references:
- reference: PMID:20301490
  title: "Calpainopathy."
  tags:
  - GeneReviews
- reference: PMID:20301480
  title: "Dysferlinopathy."
  tags:
  - GeneReviews

has_subtypes:
- name: LGMDR1
  display_name: LGMD R1 (calpainopathy, LGMD2A; CAPN3)
  description: >-
    Calpainopathy, caused by biallelic CAPN3 variants. The most common LGMD-R subtype
    in many cohorts (~30-40% of LGMD). Characterized by symmetric progressive proximal
    weakness, scapular winging, tiptoe walking, Achilles tendon shortening, and scoliosis,
    typically without cardiac involvement.
  genes:
  - preferred_term: CAPN3
    term:
      id: hgnc:1480
      label: CAPN3
- name: LGMDR2
  display_name: LGMD R2 (dysferlinopathy, LGMD2B; DYSF)
  description: >-
    Dysferlinopathy, caused by biallelic DYSF variants encoding the membrane-repair
    protein dysferlin. Onset usually in the late teens to thirties, with very high
    serum CK (50-200x normal) and a phenotypic spectrum that also includes Miyoshi
    distal myopathy. Cardiac involvement is rare.
  genes:
  - preferred_term: DYSF
    term:
      id: hgnc:3097
      label: DYSF
- name: LGMDR3
  display_name: LGMD R3 (alpha-sarcoglycanopathy, LGMD2D; SGCA)
  description: >-
    Alpha-sarcoglycanopathy, caused by biallelic SGCA variants. Usually childhood
    onset with proximal weakness, calf hypertrophy, and risk of cardiomyopathy.
  genes:
  - preferred_term: SGCA
    term:
      id: hgnc:10805
      label: SGCA
- name: LGMDR4
  display_name: LGMD R4 (beta-sarcoglycanopathy, LGMD2E; SGCB)
  description: >-
    Beta-sarcoglycanopathy, caused by biallelic SGCB variants. Often a severe
    childhood-onset sarcoglycanopathy with cardiac and respiratory involvement.
  genes:
  - preferred_term: SGCB
    term:
      id: hgnc:10806
      label: SGCB
- name: LGMDR5
  display_name: LGMD R5 (gamma-sarcoglycanopathy, LGMD2C; SGCG)
  description: >-
    Gamma-sarcoglycanopathy, caused by biallelic SGCG variants. Variable severity
    including a severe childhood form with early loss of ambulation, calf hypertrophy,
    and high CK.
  genes:
  - preferred_term: SGCG
    term:
      id: hgnc:10809
      label: SGCG
- name: LGMDR6
  display_name: LGMD R6 (delta-sarcoglycanopathy, LGMD2F; SGCD)
  description: >-
    Delta-sarcoglycanopathy, caused by biallelic SGCD variants. A typically severe
    childhood-to-adolescence sarcoglycanopathy with risk of cardiomyopathy and
    respiratory complications.
  genes:
  - preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
- name: LGMDR9
  display_name: LGMD R9 (FKRP-related dystroglycanopathy, LGMD2I; FKRP)
  description: >-
    FKRP-related dystroglycanopathy, caused by biallelic FKRP variants that impair
    glycosylation of alpha-dystroglycan. Variable onset; the common founder variant
    c.826C>A is associated with a later median loss of ambulation; respiratory decline
    and cardiomyopathy may occur.
  genes:
  - preferred_term: FKRP
    term:
      id: hgnc:17997
      label: FKRP
- name: LGMDR12
  display_name: LGMD R12 (anoctaminopathy, LGMD2L; ANO5)
  description: >-
    Anoctaminopathy, caused by biallelic ANO5 variants. Typically adult-onset proximal
    weakness, sometimes asymmetric or with a mixed proximal/distal pattern, with
    elevated CK and slower progression than the childhood sarcoglycanopathies.
  genes:
  - preferred_term: ANO5
    term:
      id: hgnc:27337
      label: ANO5

genetic:
- name: CAPN3 (calpainopathy / LGMDR1)
  subtype: LGMDR1
  notes: >-
    Biallelic pathogenic variants in CAPN3 (calpain-3, a muscle-specific calcium-activated
    protease) cause calpainopathy/LGMDR1, the most common LGMD-R subtype.
  gene_term:
    preferred_term: CAPN3
    term:
      id: hgnc:1480
      label: CAPN3
  evidence:
  - reference: PMID:38045992
    reference_title: "Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
    explanation: >-
      The US MD STARnet population-based surveillance study identifies CAPN3 among the
      most common genes associated with LGMD.
- name: DYSF (dysferlinopathy / LGMDR2)
  subtype: LGMDR2
  notes: >-
    Biallelic pathogenic variants in DYSF (dysferlin, a sarcolemmal membrane-repair
    protein) cause dysferlinopathy/LGMDR2.
  gene_term:
    preferred_term: DYSF
    term:
      id: hgnc:3097
      label: DYSF
  evidence:
  - reference: PMID:38540676
    reference_title: "The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are caused by mutations in the DYSF gene, which encodes the dysferlin protein
      that is crucial for repairing muscle membranes.
    explanation: >-
      Identifies DYSF/dysferlin as the cause of dysferlinopathy and its membrane-repair role.
- name: SGCA (alpha-sarcoglycanopathy / LGMDR3)
  subtype: LGMDR3
  notes: >-
    Biallelic pathogenic variants in the sarcoglycan genes (SGCA, SGCB, SGCG, SGCD)
    destabilize the sarcoglycan subcomplex of the dystrophin-glycoprotein complex,
    causing the sarcoglycanopathies (LGMDR3-R6).
  gene_term:
    preferred_term: SGCA
    term:
      id: hgnc:10805
      label: SGCA
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including the sarcoglycanopathies,
      arise from mutations in multiple distinct genes.
- name: SGCB (beta-sarcoglycanopathy / LGMDR4)
  subtype: LGMDR4
  notes: >-
    Biallelic pathogenic variants in SGCB (beta-sarcoglycan) destabilize the sarcoglycan
    subcomplex of the dystrophin-glycoprotein complex, causing beta-sarcoglycanopathy
    (LGMDR4), often a severe childhood-onset form with cardiac and respiratory involvement.
  gene_term:
    preferred_term: SGCB
    term:
      id: hgnc:10806
      label: SGCB
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including beta-sarcoglycanopathy,
      arise from mutations in multiple distinct genes.
- name: SGCG (gamma-sarcoglycanopathy / LGMDR5)
  subtype: LGMDR5
  notes: >-
    Biallelic pathogenic variants in SGCG (gamma-sarcoglycan) destabilize the sarcoglycan
    subcomplex of the dystrophin-glycoprotein complex, causing gamma-sarcoglycanopathy
    (LGMDR5), which includes a severe childhood form with early loss of ambulation.
  gene_term:
    preferred_term: SGCG
    term:
      id: hgnc:10809
      label: SGCG
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including gamma-sarcoglycanopathy,
      arise from mutations in multiple distinct genes.
- name: SGCD (delta-sarcoglycanopathy / LGMDR6)
  subtype: LGMDR6
  notes: >-
    Biallelic pathogenic variants in SGCD (delta-sarcoglycan) destabilize the sarcoglycan
    subcomplex of the dystrophin-glycoprotein complex, causing delta-sarcoglycanopathy
    (LGMDR6), a typically severe childhood-to-adolescence form with risk of cardiomyopathy.
  gene_term:
    preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including delta-sarcoglycanopathy,
      arise from mutations in multiple distinct genes.
- name: FKRP (FKRP-related dystroglycanopathy / LGMDR9)
  subtype: LGMDR9
  notes: >-
    Biallelic pathogenic variants in FKRP (fukutin-related protein) impair glycosylation
    of alpha-dystroglycan, causing the dystroglycanopathy LGMDR9; the c.826C>A founder
    variant is common in European populations.
  gene_term:
    preferred_term: FKRP
    term:
      id: hgnc:17997
      label: FKRP
  evidence:
  - reference: PMID:38045992
    reference_title: "Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
    explanation: >-
      FKRP is the most common LGMD-associated gene in the US MD STARnet surveillance cohort.
- name: ANO5 (anoctaminopathy / LGMDR12)
  subtype: LGMDR12
  notes: >-
    Biallelic pathogenic variants in ANO5 (anoctamin-5) cause the typically adult-onset
    anoctaminopathy LGMDR12.
  gene_term:
    preferred_term: ANO5
    term:
      id: hgnc:27337
      label: ANO5
  evidence:
  - reference: PMID:38045992
    reference_title: "Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
    explanation: >-
      ANO5 is among the most common LGMD-associated genes in the US MD STARnet cohort.

pathophysiology:
- name: Sarcolemmal Instability and Failed Membrane Repair
  description: >-
    Across LGMD-R subtypes the proximate defect destabilizes the myofiber plasma
    membrane (sarcolemma). Sarcoglycanopathies (SGCA-D) and dystroglycanopathies
    (FKRP) disrupt the dystrophin-glycoprotein complex that links the cytoskeleton
    to the extracellular matrix, while dysferlin (DYSF) deficiency impairs
    calcium-triggered resealing of membrane microtears. The result is a fragile
    sarcolemma that cannot withstand or repair contraction-induced injury.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: plasma membrane repair
    term:
      id: GO:0001778
      label: plasma membrane repair
    modifier: DECREASED
  evidence:
  - reference: PMID:40422224
    reference_title: "Misregulation of the Ubiquitin-Proteasome System and Autophagy in Muscular Dystrophies Associated with the Dystrophin-Glycoprotein Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A specific subgroup of muscular dystrophies is associated with genetic defects in
      components of the dystrophin-glycoprotein complex (DGC), which plays a crucial role
      in linking the cytosol to the skeletal muscle basement membrane. In these cases,
      dystrophin-associated proteins fail to correctly localize to the sarcolemma
    explanation: >-
      Establishes that DGC defects (e.g., sarcoglycanopathies, dystroglycanopathies)
      destabilize the sarcolemma, the shared upstream lesion in this node.
  - reference: PMID:38540676
    reference_title: "The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are caused by mutations in the DYSF gene, which encodes the dysferlin protein
      that is crucial for repairing muscle membranes.
    explanation: >-
      Establishes that dysferlin deficiency impairs membrane repair, the complementary
      mechanism of sarcolemmal instability in LGMDR2.
  downstream:
  - target: Myofiber Degeneration and Necrosis
    description: >-
      A fragile, poorly repaired sarcolemma cannot withstand contraction-induced stress,
      leading to repeated myofiber injury and necrosis.
    causal_link_type: DIRECT
- name: Myofiber Degeneration and Necrosis
  description: >-
    Sarcolemmal instability permits pathological calcium influx and uncontrolled
    activation of degradative pathways (calpain proteolysis, the ubiquitin-proteasome
    system, and dysregulated autophagy), driving cycles of myofiber degeneration,
    necrosis, and regeneration. Centralized nuclei, necrotic fibers, and inflammatory
    cytokine release are characteristic histological features.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: muscle cell apoptotic process
    term:
      id: GO:0010657
      label: muscle cell apoptotic process
    modifier: INCREASED
  - preferred_term: calcium ion transport
    term:
      id: GO:0006816
      label: calcium ion transport
    modifier: ABNORMAL
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40422224
    reference_title: "Misregulation of the Ubiquitin-Proteasome System and Autophagy in Muscular Dystrophies Associated with the Dystrophin-Glycoprotein Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These are characterized by the centralization of skeletal muscle syncytial nuclei,
      the replacement of muscle fibers with fibrotic tissue, the release of inflammatory
      cytokines, and the disruption of muscle protein homeostasis, ultimately leading to
      necrosis and loss of muscle functionality.
    explanation: >-
      Documents myofiber necrosis, disrupted protein homeostasis, and inflammatory
      cytokine release downstream of sarcolemmal destabilization.
  downstream:
  - target: Chronic Inflammation and Fibrofatty Replacement
    description: >-
      Repeated necrosis releases inflammatory cytokines and eventually exhausts
      regenerative capacity, leading to chronic inflammation and replacement of
      muscle with fibrotic and fatty tissue.
    causal_link_type: DIRECT
- name: Chronic Inflammation and Fibrofatty Replacement
  description: >-
    Sustained injury drives chronic inflammation (with impaired macrophage M1-to-M2
    switching) and progressive replacement of contractile muscle by fibrotic and
    adipose tissue, which is detectable as subtype-specific fatty infiltration patterns
    on muscle MRI and as fibrosis on biopsy. This is the structural substrate of
    permanent weakness.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37974208
    reference_title: "Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle
      differences, including more severe fatty infiltration of the posterior thigh
      muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those
      with LGMD-R2/LGMD2B.
    explanation: >-
      Documents fibrofatty (fatty infiltration) replacement of muscle, with subtype-specific
      MRI patterns, as a downstream consequence of repeated degeneration.
  downstream:
  - target: Progressive proximal muscle weakness
    description: >-
      Loss of functional contractile muscle and its replacement by fibrofatty tissue
      manifests clinically as progressive proximal limb-girdle weakness.
    causal_link_type: DIRECT
  - target: Elevated serum creatine kinase
    description: >-
      Ongoing myofiber membrane breakdown and necrosis releases intracellular creatine
      kinase into the circulation, producing markedly elevated serum CK.
    causal_link_type: DIRECT
  - target: Calf muscle hypertrophy
    description: >-
      In the sarcoglycanopathies, fibrofatty replacement and reactive enlargement of
      the calf musculature produce calf (pseudo)hypertrophy, a characteristic sign.
    causal_link_type: DIRECT

phenotypes:
- name: Progressive proximal muscle weakness
  description: >-
    The hallmark of LGMD-R: symmetric, progressive weakness of the pelvic and shoulder
    girdle muscles, producing difficulty rising from the floor, climbing stairs, and a
    waddling gait.
  phenotype_term:
    preferred_term: Limb-girdle muscle weakness
    term:
      id: HP:0003325
      label: Limb-girdle muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37974208
    reference_title: "Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited
      diseases predominantly characterized by limb-girdle muscle weakness and dystrophic
      changes on histological analysis.
    explanation: >-
      Establishes limb-girdle (proximal) muscle weakness as the defining clinical feature.
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Calpainopathy is characterized by symmetric and progressive weakness of proximal
      limb-girdle muscles.
    explanation: >-
      The Calpainopathy GeneReviews confirms the symmetric, progressive proximal pattern
      in the most common subtype.
- name: Elevated serum creatine kinase
  description: >-
    Serum creatine kinase is elevated across LGMD-R subtypes, often markedly so;
    in dysferlinopathy CK can reach 50-200 times the normal value.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:20301480
    reference_title: "Dysferlinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only."
    explanation: >-
      The Dysferlinopathy GeneReviews documents marked serum CK elevation, a feature
      shared across LGMD-R subtypes.
- name: Skeletal muscle atrophy
  description: >-
    Progressive muscle wasting accompanies the fibrofatty replacement of contractile
    tissue.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:40364688
    reference_title: "Recent insights into limb-girdle muscular dystrophy: Impacts, therapy, and challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of
      muscle disorders characterized by progressive muscle atrophy and loss of motor
      function.
    explanation: >-
      Identifies progressive muscle atrophy as a defining feature of LGMD.
- name: Scapular winging
  description: >-
    Weakness of the scapular stabilizer muscles produces scapular winging, a
    characteristic shoulder-girdle sign, particularly in calpainopathy.
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings of calpainopathy include the tendency to walk on tiptoe,
      difficulty in running, scapular winging, waddling gait, laxity of the abdominal
      muscles, Achilles tendon shortening, and scoliosis.
    explanation: >-
      The Calpainopathy GeneReviews lists scapular winging among the clinical findings.
- name: Waddling gait
  description: >-
    Pelvic girdle weakness produces a waddling (Trendelenburg) gait.
  phenotype_term:
    preferred_term: Waddling gait
    term:
      id: HP:0002515
      label: Waddling gait
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings of calpainopathy include the tendency to walk on tiptoe,
      difficulty in running, scapular winging, waddling gait, laxity of the abdominal
      muscles, Achilles tendon shortening, and scoliosis.
    explanation: >-
      The Calpainopathy GeneReviews lists waddling gait among the clinical findings.
- name: Scoliosis
  description: >-
    Axial and paraspinal muscle weakness commonly leads to scoliosis, particularly in
    calpainopathy.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings of calpainopathy include the tendency to walk on tiptoe,
      difficulty in running, scapular winging, waddling gait, laxity of the abdominal
      muscles, Achilles tendon shortening, and scoliosis.
    explanation: >-
      The Calpainopathy GeneReviews lists scoliosis among the clinical findings.
- name: Flexion contracture
  description: >-
    Joint contractures (e.g., Achilles tendon shortening) develop as a consequence of
    chronic muscle weakness and imbalance.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings of calpainopathy include the tendency to walk on tiptoe,
      difficulty in running, scapular winging, waddling gait, laxity of the abdominal
      muscles, Achilles tendon shortening, and scoliosis.
    explanation: >-
      The Calpainopathy GeneReviews documents Achilles tendon shortening (a contracture)
      among the clinical findings.
- name: Cardiomyopathy
  description: >-
    Dilated or hypertrophic cardiomyopathy is an important complication in the
    sarcoglycanopathies and FKRP-related LGMDR9; cardiac abnormalities were detected in
    22% of one LGMD cohort.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:37974208
    reference_title: "Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 22.0% of the patients had cardiac abnormalities"
    explanation: >-
      The Chinese LGMD cohort quantifies cardiac involvement, which is concentrated in
      the sarcoglycanopathy and dystroglycanopathy subtypes.
- name: Calf muscle hypertrophy
  description: >-
    Calf (pseudo)hypertrophy is a characteristic sign of the sarcoglycanopathies
    (LGMDR3-R6), reflecting fibrofatty replacement and reactive enlargement of the
    calf musculature.
  phenotype_term:
    preferred_term: Calf muscle hypertrophy
    term:
      id: HP:0008981
      label: Calf muscle hypertrophy
  evidence:
  - reference: PMID:39174842
    reference_title: "Molecular diagnosis of Alpha-sarcoglycanopathies by NGS in seven Moroccan families and report of two novel variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      progressive weakness of pelvic and/or scapular girdle muscles and calf
      hypertrophy, with a wide range of clinical inter- and intra-familial clinical
      variability.
    explanation: >-
      Documents calf hypertrophy as a presenting feature of alpha-sarcoglycanopathy
      (LGMD R3), representative of the sarcoglycanopathy subtypes.
- name: Respiratory insufficiency due to muscle weakness
  description: >-
    Progressive respiratory muscle weakness produces a restrictive respiratory
    insufficiency; restrictive insufficiency was present in 15.4% of one cohort.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37974208
    reference_title: "Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 15.4% of the patients had restrictive respiratory insufficiency."
    explanation: >-
      The Chinese LGMD cohort documents restrictive respiratory insufficiency from
      respiratory muscle weakness.

prevalence:
- population: Southeast China LGMD cohort (subtype distribution)
  notes: >-
    In a genetically confirmed Southeast Chinese LGMD cohort, dysferlinopathy (LGMD-R2)
    and calpainopathy (LGMD-R1) were the two most common subtypes.
  evidence:
  - reference: PMID:37974208
    reference_title: "Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 50 patients (41 families) with LGMDs, the most common subtypes were
      LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%).
    explanation: >-
      Provides the relative subtype frequencies in a population-defined LGMD cohort.

diagnosis:
- name: Next-generation sequencing gene panel / exome
  description: >-
    Diagnosis is confirmed by identifying biallelic pathogenic variants via targeted
    neuromuscular NGS gene panels, whole-exome, or whole-genome sequencing, supported
    by muscle biopsy with immunohistochemistry showing the specific protein deficiency.
  evidence:
  - reference: PMID:20301480
    reference_title: "Dysferlinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of dysferlinopathy is established in a proband with suggestive
      findings and biallelic pathogenic variants in DYSF identified by molecular genetic
      testing.
    explanation: >-
      Confirms molecular genetic testing as the diagnostic standard, exemplified for DYSF.

clinical_trials:
- name: NCT06246513
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    A Phase 3 multinational, open-label systemic gene-delivery study evaluating the
    safety and efficacy of a single systemic dose of SRP-9003 (bidridistrogene
    xeboparvovec), an AAVrh74 beta-sarcoglycan gene-transfer therapy, in ambulatory
    and non-ambulatory participants with beta-sarcoglycanopathy (LGMD2E/R4).
  target_phenotypes:
  - preferred_term: Limb-girdle muscle weakness
    term:
      id: HP:0003325
      label: Limb-girdle muscle weakness
  evidence:
  - reference: clinicaltrials:NCT06246513
    reference_title: "A Phase 3 Multinational, Open-label, Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9003 in Subjects With Limb Girdle Muscular Dystrophy 2E/R4"
    supports: SUPPORT
    snippet: >-
      This is a multicenter, global study of the effects of a single systemic dose of
      SRP-9003 on beta-sarcoglycan (β-SG) gene expression in participants with
      limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4).
    explanation: >-
      The trial summary confirms SRP-9003 is a systemic beta-sarcoglycan gene therapy
      in Phase 3 development for LGMD2E/R4 (beta-sarcoglycanopathy).

treatments:
- name: Physical therapy and rehabilitation
  description: >-
    No curative therapy is approved; management is supportive. Physical therapy and
    stretching promote mobility and prevent contractures, with mobility aids as needed.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical therapy and stretching exercises to promote mobility and prevent
      contractures; supervised strengthening and gentle low-impact aerobic exercise
    explanation: >-
      The Calpainopathy GeneReviews recommends physical therapy and stretching as
      mainstay supportive management.
- name: Noninvasive ventilation
  description: >-
    Nocturnal and chronic noninvasive ventilatory support is used as respiratory muscle
    weakness progresses to respiratory insufficiency.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: MAXO:0000506
      label: noninvasive ventilation
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nocturnal ventilator assistance as needed; respiratory aids to treat chronic
      respiratory insufficiency in late stages of the disease
    explanation: >-
      The Calpainopathy GeneReviews recommends ventilatory support for respiratory
      insufficiency in advanced disease.
- name: Genetic counseling
  description: >-
    Genetic counseling is essential for carrier identification, recurrence-risk
    assessment, and reproductive planning given autosomal recessive inheritance.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301480
    reference_title: "Dysferlinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the DYSF pathogenic variants have been identified in an affected family
      member, carrier testing for at-risk
    explanation: >-
      The Dysferlinopathy GeneReviews describes carrier testing and genetic counseling
      following identification of family pathogenic variants.
- name: AAV gene replacement therapy (investigational)
  description: >-
    Adeno-associated virus (AAV) gene replacement therapies are in clinical development
    for the sarcoglycanopathies, including bidridistrogene xeboparvovec (SRP-9003) for
    beta-sarcoglycanopathy/LGMDR4, which has progressed to a Phase 3 trial.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  therapeutic_modality: GENE_THERAPY
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the last decade, multiple other potential treatments were developed and studied,
      such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene
      editing.
    explanation: >-
      The classification/therapy review documents gene delivery (gene replacement) among
      the molecular therapies in development for LGMD.
- name: Cardiac management for LGMD-associated cardiomyopathy
  description: >-
    Cardiac surveillance and standard heart-failure pharmacotherapy are indicated in the
    subtypes with cardiac involvement (sarcoglycanopathies LGMDR3-R6 and FKRP-related
    LGMDR9). Guideline-directed medical therapy for dilated cardiomyopathy uses
    angiotensin-converting-enzyme (ACE) inhibitors and beta-adrenergic antagonists
    (beta-blockers) to reduce afterload and neurohormonal activation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  evidence:
  - reference: PMID:20301582
    reference_title: "Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitoring for cardiomyopathy in LGMD types with cardiac involvement"
    explanation: >-
      The Limb-Girdle Muscular Dystrophy Overview GeneReviews recommends monitoring for
      cardiomyopathy in the LGMD subtypes with cardiac involvement, which underpins the
      ACE-inhibitor/beta-blocker heart-failure management standard of care.
- name: Agents and circumstances to avoid
  description: >-
    Because of a malignant-hyperthermia-like anesthetic risk and drug-induced myotoxicity,
    succinylcholine and halogenated (volatile) anesthetic agents should be avoided when
    possible, and cholesterol-lowering statins should be avoided when possible in
    calpainopathy and related LGMD-R subtypes.
  treatment_term:
    preferred_term: avoidance of myotoxic and anesthetic triggers
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoid succinylcholine and halogenated anesthetic agents when possible; avoid
      cholesterol-lowering agents (e.g., statins) when possible.
    explanation: >-
      The Calpainopathy GeneReviews lists succinylcholine, halogenated anesthetics, and
      statins among the agents/circumstances to avoid.

datasets: []
📚

References & Deep Research

References

2
PMID:20301490
Calpainopathy.
No top-level findings curated for this source.
PMID:20301480
Dysferlinopathy.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 33 citations 2026-06-30T10:49:36.377844

1. Disease Information

Overview

Autosomal recessive limb-girdle muscular dystrophies (AR-LGMDs) are a heterogeneous group of inherited muscular dystrophies characterized by progressive proximal muscle weakness predominantly affecting the shoulder and hip girdle muscles, leading to progressive disability (sun2025recentinsightsinto pages 1-5, sun2025recentinsightsinto pages 5-7). The classification of LGMDs has evolved substantially. At the 2017 European Neuromuscular Centre (ENMC) workshop, a revised nomenclature was established: autosomal dominant forms are designated LGMD D (type 1) and autosomal recessive forms LGMD R (type 2), with currently 31 recognized subtypes—26 of which are autosomal recessive (sun2025recentinsightsinto pages 5-7, sun2025recentinsightsinto pages 1-5). The autosomal recessive forms account for approximately 80–90% of all LGMD cases (sun2025recentinsightsinto pages 1-5, luglio2024hereditaryneuromusculardisorders pages 18-19).

Key Identifiers

  • MONDO ID: MONDO:0016971 (limb-girdle muscular dystrophy) (OpenTargets Search: limb-girdle muscular dystrophy)
  • OMIM: Multiple entries per subtype (e.g., LGMD2A/OMIM #253600; LGMD2B/OMIM #253601; LGMD2C/OMIM #253700; LGMD2D/OMIM #608099; LGMD2E/OMIM #604286; LGMD2I/OMIM #607155)
  • Orphanet: ORPHA:263 (limb-girdle muscular dystrophy); specific subtypes have individual Orphanet entries
  • ICD-10: G71.0 (Muscular dystrophy); ICD-11: 8C73 (Limb girdle muscular dystrophy)
  • MeSH: D049288 (Muscular Dystrophies, Limb-Girdle)

Synonyms

Common synonyms include: Limb-girdle muscular dystrophy type 2 (LGMD2), Limb-girdle muscular dystrophy autosomal recessive, LGMD-R; subtype-specific names include calpainopathy (LGMDR1), dysferlinopathy (LGMDR2), sarcoglycanopathies (LGMDR3-R6), and dystroglycanopathies (LGMDR9, R11, R13-R15, R20).

2. Etiology

Disease Causal Factors

AR-LGMDs are exclusively genetic in origin, caused by biallelic (homozygous or compound heterozygous) pathogenic variants in genes encoding proteins essential for skeletal muscle structure, membrane integrity, and cellular signaling (bouchard2023limb–girdlemusculardystrophies pages 5-6, lin2023clinicalfeaturesimaging pages 1-2). No environmental, infectious, or acquired causes are recognized.

Genetic Risk Factors

The primary causal genes include CAPN3 (calpain 3), DYSF (dysferlin), SGCA/SGCB/SGCG/SGCD (sarcoglycans α/β/γ/δ), FKRP (fukutin-related protein), ANO5 (anoctamin 5), TCAP (telethonin), and numerous glycosyltransferase genes involved in α-dystroglycan modification (bouchard2023limb–girdlemusculardystrophies pages 5-6, bouchard2023limb–girdlemusculardystrophies pages 4-5, lin2023clinicalfeaturesimaging pages 1-2). Consanguinity substantially increases risk in populations with high rates of endogamy (lin2023clinicalfeaturesimaging pages 1-2).

Gene-Environment Interactions

While no classical gene-environment interactions have been established for AR-LGMD, physical exercise may influence disease expression. In calpainopathy models, zebrafish with capn3b inactivation showed increased susceptibility to muscle defects with elevated muscle activity (akyurek2025zebrafishasa pages 6-7). The role of exercise as a modifying factor in human AR-LGMD is being investigated.

3. Phenotypes

Core Phenotypes

Progressive proximal muscle weakness (HPO: HP:0003701 - Proximal muscle weakness): The hallmark feature across all AR-LGMD subtypes, affecting pelvic and shoulder girdle muscles with variable age of onset (sun2025recentinsightsinto pages 5-7).

Elevated serum creatine kinase (CK) (HPO: HP:0003236 - Elevated circulating creatine kinase concentration): Universally present across subtypes, ranging from 4,000 to over 40,000 U/L. In dysferlinopathy, CK levels reach 50–200 times normal values (anwar2024thedysferlinopathiesconundrum pages 2-3, anwar2024thedysferlinopathiesconundrum pages 3-4, sun2025recentinsightsinto pages 5-7).

Muscle atrophy and fatty replacement (HPO: HP:0003202 - Skeletal muscle atrophy): Progressive fibrofatty replacement of muscle tissue is characteristic, with distinct MRI patterns per subtype (bouchard2023limb–girdlemusculardystrophies pages 2-4, lin2023clinicalfeaturesimaging pages 1-2).

Subtype-Specific Features

  • Calpainopathy (LGMDR1): Onset 2–53 years; early contractures and scoliosis; approximately 80% of patients become wheelchair-bound between the second and fourth decades of life (lin2023clinicalfeaturesimaging pages 1-2, sun2025recentinsightsinto pages 5-7).
  • Dysferlinopathy (LGMDR2): Onset typically 13–40 years; characteristic "dysferlin gait" from quadriceps weakness; "diamond-shaped" quadriceps bulge; 15–50% lose ambulation; cardiac involvement is rare (3–10%) but respiratory impairment affects 20–30% (anwar2024thedysferlinopathiesconundrum pages 3-4, bouchard2023limb–girdlemusculardystrophies pages 2-4).
  • Sarcoglycanopathies (LGMDR3–R6): Usually childhood onset (<10 years); account for 10–15% of LGMD cases; calf hypertrophy; CK 4–180× upper limit of normal; loss of ambulation typically ages 12–16 years; dilated/hypertrophic cardiomyopathy and respiratory failure are important complications (wicklund2025limbgirdlemusculardystrophy pages 2-3, lin2023clinicalfeaturesimaging pages 1-2).
  • LGMDR9 (FKRP-related): Variable onset; progressive weakness with ~2% annual decline in respiratory function in adults; median loss of ambulation at age 43 for the common c.826C>A genotype (wicklund2025limbgirdlemusculardystrophy pages 2-3).

Quality of Life Impact

Overall, approximately 60.8% of LGMD patients experience loss of ambulation, with early childhood-onset forms showing higher rates (71.1% becoming non-ambulatory by mean age 17.7 years) (luglio2024hereditaryneuromusculardisorders pages 18-19). Quality of life is significantly impacted with substantial disability, psychosocial challenges, and the need for multidisciplinary care (anwar2024thedysferlinopathiesconundrum pages 3-4).

Suggested HPO Terms

  • HP:0003701 (Proximal muscle weakness)
  • HP:0003236 (Elevated circulating creatine kinase concentration)
  • HP:0003202 (Skeletal muscle atrophy)
  • HP:0003560 (Muscular dystrophy)
  • HP:0001638 (Cardiomyopathy)
  • HP:0002747 (Respiratory insufficiency due to muscle weakness)
  • HP:0003551 (Difficulty climbing stairs)
  • HP:0002359 (Frequent falls)
  • HP:0008981 (Calf muscle hypertrophy)
  • HP:0001371 (Flexion contracture)
  • HP:0002650 (Scoliosis)
  • HP:0003391 (Gowers sign)

4. Genetic/Molecular Information

Causal Genes and Pathogenic Variants

The following table summarizes the major AR-LGMD subtypes with their causal genes:

New Name Old Name Gene Symbol Protein Chromosomal Locus Key Clinical Features Age of Onset
LGMDR1 LGMD2A CAPN3 Calpain-3 15q15.1 Progressive proximal pelvic/shoulder weakness; early contractures and scoliosis may occur; posterior thigh involvement common; often wheelchair dependence in 2nd-4th decade (bouchard2023limb–girdlemusculardystrophies pages 2-4, lin2023clinicalfeaturesimaging pages 1-2, sun2025recentinsightsinto pages 5-7) Variable, ~2-53 years; often childhood/adolescence (lin2023clinicalfeaturesimaging pages 1-2, sun2025recentinsightsinto pages 5-7)
LGMDR2 LGMD2B DYSF Dysferlin 2p13.2 Proximal weakness with gluteus maximus/quadriceps involvement; very high CK; dysferlin gait; fatty replacement of posterior thigh/leg muscles; distal spread later (bouchard2023limb–girdlemusculardystrophies pages 2-4, anwar2024thedysferlinopathiesconundrum pages 2-3, anwar2024thedysferlinopathiesconundrum pages 3-4) Usually teens to 30s; ~13-40 years (anwar2024thedysferlinopathiesconundrum pages 3-4, anwar2024thedysferlinopathiesconundrum pages 2-3)
LGMDR3 LGMD2D SGCA α-Sarcoglycan 17q21.33 Pelvic girdle weakness, exercise intolerance, muscle atrophy; sarcoglycanopathy phenotype with possible calf hypertrophy and cardiomyopathy in severe cases (bouchard2023limb–girdlemusculardystrophies pages 2-4, lin2023clinicalfeaturesimaging pages 1-2, wicklund2025limbgirdlemusculardystrophy pages 2-3, sun2025recentinsightsinto pages 5-7) Usually childhood, often <10 years (wicklund2025limbgirdlemusculardystrophy pages 2-3, sun2025recentinsightsinto pages 5-7)
LGMDR4 LGMD2E SGCB β-Sarcoglycan 4q12 Weakness with fatty replacement in dorsal, spinal, and limb muscles; often severe sarcoglycanopathy with possible cardiac/respiratory involvement (bouchard2023limb–girdlemusculardystrophies pages 2-4, wicklund2025limbgirdlemusculardystrophy pages 2-3) Usually childhood (wicklund2025limbgirdlemusculardystrophy pages 2-3, lin2023clinicalfeaturesimaging pages 1-2)
LGMDR5 LGMD2C SGCG γ-Sarcoglycan 13q12 Variable severity, including severe childhood form; loss of ambulation before age 13 in severe cases; calf hypertrophy and high CK common (bouchard2023limb–girdlemusculardystrophies pages 2-4, wicklund2025limbgirdlemusculardystrophy pages 2-3) Usually childhood (wicklund2025limbgirdlemusculardystrophy pages 2-3, lin2023clinicalfeaturesimaging pages 1-2)
LGMDR6 LGMD2F SGCD δ-Sarcoglycan 5q33.2-q33.3 Variable sarcoglycanopathy phenotype; proximal weakness with risk of cardiomyopathy/respiratory complications (bouchard2023limb–girdlemusculardystrophies pages 2-4, lin2023clinicalfeaturesimaging pages 1-2, wicklund2025limbgirdlemusculardystrophy pages 2-3) Usually childhood to adolescence (wicklund2025limbgirdlemusculardystrophy pages 2-3, lin2023clinicalfeaturesimaging pages 1-2)
LGMDR7 LGMD2G TCAP Telethonin 17q12 Proximal weakness; relatively enriched in some populations (e.g., Southeast China) with founder variant c.26_33dupAGGTGCG/TCAP duplication reported frequently (bouchard2023limb–girdlemusculardystrophies pages 4-5, lin2023clinicalfeaturesimaging pages 1-2) Variable; often childhood/adolescence (lin2023clinicalfeaturesimaging pages 1-2)
LGMDR9 LGMD2I FKRP Fukutin-related protein 19q13.32 Dystroglycanopathy; progressive proximal weakness, elevated CK, muscle atrophy on MRI; respiratory decline (~2%/year in adults) and cardiomyopathy may occur; genotype influences severity (lin2023clinicalfeaturesimaging pages 1-2, wicklund2025limbgirdlemusculardystrophy pages 2-3) Variable; often childhood to early adulthood (luglio2024hereditaryneuromusculardisorders pages 18-19, wicklund2025limbgirdlemusculardystrophy pages 2-3)
LGMDR11 LGMD2K POMT1 Protein O-mannosyl-transferase 1 9q34.13 Dystroglycanopathy; childhood-onset proximal weakness, may associate with broader multisystem involvement depending on severity (bouchard2023limb–girdlemusculardystrophies pages 4-5, lin2023clinicalfeaturesimaging pages 1-2) Usually childhood (lin2023clinicalfeaturesimaging pages 1-2)
LGMDR12 LGMD2L ANO5 Anoctamin-5 11p14.3 Adult-onset proximal weakness; often asymmetric or mixed proximal/distal pattern in some patients; elevated CK; slower progression than classic childhood sarcoglycanopathies (OpenTargets Search: limb-girdle muscular dystrophy, wicklund2025limbgirdlemusculardystrophy pages 2-3) Usually adulthood (wicklund2025limbgirdlemusculardystrophy pages 2-3)
LGMDR14 LGMD2N POMT2 Protein O-mannosyl-transferase 2 14q24.3 Dystroglycanopathy; childhood-onset girdle weakness with variable severity, sometimes with extra-muscular involvement in more severe allelic disease (bouchard2023limb–girdlemusculardystrophies pages 4-5, lin2023clinicalfeaturesimaging pages 1-2) Usually childhood (lin2023clinicalfeaturesimaging pages 1-2)
LGMDR15 LGMD2O POMGNT1 Protein O-linked mannose N-acetylglucosaminyltransferase 1 1p34.1 Dystroglycanopathy; limb-girdle weakness with variable course and possible overlap with congenital muscular dystrophy spectrum (bouchard2023limb–girdlemusculardystrophies pages 4-5, lin2023clinicalfeaturesimaging pages 1-2) Usually childhood (lin2023clinicalfeaturesimaging pages 1-2)
LGMDR18 LGMD2S TRAPPC11 Trafficking protein particle complex subunit 11 4q35.1 Proximal-distal weakness; reported association with fatty liver disease and diabetes in rare cases (bouchard2023limb–girdlemusculardystrophies pages 4-5, lin2023clinicalfeaturesimaging pages 1-2) Variable; rare subtype, can present later than previously recognized (lin2023clinicalfeaturesimaging pages 1-2)
LGMDR21 LGMD2Z POGLUT1 Protein O-glucosyltransferase 1 3q13.33 Rare recessive LGMD with proximal weakness; linked to defective glycosylation/protein processing pathways (bouchard2023limb–girdlemusculardystrophies pages 5-6) Variable, often childhood/adolescence (bouchard2023limb–girdlemusculardystrophies pages 5-6)

Table: This table summarizes the principal autosomal recessive limb-girdle muscular dystrophy subtypes, aligning old and new nomenclature with causal genes, proteins, loci, and hallmark clinical features. It is useful for rapid comparison across common sarcolemmal, sarcomeric, and dystroglycanopathy-associated forms.

Variant Types and Classification

Pathogenic variants across AR-LGMD genes include missense, nonsense, frameshift, splice-site, and structural variants. In calpainopathy, common mutations include c.2120A>G in Chinese populations and c.550del in European populations (lin2023clinicalfeaturesimaging pages 1-2). For dysferlinopathy, more than 600 mutations have been identified across the DYSF gene, with c.2997G>T frequent in Japanese patients and c.1375dup in Chinese patients (lin2023clinicalfeaturesimaging pages 1-2). The common FKRP founder mutation c.826C>A (p.Leu276Ile) is prevalent in European populations (wicklund2025limbgirdlemusculardystrophy pages 2-3). Variants are classified according to ACMG/AMP guidelines, with pathogenic and likely pathogenic variants deposited in ClinVar (OpenTargets Search: limb-girdle muscular dystrophy).

Founder Effects

Several population-specific founder mutations have been documented: α-sarcoglycan mutations in Acadian populations; FKRP mutations in Hutterite communities; γ-sarcoglycan mutations in Romani (Gypsy) populations; SGCG mutations in Puerto Rican Hispanics; and TCAP c.26_33dupAGGTGTCG in Southeast Chinese populations (83.3% of LGMDR7 cases) (kang2023geneticpatternsof pages 9-10, lin2023clinicalfeaturesimaging pages 1-2).

OpenTargets Disease-Target Associations

OpenTargets identifies 12 primary targets associated with LGMD (MONDO:0016971), with the highest association scores for CAPN3 (0.86), DYSF (0.86), LMNA (0.85), ANO5 (0.85), SGCA (0.85), SGCB (0.84), FKRP (0.84), GMPPB (0.83), SGCG (0.83), PLEC (0.82), TRAPPC11 (0.81), and DAG1 (0.81) (OpenTargets Search: limb-girdle muscular dystrophy).

5. Mechanism / Pathophysiology

Molecular Pathways

The pathophysiology of AR-LGMD involves multiple interconnected cascades initiated by protein dysfunction at the muscle cell membrane:

Dystrophin-Glycoprotein Complex (DGC) Disruption: In sarcoglycanopathies, mutations in sarcoglycan genes destabilize the entire sarcoglycan complex and the DGC, which normally links the intracellular cytoskeleton to the extracellular matrix. This compromises sarcolemmal integrity, leading to muscle weakness, atrophy, and potential cardiac/respiratory failure (bozzi2025misregulationofthe pages 17-19, lin2023clinicalfeaturesimaging pages 1-2).

Calcium Dysregulation: Muscle membrane damage causes intracellular Ca²⁺ concentration to increase from 100 nM to 1–10 µM, activating calpain 3 protease. This calcium dysregulation initiates a three-level cascade: immediate calpain hyperactivation and protein degradation, middle-term mitochondrial permeability transition pore opening with decreased ATP production, and long-term fiber type conversion from slow-twitch to fast-twitch fibers (sun2025recentinsightsinto pages 14-16).

Oxidative Stress: ROS/RNS imbalance occurs with increased NADPH oxidase activity, lipid peroxidation (MDA), and protein carbonylation. ROS damages cell membranes, reduces myosin heavy chain contraction efficiency, and triggers NF-κB-mediated inflammatory cycles (sun2025recentinsightsinto pages 11-14, sun2025recentinsightsinto pages 14-16).

Chronic Inflammation: Mutations prevent proper macrophage switching from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, causing sustained pro-inflammatory signaling, excessive cytokine release, and impaired muscle regeneration (sun2025recentinsightsinto pages 11-14).

Autophagy and Ubiquitin-Proteasome System Dysregulation: In FKRP-related dystroglycanopathies, mTORC1 hyperactivation correlates with fibrosis and acute regeneration markers. Autophagic flux is dysregulated, with blockage occurring independently of Akt/mTOR signaling changes. ERK1/2 kinase activity is reduced in severe hypoglycosylation cases (bozzi2025misregulationofthe pages 17-19).

Mitochondrial Dysfunction: Mitochondrial impairment represents a critical pathogenic mechanism involving impaired biogenesis, dynamics, and autophagy, with decreased ATP production (sun2025recentinsightsinto pages 14-16).

Subtype-Specific Mechanisms

  • Calpainopathy (CAPN3): Loss-of-function mutations inactivate the proteolytic function of calpain 3, disrupting Ca²⁺ release, sarcomere remodeling, muscle contraction, and NF-κB signaling (lin2023clinicalfeaturesimaging pages 1-2, bouchard2023limb–girdlemusculardystrophies pages 2-4).
  • Dysferlinopathy (DYSF): Dysferlin deficiency disrupts Ca²⁺ homeostasis, vesicle trafficking, sarcolemmal resealing, and T-tubule system shaping (lin2023clinicalfeaturesimaging pages 1-2).
  • Dystroglycanopathies (FKRP, POMT1, POMT2, etc.): Abnormal O-glycosylation of α-dystroglycan leads to impaired ECM binding and sarcolemmal instability (bouchard2023limb–girdlemusculardystrophies pages 5-6).

Suggested GO Terms

  • GO:0043034 (costamere)
  • GO:0016529 (sarcoglycan complex)
  • GO:0016010 (dystrophin-associated glycoprotein complex)
  • GO:0042383 (sarcolemma)
  • GO:0006816 (calcium ion transport)
  • GO:0006954 (inflammatory response)
  • GO:0006979 (response to oxidative stress)
  • GO:0006914 (autophagy)

Suggested Cell Ontology Terms

  • CL:0000187 (muscle cell)
  • CL:0000188 (cell of skeletal muscle)
  • CL:0008002 (skeletal muscle fiber)
  • CL:0000235 (macrophage)
  • CL:0000057 (fibroblast)

6. Anatomical Structures Affected

Primary Organs

  • Skeletal muscle (UBERON:0001134): Proximal limb-girdle muscles are primary targets, including pelvic girdle (gluteus maximus, quadriceps, hip flexors) and shoulder girdle muscles (sun2025recentinsightsinto pages 5-7, anwar2024thedysferlinopathiesconundrum pages 2-3).
  • Heart (UBERON:0000948): Cardiomyopathy (dilated or hypertrophic) occurs in sarcoglycanopathies and FKRP-related LGMD; cardiac abnormalities detected in 22% of one Chinese cohort (wicklund2025limbgirdlemusculardystrophy pages 2-3, lin2023clinicalfeaturesimaging pages 1-2).
  • Respiratory system (UBERON:0001004): Progressive respiratory muscle weakness with restrictive insufficiency (15.4% in one cohort); adults with LGMDR9 show ~2% annual decline in respiratory function (wicklund2025limbgirdlemusculardystrophy pages 2-3, lin2023clinicalfeaturesimaging pages 1-2).

Tissue and Cell Level

  • Skeletal muscle fibers (type I and type II)
  • Sarcolemma and associated protein complexes
  • Connective tissue (fibrotic replacement)
  • Adipose tissue (fatty infiltration)

Subcellular Level

  • Sarcolemma (GO:0042383)
  • Dystrophin-glycoprotein complex (GO:0016010)
  • Sarcoplasmic reticulum (calcium handling)
  • Mitochondria (GO:0005739)
  • Lysosomes/autophagosomes (autophagy pathway)

7. Temporal Development

Onset

Age of onset varies substantially by subtype: sarcoglycanopathies typically present in childhood (<10 years); calpainopathy has a wide range (2–53 years, commonly childhood/adolescence); dysferlinopathy presents in the late teens to thirties (13–40 years); LGMDR12 (ANO5) and LGMDR9 often present in adulthood (wicklund2025limbgirdlemusculardystrophy pages 2-3, anwar2024thedysferlinopathiesconundrum pages 3-4, sun2025recentinsightsinto pages 5-7).

Progression

Disease progression is universally progressive but with variable rates. Sarcoglycanopathies tend toward rapid progression with loss of ambulation in adolescence. Dysferlinopathy shows slow progressive decline, with 15–50% losing ambulation (anwar2024thedysferlinopathiesconundrum pages 3-4). LGMDR9 (FKRP) with the common c.826C>A mutation has a later median age of ambulation loss (43 years) (wicklund2025limbgirdlemusculardystrophy pages 2-3). Calpainopathy results in wheelchair dependence typically in the second to fourth decade (lin2023clinicalfeaturesimaging pages 1-2).

Patterns

The disease course is chronic, progressive, and lifelong with no spontaneous remission. There are no well-defined disease stages analogous to cancer staging, but clinical milestones include loss of independent ambulation, onset of respiratory support requirement, and cardiac involvement.

8. Inheritance and Population

Epidemiology

LGMD prevalence estimates range from 1 in 14,500 to 1 in 123,000 individuals, varying by studied population (luglio2024hereditaryneuromusculardisorders pages 18-19). Calpainopathy (LGMDR1) specifically has an estimated prevalence of 6.8–10.2 per million worldwide and represents 30–40% of all LGMD cases (lin2023clinicalfeaturesimaging pages 1-2). Sarcoglycanopathy prevalence ranges from 0.31–0.58 per 100,000 depending on ethnicity and region (lin2023clinicalfeaturesimaging pages 1-2). The global carrier frequency for all autosomal recessive neuromuscular diseases is approximately 32.9% (OpenTargets Search: limb-girdle muscular dystrophy).

Inheritance Pattern

All AR-LGMD subtypes follow autosomal recessive inheritance. Both parents must be carriers (heterozygous) for an affected child to be born (25% recurrence risk). Penetrance is generally high (complete or near-complete) for biallelic pathogenic variants, though expressivity is variable—even siblings with identical mutations can show different severity (luglio2024hereditaryneuromusculardisorders pages 18-19, bouchard2023limb–girdlemusculardystrophies pages 2-4).

Population Demographics

In a Southeast Chinese cohort, LGMDR2 (36.6%) and LGMDR1 (29.3%) were the most common subtypes (lin2023clinicalfeaturesimaging pages 1-2). In the US MD STARnet surveillance network, the most common associated genes were FKRP, CAPN3, ANO5, and DYSF (kang2023geneticpatternsof pages 9-10). In Iranian populations, CAPN3 was the most frequently mutated gene (20%), followed by POMGNT1 and TTN (OpenTargets Search: limb-girdle muscular dystrophy). Geographic and ethnic variation is substantial (kang2023geneticpatternsof pages 9-10, kang2023geneticpatternsof pages 10-10).

9. Diagnostics

Clinical Tests

Serum Creatine Kinase (CK): Markedly elevated in all subtypes; ranges from 4× to 200× upper limit of normal depending on subtype and stage. Dysferlinopathy characteristically shows CK levels 50–200× normal (anwar2024thedysferlinopathiesconundrum pages 2-3, sun2025recentinsightsinto pages 5-7).

Muscle Biopsy: Findings include dystrophic changes (varied fiber sizes, increased internal nuclei, necrosis, regeneration), inflammatory cell infiltration, fibrotic replacement, and fatty deposits. Immunohistochemistry reveals specific protein deficiencies (absent/reduced dysferlin, sarcoglycans, α-dystroglycan hypoglycosylation) (anwar2024thedysferlinopathiesconundrum pages 2-3, sun2025recentinsightsinto pages 5-7).

Muscle MRI: Reveals characteristic fatty infiltration patterns that differ by subtype. LGMDR1 shows more severe fatty infiltration of posterior thigh muscles, while LGMDR2 shows edema in lower leg muscles. "Target signs" in rectus femoris and "sandwich signs" in vastus lateralis have high diagnostic value. A "diamond on quadriceps" sign is characteristic of dysferlinopathy (bouchard2023limb–girdlemusculardystrophies pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 11-12, lin2023clinicalfeaturesimaging pages 1-2).

Electrophysiology: EMG shows myopathic changes. Nerve conduction studies are typically normal.

Cardiac monitoring: Echocardiography and ECG for cardiomyopathy and rhythm disturbances, particularly in sarcoglycanopathies and FKRP-related LGMD (wicklund2025limbgirdlemusculardystrophy pages 2-3).

Pulmonary function tests: Forced vital capacity (FVC) monitoring for respiratory decline (wicklund2025limbgirdlemusculardystrophy pages 2-3).

Genetic Testing

Next-generation sequencing (NGS) is the primary diagnostic approach, including targeted neuromuscular gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS) (bouchard2023limb–girdlemusculardystrophies pages 11-12, lin2023clinicalfeaturesimaging pages 17-18). The diagnostic criteria established by the 2017 ENMC workshop require: (i) proximal or non-proximal muscle dystrophy; (ii) muscle fiber degeneration and necrosis; (iii) elevated serum CK levels; and (iv) muscle degenerative changes with fibrofatty infiltration (sun2025recentinsightsinto pages 5-7). A diagnostic approach typically progresses from clinical assessment and CK measurement, through muscle biopsy with immunohistochemistry, to genetic confirmation via NGS (wicklund2025limbgirdlemusculardystrophy pages 12-12).

Differential Diagnosis

  • Duchenne/Becker muscular dystrophy (X-linked)
  • Facioscapulohumeral muscular dystrophy (FSHD)
  • Emery-Dreifuss muscular dystrophy
  • Metabolic myopathies (Pompe disease/GAA deficiency)
  • Inflammatory myopathies (polymyositis, dermatomyositis)
  • Congenital muscular dystrophies

Biomarkers

miR-1, miR-133a, and miR-206 are differentially expressed in serum and muscle of LGMD animal models and change according to the degree of inflammation, fibrosis, muscle regeneration, and disease progression (OpenTargets Search: limb-girdle muscular dystrophy). Glycosylated α-dystroglycan is being evaluated as a biomarker for LGMDR9 severity.

10. Outcome/Prognosis

Survival and Morbidity

Life expectancy varies by subtype. Severe sarcoglycanopathies and some dystroglycanopathies may lead to early mortality from cardiac and respiratory complications. Dysferlinopathy and milder forms of calpainopathy have near-normal life expectancy with appropriate cardiac and respiratory management (wicklund2025limbgirdlemusculardystrophy pages 2-3, anwar2024thedysferlinopathiesconundrum pages 3-4). In one Chinese cohort, a patient with LMNA-related muscular dystrophy experienced sudden cardiac death at age 37, highlighting the cardiac risks in certain subtypes (lin2023clinicalfeaturesimaging pages 1-2).

Complications

  • Loss of ambulation (60.8% overall; 71.1% for early childhood-onset forms by mean age 17.7 years) (luglio2024hereditaryneuromusculardisorders pages 18-19)
  • Dilated or hypertrophic cardiomyopathy and rhythm disturbances (wicklund2025limbgirdlemusculardystrophy pages 2-3)
  • Restrictive respiratory insufficiency (lin2023clinicalfeaturesimaging pages 1-2)
  • Scoliosis and joint contractures (sun2025recentinsightsinto pages 5-7)
  • Secondary metabolic complications (fatty liver, diabetes reported in rare cases) (lin2023clinicalfeaturesimaging pages 1-2)

11. Treatment

Current Symptomatic Management

No curative treatments are currently approved. Management is primarily supportive, including corticosteroids (with limited evidence specific to LGMD), physical therapy, occupational therapy, orthopedic interventions, respiratory support (non-invasive ventilation), and cardiac management (ACE inhibitors, beta-blockers, pacemakers/ICDs as needed) (akyurek2025zebrafishasa pages 6-7, kaur2025towardsacure pages 12-14). MAXO terms: MAXO:0001298 (physical therapy), MAXO:0000016 (respiratory support), MAXO:0001001 (gene therapy).

Gene Therapy (Experimental)

Gene therapy is the most actively pursued therapeutic modality for AR-LGMD:

SRP-9003 (bidridistrogene xeboparvovec) for LGMDR4/LGMD2E: Uses AAVrh74 vector with MHCK7 promoter to deliver full-length β-sarcoglycan gene. Phase 1/2 interim data showed dose-dependent SGCB expression (36.2–62.1% at 60 days) and significant CK reductions (−92.4 to −94.9%), maintained through 2 years with preliminary motor function improvements. Currently in Phase 3 trial (NCT06246513) (kaur2025towardsacure pages 14-16).

ATA-200 for LGMDR5/LGMD2C: AAV8-based γ-sarcoglycan gene therapy in Phase 1b pediatric trials (NCT05973630) (kaur2025towardsacure pages 12-14).

SRP-9004 (patidistrogene bexoparvovec) for LGMDR3/LGMD2D: Completed Phase 1/2 (NCT01976091) with sustained α-sarcoglycan expression at 6 months post-treatment (bouchard2023limb–girdlemusculardystrophies pages 8-9).

CRISPR/Cas9 approaches for LGMDR1: Direct correction of CAPN3 mutations through double-strand breaks and wild-type allele insertion, with recent advances in non-viral delivery systems (kaur2025towardsacure pages 14-16).

Exon skipping: Antisense oligonucleotides have shown effectiveness in skipping exon 32 in dysferlin in vitro; multi-exon skipping cocktails have successfully corrected SGCG mutations in LGMDR5 patient-derived cell lines, though human clinical trials have not yet been conducted (bouchard2023limb–girdlemusculardystrophies pages 8-9, sun2025recentinsightsinto pages 18-21).

The following table summarizes key clinical trials:

NCT Number Study Title (abbreviated) LGMD Subtype Intervention/Drug Phase Status Sponsor
NCT00494195 Gene Transfer Therapy for LGMD2D LGMD2D / LGMDR3 AAV gene transfer (alpha-sarcoglycan) Phase 1 Completed Nationwide Children's Hospital (bouchard2023limb–girdlemusculardystrophies pages 8-9)
NCT01344798 AAV1-gamma-sarcoglycan Gene Therapy for LGMD2C LGMD2C / LGMDR5 AAV1-gamma-sarcoglycan Phase 1 Completed Genethon (sun2025recentinsightsinto pages 18-21)
NCT01976091 Safety Study of SRP-9004 for LGMD2D LGMD2D / LGMDR3 SRP-9004 (patidistrogene bexoparvovec) Phase 1/2 Completed Sarepta Therapeutics, Inc. (bouchard2023limb–girdlemusculardystrophies pages 8-9)
NCT05876780 Single-Dose SRP-9003 Study for LGMD2E/R4 LGMD2E / LGMDR4 SRP-9003 (bidridistrogene xeboparvovec; SGCB gene transfer) Phase 1 Active, not recruiting Sarepta Therapeutics, Inc. (bouchard2023limb–girdlemusculardystrophies pages 8-9, kaur2025towardsacure pages 14-16)
NCT06246513 Bidridistrogene Xeboparvovec Trial for LGMD2E/R4 LGMD2E / LGMDR4 SRP-9003 / bidridistrogene xeboparvovec Phase 3 Active, not recruiting Sarepta Therapeutics, Inc. (kaur2025towardsacure pages 14-16)
NCT05906251 SRP-6004 Gene Transfer Study for LGMD2B/R2 LGMD2B / LGMDR2 SRP-6004 (DYSF gene transfer) Phase 1 Terminated Sarepta Therapeutics, Inc. (bouchard2023limb–girdlemusculardystrophies pages 8-9)
NCT05588401 GenPHSats-bASKet Gene-edited Muscle Stem Cells LGMD (basket study) Autologous gene-edited muscle stem cells Phase 1/2 Unknown Charite University, Berlin, Germany (bouchard2023limb–girdlemusculardystrophies pages 8-9)
NCT05973630 ATA-200 for LGMD2C/R5 LGMD2C / LGMDR5 ATA-200 (AAV8 gamma-sarcoglycan gene therapy) Phase 1b Recruiting/ongoing Asklepios BioPharmaceutical, Inc. / Atamyo Therapeutics (kaur2025towardsacure pages 12-14)

Table: This table summarizes key current and recent gene therapy trials for autosomal recessive LGMD subtypes, including sarcoglycanopathies and dysferlinopathy. It is useful for quickly comparing study phase, status, intervention, and sponsor across the most relevant programs.

12. Prevention

Primary Prevention

No primary prevention exists for AR-LGMD as it is a genetic disorder. Genetic counseling is essential for carrier identification, family planning, and recurrence risk assessment (luglio2024hereditaryneuromusculardisorders pages 18-19).

Genetic Screening

  • Carrier screening: Recommended for at-risk family members and populations with high consanguinity rates
  • Prenatal diagnosis: Available through chorionic villus sampling or amniocentesis when family mutations are known
  • Preimplantation genetic testing (PGT): Available for families with identified pathogenic variants (luglio2024hereditaryneuromusculardisorders pages 18-19)
  • Cascade screening: Family members of affected individuals should be offered genetic testing

Tertiary Prevention

Regular cardiac monitoring, respiratory function assessment, and physical rehabilitation to prevent complications and optimize function (wicklund2025limbgirdlemusculardystrophy pages 2-3).

13. Model Organisms

Mouse Models

Multiple mouse models have been developed for AR-LGMD subtypes:

  • Dysferlinopathy: BLA/J mice (A/J × C57BL/6 hybrid, retrotransposon in Dysf intron 4), extensively used for therapeutic studies; A/J mice (inbred, retrotransposon insertion); SJL/J mice (splice-site mutation with 15% residual dysferlin expression); and 129 and MMex38 strains. These models exhibit varying disease onset and progression patterns (anwar2024thedysferlinopathiesconundrum pages 15-16).
  • Sarcoglycanopathy: Naturally occurring and genetically modified Sgca, Sgcb, and Sgcg knockout mice recapitulate human disease phenotypes. Sarcospan overexpression in Sgcg-null mice has been shown to protect against LGMDR5 by enabling substitution of γ-sarcoglycan by ζ-sarcoglycan (akyurek2025zebrafishasa pages 7-8).

Zebrafish Models

Zebrafish (Danio rerio) have become increasingly important for LGMD research:

  • Calpainopathy: capn3b-inactivated zebrafish generated using CRISPR/Cas9 show muscle damage under challenging conditions (akyurek2025zebrafishasa pages 6-7).
  • Dysferlinopathy: Morpholino knockdown models used to understand dysferlin's role in muscle structure stabilization and sarcolemma repair (akyurek2025zebrafishasa pages 6-7, akyurek2025zebrafishasa pages 4-6).
  • Sarcoglycanopathies: CRISPR/Cas9 knockout lines for β-SG and δ-SG showing progressive dystrophic phenotypes mirroring human disease (akyurek2025zebrafishasa pages 7-8, akyurek2025zebrafishasa pages 4-6).
  • Additional models: TALEN-based exon skipping for collagen VI-related myopathies; morpholino depletion of telethonin/Tcap affecting sarcomere-membrane interaction (akyurek2025zebrafishasa pages 14-16, akyurek2025zebrafishasa pages 8-10).

These models are extensively used for drug screening, gene therapy testing, and understanding pathogenetic mechanisms (akyurek2025zebrafishasa pages 7-8, akyurek2025zebrafishasa pages 14-16).

14. Environmental Information and Lifestyle Factors

No specific environmental toxins, infectious agents, or lifestyle factors are known to cause AR-LGMD. However, physical exercise and activity patterns may influence disease expression and progression. Aerobic exercise at moderate intensity is generally recommended for maintaining function, while excessive strenuous activity may exacerbate muscle damage. Nutritional optimization and weight management are important supportive measures.

15. Summary

Autosomal recessive limb-girdle muscular dystrophies represent a complex group of at least 26 genetically distinct conditions unified by progressive proximal muscle weakness. The field has advanced substantially in recent years with the revised ENMC nomenclature system, improved genetic diagnostic capabilities through NGS, and—most promisingly—the emergence of AAV-based gene therapy clinical trials for sarcoglycanopathies and other subtypes. SRP-9003 for LGMDR4 has shown encouraging Phase 1/2 data with significant protein restoration and CK reduction, and has progressed to Phase 3 trials (kaur2025towardsacure pages 14-16). The heterogeneity across and within LGMD subtypes continues to present significant challenges for drug development, necessitating natural history studies and validated clinical outcome assessments to support future therapeutic trials (wicklund2025limbgirdlemusculardystrophy pages 2-3). Multidisciplinary management remains essential, combining cardiac and respiratory surveillance with physical rehabilitation, while gene therapy and other molecular approaches offer hope for disease-modifying treatments in the coming years.

References

  1. (sun2025recentinsightsinto pages 1-5): Chen-Chen Sun, Jiang-Ling Xiao, Zhe Zhao, Heng-Yuan Liu, and Chang-Fa Tang. Recent insights into limb-girdle muscular dystrophy: impacts, therapy, and challenges. Histology and histopathology, pages 18929, Apr 2025. URL: https://doi.org/10.14670/hh-18-929, doi:10.14670/hh-18-929. This article has 3 citations and is from a peer-reviewed journal.

  2. (sun2025recentinsightsinto pages 5-7): Chen-Chen Sun, Jiang-Ling Xiao, Zhe Zhao, Heng-Yuan Liu, and Chang-Fa Tang. Recent insights into limb-girdle muscular dystrophy: impacts, therapy, and challenges. Histology and histopathology, pages 18929, Apr 2025. URL: https://doi.org/10.14670/hh-18-929, doi:10.14670/hh-18-929. This article has 3 citations and is from a peer-reviewed journal.

  3. (luglio2024hereditaryneuromusculardisorders pages 18-19): Agnese Luglio, Elena Maggi, Francesco Nicola Riviello, Alessandro Conforti, Ugo Sorrentino, and Daniela Zuccarello. Hereditary neuromuscular disorders in reproductive medicine. Genes, 15:1409, Oct 2024. URL: https://doi.org/10.3390/genes15111409, doi:10.3390/genes15111409. This article has 8 citations.

  4. (OpenTargets Search: limb-girdle muscular dystrophy): Open Targets Query (limb-girdle muscular dystrophy, 25 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  5. (bouchard2023limb–girdlemusculardystrophies pages 5-6): Camille Bouchard and Jacques P. Tremblay. Limb–girdle muscular dystrophies classification and therapies. Journal of Clinical Medicine, 12:4769, Jul 2023. URL: https://doi.org/10.3390/jcm12144769, doi:10.3390/jcm12144769. This article has 73 citations.

  6. (lin2023clinicalfeaturesimaging pages 1-2): Feng Lin, Kang Yang, Xin Lin, Ming Jin, Long Chen, Fu-ze Zheng, Liang-liang Qiu, Zhi-xian Ye, Hai-zhu Chen, Min-ting Lin, Ning Wang, and Zhi-qiang Wang. Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of chinese patients. Orphanet Journal of Rare Diseases, Nov 2023. URL: https://doi.org/10.1186/s13023-023-02897-x, doi:10.1186/s13023-023-02897-x. This article has 17 citations and is from a peer-reviewed journal.

  7. (bouchard2023limb–girdlemusculardystrophies pages 4-5): Camille Bouchard and Jacques P. Tremblay. Limb–girdle muscular dystrophies classification and therapies. Journal of Clinical Medicine, 12:4769, Jul 2023. URL: https://doi.org/10.3390/jcm12144769, doi:10.3390/jcm12144769. This article has 73 citations.

  8. (akyurek2025zebrafishasa pages 6-7): Eylem Emek Akyürek, Martina Erba, Francesco Dalla Barba, Dorianna Sandonà, and Roberta Sacchetto. Zebrafish as a model organism for research in rare genetic neuromuscular diseases. International Journal of Molecular Sciences, 26:8832, Sep 2025. URL: https://doi.org/10.3390/ijms26188832, doi:10.3390/ijms26188832. This article has 5 citations.

  9. (anwar2024thedysferlinopathiesconundrum pages 2-3): Saeed Anwar and Toshifumi Yokota. The dysferlinopathies conundrum: clinical spectra, disease mechanism and genetic approaches for treatments. Biomolecules, 14:256, Feb 2024. URL: https://doi.org/10.3390/biom14030256, doi:10.3390/biom14030256. This article has 15 citations.

  10. (anwar2024thedysferlinopathiesconundrum pages 3-4): Saeed Anwar and Toshifumi Yokota. The dysferlinopathies conundrum: clinical spectra, disease mechanism and genetic approaches for treatments. Biomolecules, 14:256, Feb 2024. URL: https://doi.org/10.3390/biom14030256, doi:10.3390/biom14030256. This article has 15 citations.

  11. (bouchard2023limb–girdlemusculardystrophies pages 2-4): Camille Bouchard and Jacques P. Tremblay. Limb–girdle muscular dystrophies classification and therapies. Journal of Clinical Medicine, 12:4769, Jul 2023. URL: https://doi.org/10.3390/jcm12144769, doi:10.3390/jcm12144769. This article has 73 citations.

  12. (wicklund2025limbgirdlemusculardystrophy pages 2-3): Matthew P. Wicklund, Lindsay N. Alfano, Nicholas E. Johnson, Peter B. Kang, Peter Marks, Katherine D. Mathews, Jerry R. Mendell, Louise Rodino-Klapac, Douglas Sproule, Nicole Verdun, and Kathryn Bryant. Limb-girdle muscular dystrophy scientific workshop: a multistakeholder discussion focused on charting the path forward for drug development. Neurology. Clinical practice, 15 5:e200496, Oct 2025. URL: https://doi.org/10.1212/cpj.0000000000200496, doi:10.1212/cpj.0000000000200496. This article has 1 citations.

  13. (kang2023geneticpatternsof pages 9-10): Peter B. Kang, Magali Jorand-Fletcher, Wanfang Zhang, Suzanne W. McDermott, Reba Berry, Chelsea Chambers, Kristen N. Wong, Yara Mohamed, Shiny Thomas, Y Swamy Venkatesh, Christina Westfield, Nedra Whitehead, and Nicholas E. Johnson. Genetic patterns of selected muscular dystrophies in the muscular dystrophy surveillance, tracking, and research network. Neurology Genetics, Dec 2023. URL: https://doi.org/10.1212/nxg.0000000000200113, doi:10.1212/nxg.0000000000200113. This article has 7 citations.

  14. (bozzi2025misregulationofthe pages 17-19): Manuela Bozzi, Francesca Sciandra, Maria Giulia Bigotti, and Andrea Brancaccio. Misregulation of the ubiquitin–proteasome system and autophagy in muscular dystrophies associated with the dystrophin–glycoprotein complex. Cells, 14:721, May 2025. URL: https://doi.org/10.3390/cells14100721, doi:10.3390/cells14100721. This article has 2 citations.

  15. (sun2025recentinsightsinto pages 14-16): Chen-Chen Sun, Jiang-Ling Xiao, Zhe Zhao, Heng-Yuan Liu, and Chang-Fa Tang. Recent insights into limb-girdle muscular dystrophy: impacts, therapy, and challenges. Histology and histopathology, pages 18929, Apr 2025. URL: https://doi.org/10.14670/hh-18-929, doi:10.14670/hh-18-929. This article has 3 citations and is from a peer-reviewed journal.

  16. (sun2025recentinsightsinto pages 11-14): Chen-Chen Sun, Jiang-Ling Xiao, Zhe Zhao, Heng-Yuan Liu, and Chang-Fa Tang. Recent insights into limb-girdle muscular dystrophy: impacts, therapy, and challenges. Histology and histopathology, pages 18929, Apr 2025. URL: https://doi.org/10.14670/hh-18-929, doi:10.14670/hh-18-929. This article has 3 citations and is from a peer-reviewed journal.

  17. (kang2023geneticpatternsof pages 10-10): Peter B. Kang, Magali Jorand-Fletcher, Wanfang Zhang, Suzanne W. McDermott, Reba Berry, Chelsea Chambers, Kristen N. Wong, Yara Mohamed, Shiny Thomas, Y Swamy Venkatesh, Christina Westfield, Nedra Whitehead, and Nicholas E. Johnson. Genetic patterns of selected muscular dystrophies in the muscular dystrophy surveillance, tracking, and research network. Neurology Genetics, Dec 2023. URL: https://doi.org/10.1212/nxg.0000000000200113, doi:10.1212/nxg.0000000000200113. This article has 7 citations.

  18. (bouchard2023limb–girdlemusculardystrophies pages 11-12): Camille Bouchard and Jacques P. Tremblay. Limb–girdle muscular dystrophies classification and therapies. Journal of Clinical Medicine, 12:4769, Jul 2023. URL: https://doi.org/10.3390/jcm12144769, doi:10.3390/jcm12144769. This article has 73 citations.

  19. (lin2023clinicalfeaturesimaging pages 17-18): Feng Lin, Kang Yang, Xin Lin, Ming Jin, Long Chen, Fu-ze Zheng, Liang-liang Qiu, Zhi-xian Ye, Hai-zhu Chen, Min-ting Lin, Ning Wang, and Zhi-qiang Wang. Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of chinese patients. Orphanet Journal of Rare Diseases, Nov 2023. URL: https://doi.org/10.1186/s13023-023-02897-x, doi:10.1186/s13023-023-02897-x. This article has 17 citations and is from a peer-reviewed journal.

  20. (wicklund2025limbgirdlemusculardystrophy pages 12-12): Matthew P. Wicklund, Lindsay N. Alfano, Nicholas E. Johnson, Peter B. Kang, Peter Marks, Katherine D. Mathews, Jerry R. Mendell, Louise Rodino-Klapac, Douglas Sproule, Nicole Verdun, and Kathryn Bryant. Limb-girdle muscular dystrophy scientific workshop: a multistakeholder discussion focused on charting the path forward for drug development. Neurology. Clinical practice, 15 5:e200496, Oct 2025. URL: https://doi.org/10.1212/cpj.0000000000200496, doi:10.1212/cpj.0000000000200496. This article has 1 citations.

  21. (kaur2025towardsacure pages 12-14): Devinder Kaur and Akash Ajay. Towards a cure: emerging therapeutic advances for dmd, lgmd, and gnem- insights from pre-clinical and clinical research. Unknown journal, Dec 2025. URL: https://doi.org/10.20944/preprints202512.1267.v1, doi:10.20944/preprints202512.1267.v1.

  22. (kaur2025towardsacure pages 14-16): Devinder Kaur and Akash Ajay. Towards a cure: emerging therapeutic advances for dmd, lgmd, and gnem- insights from pre-clinical and clinical research. Unknown journal, Dec 2025. URL: https://doi.org/10.20944/preprints202512.1267.v1, doi:10.20944/preprints202512.1267.v1.

  23. (bouchard2023limb–girdlemusculardystrophies pages 8-9): Camille Bouchard and Jacques P. Tremblay. Limb–girdle muscular dystrophies classification and therapies. Journal of Clinical Medicine, 12:4769, Jul 2023. URL: https://doi.org/10.3390/jcm12144769, doi:10.3390/jcm12144769. This article has 73 citations.

  24. (sun2025recentinsightsinto pages 18-21): Chen-Chen Sun, Jiang-Ling Xiao, Zhe Zhao, Heng-Yuan Liu, and Chang-Fa Tang. Recent insights into limb-girdle muscular dystrophy: impacts, therapy, and challenges. Histology and histopathology, pages 18929, Apr 2025. URL: https://doi.org/10.14670/hh-18-929, doi:10.14670/hh-18-929. This article has 3 citations and is from a peer-reviewed journal.

  25. (anwar2024thedysferlinopathiesconundrum pages 15-16): Saeed Anwar and Toshifumi Yokota. The dysferlinopathies conundrum: clinical spectra, disease mechanism and genetic approaches for treatments. Biomolecules, 14:256, Feb 2024. URL: https://doi.org/10.3390/biom14030256, doi:10.3390/biom14030256. This article has 15 citations.

  26. (akyurek2025zebrafishasa pages 7-8): Eylem Emek Akyürek, Martina Erba, Francesco Dalla Barba, Dorianna Sandonà, and Roberta Sacchetto. Zebrafish as a model organism for research in rare genetic neuromuscular diseases. International Journal of Molecular Sciences, 26:8832, Sep 2025. URL: https://doi.org/10.3390/ijms26188832, doi:10.3390/ijms26188832. This article has 5 citations.

  27. (akyurek2025zebrafishasa pages 4-6): Eylem Emek Akyürek, Martina Erba, Francesco Dalla Barba, Dorianna Sandonà, and Roberta Sacchetto. Zebrafish as a model organism for research in rare genetic neuromuscular diseases. International Journal of Molecular Sciences, 26:8832, Sep 2025. URL: https://doi.org/10.3390/ijms26188832, doi:10.3390/ijms26188832. This article has 5 citations.

  28. (akyurek2025zebrafishasa pages 14-16): Eylem Emek Akyürek, Martina Erba, Francesco Dalla Barba, Dorianna Sandonà, and Roberta Sacchetto. Zebrafish as a model organism for research in rare genetic neuromuscular diseases. International Journal of Molecular Sciences, 26:8832, Sep 2025. URL: https://doi.org/10.3390/ijms26188832, doi:10.3390/ijms26188832. This article has 5 citations.

  29. (akyurek2025zebrafishasa pages 8-10): Eylem Emek Akyürek, Martina Erba, Francesco Dalla Barba, Dorianna Sandonà, and Roberta Sacchetto. Zebrafish as a model organism for research in rare genetic neuromuscular diseases. International Journal of Molecular Sciences, 26:8832, Sep 2025. URL: https://doi.org/10.3390/ijms26188832, doi:10.3390/ijms26188832. This article has 5 citations.

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