Limb-Girdle Muscular Dystrophy, Autosomal Dominant

Mendelian MONDO:0015151 Pathograph 9 Show in embeddings browser Limb-Girdle Muscular Dystrophy

Autosomal dominant limb-girdle muscular dystrophies (LGMD-D) are a genetically heterogeneous group of inherited myopathies caused by heterozygous pathogenic variants in distinct genes, sharing the cardinal clinical features of progressive proximal pelvic and shoulder girdle muscle weakness with onset after age 2 years, elevated serum creatine kinase, and dystrophic changes on muscle biopsy. The 2018 ENMC workshop reformed LGMD nomenclature and designated the autosomal dominant subtypes as LGMD-D1 (DNAJB6), LGMD-D2 (TNPO3), LGMD-D3 (HNRNPDL), LGMD-D4 (CAPN3 dominant), and LGMD-D5 (COL6A1/COL6A2/COL6A3; Bethlem myopathy). The underlying molecular mechanisms are diverse, encompassing defects in Z-disc proteostasis (LGMD-D1), nuclear import of splicing factors (LGMD-D2), RNA-binding protein phase separation and fibrillation (LGMD-D3), and sarcomere remodeling (LGMD-D4). All LGMD-D subtypes are adult-onset and slowly progressive with a generally better prognosis than autosomal recessive forms.

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1
Inheritance
5
Pathophys.
6
Phenotypes
9
Pathograph
4
Genes
4
Medical Actions
4
Subtypes
1
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
All LGMD-D subtypes follow autosomal dominant inheritance with 50% recurrence risk for offspring of affected individuals. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:39215466 SUPPORT Human Clinical
"Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity."
The ClinGen expert panel curation paper confirms the autosomal inheritance basis of LGMD including the dominant subtypes.
◆

Subtypes

4
LGMD-D1 (DNAJB6-related) MONDO:0021018
LGMD-D1 is caused by heterozygous dominant missense mutations in DNAJB6 (DnaJ heat shock protein family member B6), an Hsp40 co-chaperone localized to the Z-disc in skeletal muscle. Pathogenic variants cluster in the G/F domain and impair the protein's anti-aggregation function. The muscle-expressed b-isoform (DNAJB6b) is primarily responsible for disease pathogenesis; mutations in DNAJB6b cause myofibrillar disorganization and inclusion formation at the Z-disc. Adult-onset slowly progressive proximal pelvic girdle weakness is characteristic; rimmed vacuoles and p62/ubiquitin-positive aggregates on biopsy.
Show evidence (1 reference)
PMID:31034989 SUPPORT Human Clinical
"LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement"
This clinical case series directly characterizes LGMD-D1 as adult-onset, progressive, and caused by DNAJB6 variants.
LGMD-D2 (TNPO3-related) MONDO:0012034
LGMD-D2 is caused by heterozygous mutations in TNPO3 (transportin-3), a nuclear import receptor for SR domain-containing serine/arginine-rich splicing factors. Pathogenic TNPO3 variants impair nuclear import of splicing factors such as SRSF1, leading to their cytoplasmic mislocalization and aggregation, myofibrillar disorganization, and progressive muscle weakness. The clinical presentation includes variable age of onset, proximal pelvic and shoulder girdle weakness, calf hypertrophy, and dysphagia.
Show evidence (1 reference)
PMID:32690349 SUPPORT Human Clinical
"LGMD D2 is a disease caused by TNPO3 mutation. We describe the expression of TNPO3 and selected proteins, likely modified by TNPO3 mutation, in muscle biopsies of affected patients."
This morphological study directly characterizes LGMD-D2 as caused by TNPO3 mutation and documents associated protein expression changes in patient muscle biopsies.
LGMD-D3 (HNRNPDL-related) MONDO:0012193
LGMD-D3 is caused by heterozygous missense mutations in HNRNPDL (heterogeneous nuclear ribonucleoprotein D-like), an RNA-binding protein involved in transcription and RNA processing. Pathogenic mutations cluster in the prion-like domain (codon 378 is a mutational hotspot) and alter the protein's self-assembly properties. Cryo-EM evidence suggests LGMD-D3 may be a loss-of-function disease associated with impaired fibrillation of the functional hnRNPDL-2 amyloid. Clinical features include adult-onset proximal limb-girdle weakness, rimmed vacuoles on biopsy, and finger/toe flexion limitation.
Show evidence (1 reference)
PMID:30604053 SUPPORT Human Clinical
"Twenty-four recessive LGMD (types R1-R24) and five dominant LGMD (types D1-D5) have been identified with characterization of mutations in various genes."
Confirms the five-subtype LGMD-D classification framework, within which LGMD-D3 is the HNRNPDL-related dominant subtype.
LGMD-D4 (CAPN3-related, dominant) MONDO:0029133
LGMD-D4 is caused by heterozygous dominant-acting pathogenic variants in CAPN3 (calpain-3), a calcium-dependent cytoplasmic cysteine protease essential for sarcomere remodeling. CAPN3 also causes autosomal recessive calpainopathy (LGMD-R1); the dominant form is clinically milder and more variable than the recessive form, ranging from near-asymptomatic to wheelchair dependence in late adulthood. Reduced calpain-3 immunoblot in muscle biopsy is a diagnostic feature. Dominant variants are thought to act via haploinsufficiency or dominant-negative mechanisms.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"The autosomal dominant form of calpainopathy is clinically variable, ranging from almost asymptomatic to wheelchair dependence after age 60 years in a few individuals; phenotype is generally milder than the recessive form."
The GeneReviews for calpainopathy (PMID:20301490) directly describes the clinical features of the dominant form of CAPN3-related disease.
⚙

Pathophysiology

5
DNAJB6b Co-Chaperone Dysfunction and Z-Disc Aggregate Formation
DNAJB6 is an Hsp40 co-chaperone that suppresses aggregation of polyglutamine and amyloidogenic proteins. In skeletal muscle, the b-isoform (DNAJB6b) is sarcoplasmic and localizes to the Z-disc. Dominant missense mutations in the G/F domain impair DNAJB6b's anti-aggregation function, causing accumulation of protein aggregates at the Z-disc and myofibrillar disorganization. Inclusion bodies containing DNAJB6, Z-disc proteins (desmin), TDP-43, and RNA-binding proteins hnRNPA1/A2B1 form as sarcoplasmic stress granules. These aggregates disrupt sarcomere organization, leading to progressive myofiber dysfunction. The b-isoform is disease-specific; DNAJB6a mutations alone are insufficient to cause disease.
skeletal muscle fiber CL:0008002
DNAJB6 hgnc:14888
protein quality control for misfolded or incompletely synthesized proteins GO:0006515 ↓ DECREASED sarcomere organization GO:0045214 ↓ DECREASED
Downstream
Progressive Proximal Myofiber Degeneration and Weakness Z-disc aggregate accumulation and impaired proteostasis lead to progressive myofiber injury, degeneration with rimmed vacuoles, and limb-girdle muscle weakness in LGMD-D1.
Show evidence (2 references)
PMID:26362252 SUPPORT Model Organism
"Limb-girdle muscular dystrophy type 1D (LGMD1D) is caused by dominantly inherited missense mutations in DNAJB6, an Hsp40 co-chaperone. LGMD1D muscle has rimmed vacuoles and inclusion bodies containing DNAJB6, Z-disc proteins and TDP-43."
This mouse model study defines the molecular mechanism of LGMD-D1: DNAJB6b dysfunction leads to Z-disc aggregate formation and myofibrillar disruption.
PMID:37346979 SUPPORT Model Organism
"Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests..."
Confirms the isoform-specific pathogenesis of LGMD-D1 with DNAJB6b as the primary driver.
TNPO3 Nuclear Import Defect and Splicing Factor Mislocalization
TNPO3 (transportin-3) is a nuclear import receptor (importin beta family) that shuttles SR-rich serine/arginine-containing domain splicing factors, including SRSF1, from the cytoplasm to the nucleus. Pathogenic heterozygous TNPO3 variants reduce nuclear import of SR splicing factors, resulting in cytoplasmic mislocalization and sporadic cytoplasmic TNPO3 aggregates. Mislocalization of SRSF1 and altered sarcomeric alpha-actinin distribution indicate impaired pre-mRNA splicing and myofibrillar organization. In silico analysis implicates downstream effects on muscle contraction pathway genes (TNPO3, SRSF1, p62, MuRF-1), pointing to myofibrillar network dysfunction as the proximal cause of weakness.
skeletal muscle fiber CL:0008002
TNPO3 hgnc:17103
protein import into nucleus GO:0006606 ↓ DECREASED mRNA processing GO:0006397 ↓ DECREASED
Downstream
Progressive Proximal Myofiber Degeneration and Weakness Splicing factor mislocalization and myofibrillar disorganization caused by mutant TNPO3 lead to progressive proximal muscle weakness in LGMD-D2.
Show evidence (1 reference)
PMID:32690349 SUPPORT Human Clinical
"In patients' muscles TNPO3 appeared weaker and randomly organized, with sporadic cytoplasmic aggregates positive for TNPO3; both SRSF1 and sarcomeric alpha actinin showed a different expression, while there were no alterations in the expression of the nuclear proteins."
Direct morphological evidence in LGMD-D2 patient muscle biopsies showing TNPO3 and SRSF1 misexpression consistent with nuclear import failure.
HNRNPDL Prion-Like Domain Mutation and Impaired Functional Fibrillation
HNRNPDL (heterogeneous nuclear ribonucleoprotein D-like) is a ribonucleoprotein involved in transcription regulation and mRNA processing. The protein contains a prion-like domain (PLD) that enables regulated liquid-liquid phase separation and functional amyloid fibril assembly. The predominant human isoform hnRNPDL-2 forms stable, non-toxic, nucleic acid-binding functional amyloid fibrils. Pathogenic missense mutations in the PLD (codon 378 is a mutational hotspot) alter the protein's self-assembly properties. Cryo-EM structural evidence suggests that LGMD-D3 may represent a loss-of-function disease caused by impaired fibrillation of hnRNPDL-2, rather than toxic aggregation. Alternatively, accelerated intrinsic self-aggregation may cause pathological aggregate accumulation; rimmed vacuoles on muscle biopsy are a consistent histological finding.
skeletal muscle fiber CL:0008002
HNRNPDL hgnc:5037
mRNA processing GO:0006397 ↓ DECREASED
Downstream
Progressive Proximal Myofiber Degeneration and Weakness Aberrant HNRNPDL assembly impairs mRNA metabolism and leads to muscle fiber dysfunction with rimmed vacuoles, and progressive proximal weakness.
Show evidence (3 references)
PMID:36646699 SUPPORT In Vitro
"hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3)."
Establishes the molecular identity of HNRNPDL as the causative gene/protein in LGMD-D3 and its role in RNA processing.
PMID:36646699 SUPPORT In Vitro
"our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation"
Cryo-EM structural evidence supports a loss-of-function model for LGMD-D3 pathogenesis via impaired hnRNPDL-2 fibril assembly.
PMID:30604053 SUPPORT Human Clinical
"Acceleration of intrinsic self-aggregation of HNRNPDL caused by mutation of the prior-like domain may contribute to the pathogenesis of the disease."
Alternative pathogenesis model: pathological self-aggregation driven by PLD mutations. This complements the loss-of-function model.
Dominant-Negative CAPN3 Dysfunction and Sarcomere Remodeling Defect
Calpain-3 (CAPN3) is a calcium-dependent cysteine protease essential for sarcomere remodeling during muscle contraction cycles and repair. In the autosomal recessive form (LGMD-R1), biallelic loss-of-function variants cause calpain-3 deficiency. In the dominant LGMD-D4, heterozygous pathogenic CAPN3 variants act via haploinsufficiency or dominant-negative mechanisms, reducing total calpain-3 activity in muscle. Impaired calpain-3-mediated sarcomere remodeling disrupts myofibril maintenance, leading to dystrophic changes on biopsy and progressive weakness. The dominant form is generally milder than the recessive form; CK elevation and reduced calpain-3 immunoblot are characteristic.
skeletal muscle fiber CL:0008002
CAPN3 hgnc:1480
sarcomere organization GO:0045214 ↓ DECREASED
Downstream
Progressive Proximal Myofiber Degeneration and Weakness Impaired calpain-3-mediated sarcomere remodeling leads to myofiber degeneration and progressive proximal limb-girdle muscle weakness in LGMD-D4.
Show evidence (2 references)
PMID:20301490 SUPPORT Human Clinical
"The diagnosis of calpainopathy is established by identification of biallelic pathogenic variants in CAPN3 or a dominantly acting heterozygous CAPN3 pathogenic variant by molecular genetic testing."
The GeneReviews for calpainopathy directly identifies heterozygous dominant CAPN3 pathogenic variants as the genetic basis of the dominant form.
PMID:39215466 SUPPORT Human Clinical
"Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns"
ClinGen expert panel confirms CAPN3 as causing two distinct disease entities based on inheritance pattern, including the dominant form (LGMD-D4).
Progressive Proximal Myofiber Degeneration and Weakness
The converging downstream consequence shared by all LGMD-D subtypes is progressive skeletal muscle fiber degeneration with inadequate regenerative response. Histologically, this manifests as dystrophic changes: increased fiber size variation, central nuclei, necrosis and regeneration, fibrofatty infiltration, and in LGMD-D1 and D3, rimmed vacuoles with protein aggregates. Clinically, the shared end result is progressive proximal pelvic and shoulder girdle weakness causing functional limitations including difficulty walking, climbing stairs, rising from a chair, and lifting arms. Serum creatine kinase is elevated in all subtypes, reflecting ongoing sarcolemmal injury.
skeletal muscle fiber CL:0008002 skeletal muscle satellite cell CL:0000594
skeletal muscle tissue regeneration GO:0043403 ↓ DECREASED
Show evidence (1 reference)
PMID:39215466 SUPPORT Human Clinical
"LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
ClinGen expert panel establishes the shared clinical definition of LGMD applicable to all subtypes including the dominant forms.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Limb-Girdle Muscular Dystrophy, Autosomal Dominant 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

6
Metabolism 1
Elevated Serum Creatine Kinase Elevated circulating creatine kinase concentration HP:0003236
Show evidence (1 reference)
PMID:39215466 SUPPORT Human Clinical
"LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
Elevated CK is part of the defining clinical criteria for LGMD per the ClinGen expert panel framework.
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."
GeneReviews documents waddling gait as a clinical feature of calpainopathy (LGMD-D4) and by extension other LGMD-D forms with pelvic girdle weakness.
Other 4
Limb-Girdle Muscle Weakness Limb-girdle muscle weakness HP:0003325
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:39215466 SUPPORT Human Clinical
"LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
The ClinGen expert panel curation defines progressive proximal weakness as a cardinal feature of all LGMD subtypes including dominant forms.
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."
GeneReviews documents scapular winging as a clinical feature of calpainopathy (LGMD-D4) and by extension other LGMD-D forms.
Progressive Proximal Muscle Weakness Progressive proximal muscle weakness HP:0009073
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:31034989 SUPPORT Human Clinical
"LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement"
Adult-onset moderately progressive proximal weakness without respiratory or bulbar involvement is characteristic of LGMD-D1 and similar for other LGMD-D subtypes.
Abnormal Muscle Fiber Morphology Abnormal muscle fiber morphology HP:0004303
Show evidence (1 reference)
PMID:39215466 SUPPORT Human Clinical
"LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
Dystrophic features on muscle biopsy are part of the LGMD diagnostic criteria per ClinGen expert panel.
🧬

Genetic Associations

4
DNAJB6 (Causative)
Gene: DNAJB6 hgnc:14888 variant_origin: GERMLINE
Show evidence (1 reference)
PMID:37346979 SUPPORT Model Organism
"Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available."
Confirms DNAJB6 as the causative gene for LGMD-D1.
TNPO3 (Causative)
Gene: TNPO3 hgnc:17103 variant_origin: GERMLINE
Show evidence (1 reference)
PMID:32690349 SUPPORT Human Clinical
"LGMD D2 is a disease caused by TNPO3 mutation."
Directly identifies TNPO3 mutation as the cause of LGMD-D2.
HNRNPDL (Causative)
Gene: HNRNPDL hgnc:5037 variant_origin: GERMLINE
Show evidence (1 reference)
PMID:30604053 SUPPORT Human Clinical
"Sequencing analysis revealed a heterozygous c.1132G > A (p.D378N) mutation in HNRNPDL that co-segregated with disease phenotype in the family."
Documents the co-segregation of HNRNPDL p.D378N with LGMD-D3 in a Chinese family, confirming HNRNPDL as the causative gene.
CAPN3 (Dominant) (Causative)
Gene: CAPN3 hgnc:1480 variant_origin: GERMLINE
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"The diagnosis of calpainopathy is established by identification of biallelic pathogenic variants in CAPN3 or a dominantly acting heterozygous CAPN3 pathogenic variant by molecular genetic testing."
GeneReviews identifies dominantly acting heterozygous CAPN3 pathogenic variants as a distinct form of calpainopathy (LGMD-D4).
💊

Medical Actions

4
Physical Therapy and Rehabilitation
Action: physical therapy MAXO:0000011
Physical therapy and stretching exercises to promote mobility, maintain muscle strength, and prevent contractures are the mainstay of management for all LGMD-D subtypes. Low-impact aerobic exercise is beneficial; strenuous exercise should be avoided. Respiratory physiotherapy is recommended for patients with late-stage respiratory involvement.
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"
GeneReviews for calpainopathy recommends physical therapy and supervised low-impact exercise as a key management component.
Mobility Aids
Action: supportive care MAXO:0000950
As disease progresses, mobility aids including canes, walkers, orthotics, and wheelchairs help maintain independence and quality of life for patients with LGMD-D. Knee-ankle-foot orthoses may prevent contractures.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"mobility aids such as canes, walkers, orthotics, and wheelchairs to help maintain independence; knee-ankle-foot orthoses while sleeping to prevent contractures"
GeneReviews for calpainopathy recommends mobility aids as a management component, applicable to all LGMD-D subtypes.
Genetic Counseling
Action: genetic counseling MAXO:0000079
All LGMD-D subtypes follow autosomal dominant inheritance with 50% recurrence risk for offspring of affected individuals. Genetic counseling regarding recurrence risk, cascade genetic testing of at-risk relatives, and discussion of reproductive options including preimplantation genetic testing are recommended.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Each child of an individual with autosomal dominant calpainopathy has a 50% chance of inheriting the CAPN3 pathogenic variant."
Genetic counseling regarding 50% inheritance risk is relevant for all LGMD-D subtypes.
DNAJB6-b Isoform-Specific Antisense Oligonucleotide Therapy (Investigational)
Action: Pharmacotherapy NCIT:C15986
Isoform-specific knockdown of the DNAJB6b (muscle-expressed) isoform using morpholino antisense oligonucleotides has shown preclinical therapeutic potential in LGMD-D1. The approach exploits selective muscle expression of the pathogenic b-isoform; selective reduction of DNAJB6b corrected much of the LGMD-D1 proteomic disease signature in primary myotubes and mouse models. This is investigational and not yet in clinical trials.
Show evidence (1 reference)
PMID:37346979 SUPPORT Model Organism
"Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature toward wild type levels."
Preclinical evidence supports DNAJB6b isoform-specific knockdown as a therapeutic strategy for LGMD-D1, with morpholino ASOs showing efficacy in vitro and in vivo mouse models.
{ }

Source YAML

click to show 
name: Limb-Girdle Muscular Dystrophy, Autosomal Dominant
creation_date: "2026-07-01T00:00:00Z"
category: Mendelian
description: >-
  Autosomal dominant limb-girdle muscular dystrophies (LGMD-D) are a genetically
  heterogeneous group of inherited myopathies caused by heterozygous pathogenic
  variants in distinct genes, sharing the cardinal clinical features of progressive
  proximal pelvic and shoulder girdle muscle weakness with onset after age 2 years,
  elevated serum creatine kinase, and dystrophic changes on muscle biopsy. The 2018
  ENMC workshop reformed LGMD nomenclature and designated the autosomal dominant
  subtypes as LGMD-D1 (DNAJB6), LGMD-D2 (TNPO3), LGMD-D3 (HNRNPDL), LGMD-D4
  (CAPN3 dominant), and LGMD-D5 (COL6A1/COL6A2/COL6A3; Bethlem myopathy). The
  underlying molecular mechanisms are diverse, encompassing defects in Z-disc
  proteostasis (LGMD-D1), nuclear import of splicing factors (LGMD-D2), RNA-binding
  protein phase separation and fibrillation (LGMD-D3), and sarcomere remodeling
  (LGMD-D4). All LGMD-D subtypes are adult-onset and slowly progressive with a
  generally better prognosis than autosomal recessive forms.

disease_term:
  preferred_term: muscular dystrophy, limb-girdle, autosomal dominant
  term:
    id: MONDO:0015151
    label: muscular dystrophy, limb-girdle, autosomal dominant

synonyms:
  - autosomal dominant limb-girdle muscular dystrophy
  - LGMD-D
  - AD-LGMD

parents:
  - Limb-Girdle Muscular Dystrophy

has_subtypes:
  - name: LGMD-D1
    display_name: LGMD-D1 (DNAJB6-related)
    subtype_term:
      preferred_term: autosomal dominant limb-girdle muscular dystrophy type 1D
      term:
        id: MONDO:0021018
        label: autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)
    description: >-
      LGMD-D1 is caused by heterozygous dominant missense mutations in DNAJB6
      (DnaJ heat shock protein family member B6), an Hsp40 co-chaperone localized
      to the Z-disc in skeletal muscle. Pathogenic variants cluster in the G/F
      domain and impair the protein's anti-aggregation function. The muscle-expressed
      b-isoform (DNAJB6b) is primarily responsible for disease pathogenesis; mutations
      in DNAJB6b cause myofibrillar disorganization and inclusion formation at the
      Z-disc. Adult-onset slowly progressive proximal pelvic girdle weakness is
      characteristic; rimmed vacuoles and p62/ubiquitin-positive aggregates on biopsy.
    evidence:
      - reference: PMID:31034989
        reference_title: "Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement"
        explanation: >-
          This clinical case series directly characterizes LGMD-D1 as adult-onset,
          progressive, and caused by DNAJB6 variants.

  - name: LGMD-D2
    display_name: LGMD-D2 (TNPO3-related)
    subtype_term:
      preferred_term: autosomal dominant limb-girdle muscular dystrophy type 1F
      term:
        id: MONDO:0012034
        label: autosomal dominant limb-girdle muscular dystrophy type 1F
    description: >-
      LGMD-D2 is caused by heterozygous mutations in TNPO3 (transportin-3), a
      nuclear import receptor for SR domain-containing serine/arginine-rich splicing
      factors. Pathogenic TNPO3 variants impair nuclear import of splicing factors
      such as SRSF1, leading to their cytoplasmic mislocalization and aggregation,
      myofibrillar disorganization, and progressive muscle weakness. The clinical
      presentation includes variable age of onset, proximal pelvic and shoulder
      girdle weakness, calf hypertrophy, and dysphagia.
    evidence:
      - reference: PMID:32690349
        reference_title: "Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD D2 is a disease caused by TNPO3 mutation. We describe the expression of TNPO3 and selected proteins, likely modified by TNPO3 mutation, in muscle biopsies of affected patients."
        explanation: >-
          This morphological study directly characterizes LGMD-D2 as caused by
          TNPO3 mutation and documents associated protein expression changes in
          patient muscle biopsies.

  - name: LGMD-D3
    display_name: LGMD-D3 (HNRNPDL-related)
    subtype_term:
      preferred_term: autosomal dominant limb-girdle muscular dystrophy type 1G
      term:
        id: MONDO:0012193
        label: autosomal dominant limb-girdle muscular dystrophy type 1G
    description: >-
      LGMD-D3 is caused by heterozygous missense mutations in HNRNPDL (heterogeneous
      nuclear ribonucleoprotein D-like), an RNA-binding protein involved in
      transcription and RNA processing. Pathogenic mutations cluster in the prion-like
      domain (codon 378 is a mutational hotspot) and alter the protein's self-assembly
      properties. Cryo-EM evidence suggests LGMD-D3 may be a loss-of-function disease
      associated with impaired fibrillation of the functional hnRNPDL-2 amyloid.
      Clinical features include adult-onset proximal limb-girdle weakness, rimmed
      vacuoles on biopsy, and finger/toe flexion limitation.
    evidence:
      - reference: PMID:30604053
        reference_title: "Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Twenty-four recessive LGMD (types R1-R24) and five dominant LGMD (types D1-D5) have been identified with characterization of mutations in various genes."
        explanation: >-
          Confirms the five-subtype LGMD-D classification framework, within which
          LGMD-D3 is the HNRNPDL-related dominant subtype.

  - name: LGMD-D4
    display_name: LGMD-D4 (CAPN3-related, dominant)
    subtype_term:
      preferred_term: muscular dystrophy, limb-girdle, autosomal dominant 4
      term:
        id: MONDO:0029133
        label: muscular dystrophy, limb-girdle, autosomal dominant 4
    description: >-
      LGMD-D4 is caused by heterozygous dominant-acting pathogenic variants in
      CAPN3 (calpain-3), a calcium-dependent cytoplasmic cysteine protease essential
      for sarcomere remodeling. CAPN3 also causes autosomal recessive calpainopathy
      (LGMD-R1); the dominant form is clinically milder and more variable than the
      recessive form, ranging from near-asymptomatic to wheelchair dependence in
      late adulthood. Reduced calpain-3 immunoblot in muscle biopsy is a diagnostic
      feature. Dominant variants are thought to act via haploinsufficiency or
      dominant-negative mechanisms.
    evidence:
      - reference: PMID:20301490
        reference_title: "Calpainopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The autosomal dominant form of calpainopathy is clinically variable, ranging from almost asymptomatic to wheelchair dependence after age 60 years in a few individuals; phenotype is generally milder than the recessive form."
        explanation: >-
          The GeneReviews for calpainopathy (PMID:20301490) directly describes the
          clinical features of the dominant form of CAPN3-related disease.

inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      All LGMD-D subtypes follow autosomal dominant inheritance with 50% recurrence
      risk for offspring of affected individuals. Each child of an affected individual
      has a 50% chance of inheriting the pathogenic variant.
    evidence:
      - reference: PMID:39215466
        reference_title: "Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity."
        explanation: >-
          The ClinGen expert panel curation paper confirms the autosomal inheritance
          basis of LGMD including the dominant subtypes.

pathophysiology:
  - name: DNAJB6b Co-Chaperone Dysfunction and Z-Disc Aggregate Formation
    description: >-
      DNAJB6 is an Hsp40 co-chaperone that suppresses aggregation of polyglutamine
      and amyloidogenic proteins. In skeletal muscle, the b-isoform (DNAJB6b) is
      sarcoplasmic and localizes to the Z-disc. Dominant missense mutations in the
      G/F domain impair DNAJB6b's anti-aggregation function, causing accumulation of
      protein aggregates at the Z-disc and myofibrillar disorganization. Inclusion
      bodies containing DNAJB6, Z-disc proteins (desmin), TDP-43, and RNA-binding
      proteins hnRNPA1/A2B1 form as sarcoplasmic stress granules. These aggregates
      disrupt sarcomere organization, leading to progressive myofiber dysfunction.
      The b-isoform is disease-specific; DNAJB6a mutations alone are insufficient
      to cause disease.
    subtypes:
      - LGMD-D1
    genes:
      - preferred_term: DNAJB6
        term:
          id: hgnc:14888
          label: DNAJB6
    cell_types:
      - preferred_term: skeletal muscle fiber
        term:
          id: CL:0008002
          label: skeletal muscle fiber
    biological_processes:
      - preferred_term: protein quality control for misfolded or incompletely synthesized proteins
        term:
          id: GO:0006515
          label: protein quality control for misfolded or incompletely synthesized proteins
        modifier: DECREASED
      - preferred_term: sarcomere organization
        term:
          id: GO:0045214
          label: sarcomere organization
        modifier: DECREASED
    evidence:
      - reference: PMID:26362252
        reference_title: "Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Limb-girdle muscular dystrophy type 1D (LGMD1D) is caused by dominantly inherited missense mutations in DNAJB6, an Hsp40 co-chaperone. LGMD1D muscle has rimmed vacuoles and inclusion bodies containing DNAJB6, Z-disc proteins and TDP-43."
        explanation: >-
          This mouse model study defines the molecular mechanism of LGMD-D1: DNAJB6b
          dysfunction leads to Z-disc aggregate formation and myofibrillar disruption.
      - reference: PMID:37346979
        reference_title: "DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests that DNAJB6b is primarily responsible for disease pathogenesis."
        explanation: >-
          Confirms the isoform-specific pathogenesis of LGMD-D1 with DNAJB6b as the
          primary driver.
    downstream:
      - target: Progressive Proximal Myofiber Degeneration and Weakness
        description: >-
          Z-disc aggregate accumulation and impaired proteostasis lead to progressive
          myofiber injury, degeneration with rimmed vacuoles, and limb-girdle muscle
          weakness in LGMD-D1.
        evidence:
          - reference: PMID:31034989
            reference_title: "Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement"
            explanation: >-
              Clinical evidence links DNAJB6 dysfunction to moderately progressive
              proximal muscle weakness in adult-onset LGMD-D1.

  - name: TNPO3 Nuclear Import Defect and Splicing Factor Mislocalization
    description: >-
      TNPO3 (transportin-3) is a nuclear import receptor (importin beta family) that
      shuttles SR-rich serine/arginine-containing domain splicing factors, including
      SRSF1, from the cytoplasm to the nucleus. Pathogenic heterozygous TNPO3 variants
      reduce nuclear import of SR splicing factors, resulting in cytoplasmic
      mislocalization and sporadic cytoplasmic TNPO3 aggregates. Mislocalization of
      SRSF1 and altered sarcomeric alpha-actinin distribution indicate impaired
      pre-mRNA splicing and myofibrillar organization. In silico analysis implicates
      downstream effects on muscle contraction pathway genes (TNPO3, SRSF1, p62,
      MuRF-1), pointing to myofibrillar network dysfunction as the proximal cause of
      weakness.
    subtypes:
      - LGMD-D2
    genes:
      - preferred_term: TNPO3
        term:
          id: hgnc:17103
          label: TNPO3
    cell_types:
      - preferred_term: skeletal muscle fiber
        term:
          id: CL:0008002
          label: skeletal muscle fiber
    biological_processes:
      - preferred_term: protein import into nucleus
        term:
          id: GO:0006606
          label: protein import into nucleus
        modifier: DECREASED
      - preferred_term: mRNA processing
        term:
          id: GO:0006397
          label: mRNA processing
        modifier: DECREASED
    evidence:
      - reference: PMID:32690349
        reference_title: "Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "In patients' muscles TNPO3 appeared weaker and randomly organized, with sporadic cytoplasmic aggregates positive for TNPO3; both SRSF1 and sarcomeric alpha actinin showed a different expression, while there were no alterations in the expression of the nuclear proteins."
        explanation: >-
          Direct morphological evidence in LGMD-D2 patient muscle biopsies showing
          TNPO3 and SRSF1 misexpression consistent with nuclear import failure.
    downstream:
      - target: Progressive Proximal Myofiber Degeneration and Weakness
        description: >-
          Splicing factor mislocalization and myofibrillar disorganization caused by
          mutant TNPO3 lead to progressive proximal muscle weakness in LGMD-D2.
        evidence:
          - reference: PMID:32690349
            reference_title: "Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "possible interference in the morphology and function of myofibrillar network by mutated TNPO3"
            explanation: >-
              A morphological study of LGMD-D2 patient muscle biopsies concluded
              that mutated TNPO3 interferes with the morphology and function of the
              myofibrillar network, supporting the myofibrillar-disorganization step
              that underlies progression to proximal muscle weakness in LGMD-D2.

  - name: HNRNPDL Prion-Like Domain Mutation and Impaired Functional Fibrillation
    description: >-
      HNRNPDL (heterogeneous nuclear ribonucleoprotein D-like) is a ribonucleoprotein
      involved in transcription regulation and mRNA processing. The protein contains
      a prion-like domain (PLD) that enables regulated liquid-liquid phase separation
      and functional amyloid fibril assembly. The predominant human isoform hnRNPDL-2
      forms stable, non-toxic, nucleic acid-binding functional amyloid fibrils.
      Pathogenic missense mutations in the PLD (codon 378 is a mutational hotspot)
      alter the protein's self-assembly properties. Cryo-EM structural evidence
      suggests that LGMD-D3 may represent a loss-of-function disease caused by
      impaired fibrillation of hnRNPDL-2, rather than toxic aggregation. Alternatively,
      accelerated intrinsic self-aggregation may cause pathological aggregate
      accumulation; rimmed vacuoles on muscle biopsy are a consistent histological
      finding.
    subtypes:
      - LGMD-D3
    genes:
      - preferred_term: HNRNPDL
        term:
          id: hgnc:5037
          label: HNRNPDL
    cell_types:
      - preferred_term: skeletal muscle fiber
        term:
          id: CL:0008002
          label: skeletal muscle fiber
    biological_processes:
      - preferred_term: mRNA processing
        term:
          id: GO:0006397
          label: mRNA processing
        modifier: DECREASED
    evidence:
      - reference: PMID:36646699
        reference_title: "Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3)."
        explanation: >-
          Establishes the molecular identity of HNRNPDL as the causative gene/protein
          in LGMD-D3 and its role in RNA processing.
      - reference: PMID:36646699
        reference_title: "Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation"
        explanation: >-
          Cryo-EM structural evidence supports a loss-of-function model for LGMD-D3
          pathogenesis via impaired hnRNPDL-2 fibril assembly.
      - reference: PMID:30604053
        reference_title: "Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Acceleration of intrinsic self-aggregation of HNRNPDL caused by mutation of the prior-like domain may contribute to the pathogenesis of the disease."
        explanation: >-
          Alternative pathogenesis model: pathological self-aggregation driven by
          PLD mutations. This complements the loss-of-function model.
    downstream:
      - target: Progressive Proximal Myofiber Degeneration and Weakness
        description: >-
          Aberrant HNRNPDL assembly impairs mRNA metabolism and leads to muscle
          fiber dysfunction with rimmed vacuoles, and progressive proximal weakness.
        evidence:
          - reference: PMID:30604053
            reference_title: "Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "distal as well as proximal limb weakness"
            explanation: >-
              An HNRNPDL prion-like-domain mutation family exhibited proximal (in
              addition to distal) limb weakness, supporting HNRNPDL dysfunction as a
              cause of proximal limb-girdle muscle weakness in LGMD-D3. The
              phenotypic spectrum ranges from proximal-predominant to
              distal-predominant presentations.

  - name: Dominant-Negative CAPN3 Dysfunction and Sarcomere Remodeling Defect
    description: >-
      Calpain-3 (CAPN3) is a calcium-dependent cysteine protease essential for
      sarcomere remodeling during muscle contraction cycles and repair. In the
      autosomal recessive form (LGMD-R1), biallelic loss-of-function variants cause
      calpain-3 deficiency. In the dominant LGMD-D4, heterozygous pathogenic CAPN3
      variants act via haploinsufficiency or dominant-negative mechanisms, reducing
      total calpain-3 activity in muscle. Impaired calpain-3-mediated sarcomere
      remodeling disrupts myofibril maintenance, leading to dystrophic changes on
      biopsy and progressive weakness. The dominant form is generally milder than
      the recessive form; CK elevation and reduced calpain-3 immunoblot are
      characteristic.
    subtypes:
      - LGMD-D4
    genes:
      - preferred_term: CAPN3
        term:
          id: hgnc:1480
          label: CAPN3
    cell_types:
      - preferred_term: skeletal muscle fiber
        term:
          id: CL:0008002
          label: skeletal muscle fiber
    biological_processes:
      - preferred_term: sarcomere organization
        term:
          id: GO:0045214
          label: sarcomere organization
        modifier: DECREASED
    evidence:
      - reference: PMID:20301490
        reference_title: "Calpainopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The diagnosis of calpainopathy is established by identification of biallelic pathogenic variants in CAPN3 or a dominantly acting heterozygous CAPN3 pathogenic variant by molecular genetic testing."
        explanation: >-
          The GeneReviews for calpainopathy directly identifies heterozygous dominant
          CAPN3 pathogenic variants as the genetic basis of the dominant form.
      - reference: PMID:39215466
        reference_title: "Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns"
        explanation: >-
          ClinGen expert panel confirms CAPN3 as causing two distinct disease entities
          based on inheritance pattern, including the dominant form (LGMD-D4).
    downstream:
      - target: Progressive Proximal Myofiber Degeneration and Weakness
        description: >-
          Impaired calpain-3-mediated sarcomere remodeling leads to myofiber
          degeneration and progressive proximal limb-girdle muscle weakness in
          LGMD-D4.
        evidence:
          - reference: PMID:20301490
            reference_title: "Calpainopathy."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "progressive weakness of proximal limb-girdle muscles"
            explanation: >-
              GeneReviews describes calpainopathy as progressive weakness of the
              proximal limb-girdle muscles, supporting the causal link from
              CAPN3-mediated sarcomere remodeling defect to progressive proximal
              weakness in LGMD-D4.

  - name: Progressive Proximal Myofiber Degeneration and Weakness
    description: >-
      The converging downstream consequence shared by all LGMD-D subtypes is
      progressive skeletal muscle fiber degeneration with inadequate regenerative
      response. Histologically, this manifests as dystrophic changes: increased fiber
      size variation, central nuclei, necrosis and regeneration, fibrofatty
      infiltration, and in LGMD-D1 and D3, rimmed vacuoles with protein aggregates.
      Clinically, the shared end result is progressive proximal pelvic and shoulder
      girdle weakness causing functional limitations including difficulty walking,
      climbing stairs, rising from a chair, and lifting arms. Serum creatine kinase
      is elevated in all subtypes, reflecting ongoing sarcolemmal injury.
    cell_types:
      - preferred_term: skeletal muscle fiber
        term:
          id: CL:0008002
          label: skeletal muscle fiber
      - preferred_term: skeletal muscle satellite cell
        term:
          id: CL:0000594
          label: skeletal muscle satellite cell
    biological_processes:
      - preferred_term: skeletal muscle tissue regeneration
        term:
          id: GO:0043403
          label: skeletal muscle tissue regeneration
        modifier: DECREASED
    evidence:
      - reference: PMID:39215466
        reference_title: "Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
        explanation: >-
          ClinGen expert panel establishes the shared clinical definition of LGMD
          applicable to all subtypes including the dominant forms.

phenotypes:
  - name: Limb-Girdle Muscle Weakness
    category: Neurological
    description: >-
      Progressive proximal muscle weakness predominantly involving the pelvic
      and shoulder girdle muscles. This is the cardinal manifestation shared by
      all LGMD-D subtypes. Pelvic girdle muscles (hip flexors, glutei) are typically
      affected first, with later involvement of shoulder girdle muscles. Onset is
      usually in adulthood. Waddling gait and difficulty rising from a chair are
      common early symptoms.
    phenotype_term:
      preferred_term: Limb-girdle muscle weakness
      term:
        id: HP:0003325
        label: Limb-girdle muscle weakness
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:39215466
        reference_title: "Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
        explanation: >-
          The ClinGen expert panel curation defines progressive proximal weakness as
          a cardinal feature of all LGMD subtypes including dominant forms.

  - name: Elevated Serum Creatine Kinase
    category: Biochemical
    description: >-
      Elevated serum creatine kinase (CK) is a consistent laboratory finding across
      all LGMD-D subtypes, reflecting ongoing sarcolemmal injury and muscle fiber
      necrosis. Levels range from mildly to markedly elevated (typically 2-10x
      normal) but vary by subtype and disease stage.
    phenotype_term:
      preferred_term: Elevated serum creatine kinase
      term:
        id: HP:0003236
        label: Elevated circulating creatine kinase concentration
    evidence:
      - reference: PMID:39215466
        reference_title: "Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
        explanation: >-
          Elevated CK is part of the defining clinical criteria for LGMD per the
          ClinGen expert panel framework.

  - name: Scapular Winging
    category: Neurological
    description: >-
      Winging of the scapulae due to periscapular and serratus anterior muscle
      weakness is frequently observed in LGMD-D subtypes, particularly as
      shoulder girdle involvement develops with disease progression.
    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: >-
          GeneReviews documents scapular winging as a clinical feature of
          calpainopathy (LGMD-D4) and by extension other LGMD-D forms.

  - name: Progressive Proximal Muscle Weakness
    category: Neurological
    description: >-
      Adult-onset slowly progressive weakness predominantly affecting proximal
      muscle groups. Pelvic girdle muscles are typically more affected early,
      leading to gait difficulties including waddling gait, difficulty climbing
      stairs, and difficulty rising from a chair.
    phenotype_term:
      preferred_term: Progressive proximal muscle weakness
      term:
        id: HP:0009073
        label: Progressive proximal muscle weakness
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:31034989
        reference_title: "Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement"
        explanation: >-
          Adult-onset moderately progressive proximal weakness without respiratory
          or bulbar involvement is characteristic of LGMD-D1 and similar for other
          LGMD-D subtypes.

  - name: Waddling Gait
    category: Neurological
    description: >-
      Pelvic girdle muscle weakness leads to a characteristic waddling gait
      with increased lumbar lordosis, a common early symptom in LGMD-D.
    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: >-
          GeneReviews documents waddling gait as a clinical feature of
          calpainopathy (LGMD-D4) and by extension other LGMD-D forms with
          pelvic girdle weakness.

  - name: Abnormal Muscle Fiber Morphology
    category: Histological
    description: >-
      Muscle biopsy shows dystrophic changes with increased fiber size variation,
      necrotic and regenerating fibers, central nuclei, and increased fibrofatty
      infiltration. In LGMD-D1 (DNAJB6) and LGMD-D3 (HNRNPDL), rimmed vacuoles
      with p62/ubiquitin-positive protein aggregates are a characteristic
      histological hallmark.
    phenotype_term:
      preferred_term: Abnormal muscle fiber morphology
      term:
        id: HP:0004303
        label: Abnormal muscle fiber morphology
    evidence:
      - reference: PMID:39215466
        reference_title: "Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy."
        explanation: >-
          Dystrophic features on muscle biopsy are part of the LGMD diagnostic
          criteria per ClinGen expert panel.

genetic:
  - name: DNAJB6
    gene_term:
      preferred_term: DNAJB6
      term:
        id: hgnc:14888
        label: DNAJB6
    association: Causative
    variant_origin: GERMLINE
    subtype: LGMD-D1
    notes: >-
      Heterozygous dominant missense variants in DNAJB6 cause LGMD-D1. Pathogenic
      variants cluster in the G/F domain (e.g., p.Phe93Leu, p.Phe91Val, p.Tyr108Cys).
      The muscle-expressed DNAJB6b isoform is primarily responsible for disease
      pathogenesis. ClinGen classifies DNAJB6 as Definitive for LGMD-D1.
    evidence:
      - reference: PMID:37346979
        reference_title: "DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available."
        explanation: >-
          Confirms DNAJB6 as the causative gene for LGMD-D1.

  - name: TNPO3
    gene_term:
      preferred_term: TNPO3
      term:
        id: hgnc:17103
        label: TNPO3
    association: Causative
    variant_origin: GERMLINE
    subtype: LGMD-D2
    notes: >-
      Heterozygous pathogenic variants in TNPO3 (transportin 3) cause LGMD-D2.
      TNPO3 is a nuclear import receptor for SR-rich splicing factors. Pathogenic
      variants include missense and splice-site changes that impair the nuclear
      transport function of SRSF1 and related proteins.
    evidence:
      - reference: PMID:32690349
        reference_title: "Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "LGMD D2 is a disease caused by TNPO3 mutation."
        explanation: >-
          Directly identifies TNPO3 mutation as the cause of LGMD-D2.

  - name: HNRNPDL
    gene_term:
      preferred_term: HNRNPDL
      term:
        id: hgnc:5037
        label: HNRNPDL
    association: Causative
    variant_origin: GERMLINE
    subtype: LGMD-D3
    notes: >-
      Heterozygous pathogenic missense variants in HNRNPDL cause LGMD-D3.
      Pathogenic variants cluster in the prion-like domain (codon 378 is a
      mutational hotspot, e.g., p.D378N). ClinGen has curated HNRNPDL-LGMD-D3
      as a gene-disease relationship.
    evidence:
      - reference: PMID:30604053
        reference_title: "Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Sequencing analysis revealed a heterozygous c.1132G > A (p.D378N) mutation in HNRNPDL that co-segregated with disease phenotype in the family."
        explanation: >-
          Documents the co-segregation of HNRNPDL p.D378N with LGMD-D3 in a
          Chinese family, confirming HNRNPDL as the causative gene.

  - name: CAPN3 (Dominant)
    gene_term:
      preferred_term: CAPN3
      term:
        id: hgnc:1480
        label: CAPN3
    association: Causative
    variant_origin: GERMLINE
    subtype: LGMD-D4
    notes: >-
      Heterozygous dominant-acting pathogenic variants in CAPN3 cause LGMD-D4.
      These dominant variants differ from the biallelic recessive variants causing
      LGMD-R1 (autosomal recessive calpainopathy). Dominant pathogenic mechanisms
      include haploinsufficiency or dominant-negative effects. ClinGen classifies
      the CAPN3-LGMD dominant relationship as a curated gene-disease entity.
    evidence:
      - reference: PMID:20301490
        reference_title: "Calpainopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The diagnosis of calpainopathy is established by identification of biallelic pathogenic variants in CAPN3 or a dominantly acting heterozygous CAPN3 pathogenic variant by molecular genetic testing."
        explanation: >-
          GeneReviews identifies dominantly acting heterozygous CAPN3 pathogenic
          variants as a distinct form of calpainopathy (LGMD-D4).

treatments:
  - name: Physical Therapy and Rehabilitation
    description: >-
      Physical therapy and stretching exercises to promote mobility, maintain muscle
      strength, and prevent contractures are the mainstay of management for all
      LGMD-D subtypes. Low-impact aerobic exercise is beneficial; strenuous exercise
      should be avoided. Respiratory physiotherapy is recommended for patients with
      late-stage respiratory involvement.
    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: >-
          GeneReviews for calpainopathy recommends physical therapy and supervised
          low-impact exercise as a key management component.

  - name: Mobility Aids
    description: >-
      As disease progresses, mobility aids including canes, walkers, orthotics,
      and wheelchairs help maintain independence and quality of life for patients
      with LGMD-D. Knee-ankle-foot orthoses may prevent contractures.
    treatment_term:
      preferred_term: supportive care
      term:
        id: MAXO:0000950
        label: supportive care
    evidence:
      - reference: PMID:20301490
        reference_title: "Calpainopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "mobility aids such as canes, walkers, orthotics, and wheelchairs to help maintain independence; knee-ankle-foot orthoses while sleeping to prevent contractures"
        explanation: >-
          GeneReviews for calpainopathy recommends mobility aids as a management
          component, applicable to all LGMD-D subtypes.

  - name: Genetic Counseling
    description: >-
      All LGMD-D subtypes follow autosomal dominant inheritance with 50% recurrence
      risk for offspring of affected individuals. Genetic counseling regarding
      recurrence risk, cascade genetic testing of at-risk relatives, and discussion
      of reproductive options including preimplantation genetic testing are
      recommended.
    treatment_term:
      preferred_term: genetic counseling
      term:
        id: MAXO:0000079
        label: genetic counseling
    evidence:
      - reference: PMID:20301490
        reference_title: "Calpainopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Each child of an individual with autosomal dominant calpainopathy has a 50% chance of inheriting the CAPN3 pathogenic variant."
        explanation: >-
          Genetic counseling regarding 50% inheritance risk is relevant for all
          LGMD-D subtypes.

  - name: DNAJB6-b Isoform-Specific Antisense Oligonucleotide Therapy (Investigational)
    description: >-
      Isoform-specific knockdown of the DNAJB6b (muscle-expressed) isoform using
      morpholino antisense oligonucleotides has shown preclinical therapeutic
      potential in LGMD-D1. The approach exploits selective muscle expression of the
      pathogenic b-isoform; selective reduction of DNAJB6b corrected much of the
      LGMD-D1 proteomic disease signature in primary myotubes and mouse models.
      This is investigational and not yet in clinical trials.
    therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
    aso_details:
      aso_mechanism: STERIC_BLOCKADE
      target_gene:
        preferred_term: DNAJB6
        term:
          id: hgnc:14888
          label: DNAJB6
      target_transcript: DNAJB6b isoform mRNA
      aso_chemistry: PHOSPHORODIAMIDATE_MORPHOLINO
      conjugation: UNCONJUGATED
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
    evidence:
      - reference: PMID:37346979
        reference_title: "DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature toward wild type levels."
        explanation: >-
          Preclinical evidence supports DNAJB6b isoform-specific knockdown as a
          therapeutic strategy for LGMD-D1, with morpholino ASOs showing efficacy
          in vitro and in vivo mouse models.

prevalence:
  - population: Autosomal dominant forms as a fraction of all LGMD
    notes: >-
      Autosomal dominant LGMDs (LGMD-D) are a minority of all limb-girdle
      muscular dystrophies; autosomal recessive forms predominate.
    evidence:
      - reference: PMID:35309568
        reference_title: "LGMD D2 TNPO3-Related: From Clinical Spectrum to Pathogenetic Mechanism."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "dominant LGMDs represent about 10-15% of LGMDs"
        explanation: >-
          A review of LGMD-D2/TNPO3 reports that autosomal dominant LGMDs
          account for approximately 10-15% of all limb-girdle muscular
          dystrophies, the remainder being autosomal recessive forms.
  - population: All limb-girdle muscular dystrophy (collective, global pooled estimate)
    notes: >-
      Collective pooled epidemiology across all LGMD forms; the autosomal
      dominant subset is the ~10-15% fraction above. Per-subtype AD-LGMD
      prevalence figures are not well established as these forms are
      individually rare.
    evidence:
      - reference: PMID:38491364
        reference_title: "Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "global incidence of 0.7/100,000 and prevalence of 3/100,000"
        explanation: >-
          A GRASP-LGMD study summarizes pooled epidemiological estimates of a
          global LGMD incidence of 0.7/100,000 and prevalence of 3/100,000
          across all LGMD forms collectively.

progression:
  - phase: Adult onset and slow progression
    age_range: Typically adulthood
    notes: >-
      The autosomal dominant limb-girdle muscular dystrophies are typically
      adult-onset, slowly progressive disorders in which proximal muscle
      weakness predominates. Age of onset is variable across and within
      subtypes; respiratory or bulbar involvement is generally absent early in
      the disease course.
    evidence:
      - reference: PMID:31034989
        reference_title: "Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement"
        explanation: >-
          Clinical characterization of LGMD-D1 supports the adult-onset, slowly
          (moderately) progressive proximal-predominant natural history shared
          across the LGMD-D subtypes.

references:
  - reference: PMID:20301490
    title: Calpainopathy.
    tags:
      - GeneReviews
📚

References & Deep Research

References

1
PMID:20301490
Calpainopathy.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 32 citations 2026-07-02T11:32:05.181810

1. Disease Information

Overview

Autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) encompasses a heterogeneous group of genetic muscle disorders characterized by progressive weakness of the shoulder and hip girdle musculature, inherited in an autosomal dominant pattern. AD-LGMDs represent approximately 10–15% of all LGMDs, with the remainder being autosomal recessive forms (costa2022lgmdd2tnpo3related pages 1-2). The limb-girdle muscular dystrophies as a whole include more than 30 subtypes caused by mutations in multiple genes, leading to weakness and progressive muscle degeneration (sun2025recentinsightsinto pages 5-7).

Key Identifiers

  • OMIM: LGMD1A (MIM 159000, MYOT); LGMD1B (MIM 159001, LMNA); LGMD1C (MIM 607801, CAV3); LGMD1E (MIM 615325, DES); TNPO3 gene OMIM 608423 (politano2024iscardiactransplantation pages 2-4, rodia2025novelinsightsinto pages 1-2)
  • Orphanet: ORPHA:266 (Limb-girdle muscular dystrophy, general grouping)
  • ICD-10: G71.0 (Muscular dystrophy)
  • ICD-11: 8C70.0 (Limb-girdle muscular dystrophy)
  • MONDO: MONDO:0015286 (autosomal dominant limb-girdle muscular dystrophy)

Synonyms and Alternative Names

Historical nomenclature includes LGMD1A through LGMD1I (Erb's limb-girdle dystrophy variants). The 2018 ENMC workshop established a revised classification: dominant forms are now designated LGMDD1 through LGMDD5 (jeong2023tripartitemotifcontainingprotein pages 10-11). Several classical LGMD1 designations were excluded from the refined classification because they were associated with other diseases, had limited family documentation, or were misreported (jeong2023tripartitemotifcontainingprotein pages 10-11).

Classification Summary

The following table summarizes all recognized and historically classified AD-LGMD subtypes:

Current Name Old Name Gene Chromosomal Locus Protein OMIM Disease ID Age of Onset Key Clinical Features
LGMDD1 LGMD1D DNAJB6 7q36.3 DnaJ heat shock protein family member B6 OMIM not confirmed in retrieved evidence 2nd decade to upper middle age Slowly progressive proximal weakness, often with distal involvement; fat infiltration on MRI; myofibrillar pathology/protein aggregation (sun2025recentinsightsinto pages 5-7, politano2024iscardiactransplantation pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 2-4)
LGMDD2 LGMD1F TNPO3 7q32.1 Transportin-3 OMIM not confirmed in retrieved evidence Infancy to late adulthood; highly variable Pelvic and shoulder girdle weakness, generalized atrophy, delayed walking in some cases, scapular winging/rigid spine/scoliosis, possible wheelchair dependence and respiratory insufficiency (sun2025recentinsightsinto pages 5-7, politano2024iscardiactransplantation pages 2-4, costa2022lgmdd2tnpo3related pages 1-2)
LGMDD3 LGMD1G HNRNPDL 4p21 Heterogeneous nuclear ribonucleoprotein D-like OMIM not confirmed in retrieved evidence Adult onset Slowly progressive proximal limb weakness; rimmed vacuoles reported in muscle biopsy (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4)
LGMDD4 LGMD1I CAPN3 Not confirmed in retrieved evidence Calpain-3 OMIM not confirmed in retrieved evidence 8–15 years Progressive scapular and pelvic girdle degeneration; severity may vary by mutation type (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4)
LGMDD5 Bethlem myopathy (dominant collagen VI-related LGMD) COL6A1, COL6A2, COL6A3 Not confirmed in retrieved evidence Collagen VI alpha chains 1/2/3 OMIM not confirmed in retrieved evidence 10–30 years Slowly progressive weakness with proximal atrophy, ankle contractures; characteristic muscle MRI signs including “target” and “sandwich” signs (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 5-6, bouchard2023limb–girdlemusculardystrophies pages 2-4)
Excluded from revised LGMD classification LGMD1A MYOT 5q31.2 Myotilin MIM 159000 Late onset Distal myopathy affecting ankles/feet/calves, may later involve proximal muscles; occasional respiratory insufficiency or cardiac failure (bouchard2023limb–girdlemusculardystrophies pages 2-4, politano2024iscardiactransplantation pages 2-4)
Excluded from revised LGMD classification LGMD1B LMNA 1q22 Lamin A/C MIM 159001 Variable; often childhood to adulthood Proximal weakness with prominent cardiac arrhythmia/conduction disease risk; some reclassified toward Emery-Dreifuss spectrum (bouchard2023limb–girdlemusculardystrophies pages 2-4, politano2024iscardiactransplantation pages 2-4)
Excluded from revised LGMD classification LGMD1C CAV3 3p25.3 Caveolin-3 MIM 607801 Variable; childhood to adulthood HyperCKemia, calf hypertrophy, ankle contracture, exercise intolerance, cramps; overlapping caveolinopathy phenotypes including rippling muscle disease (bouchard2023limb–girdlemusculardystrophies pages 2-4, politano2024iscardiactransplantation pages 2-4)
Excluded from revised LGMD classification LGMD1E DES 2q35 Desmin MIM 615325 Not confirmed in retrieved evidence Desmin aggregation/myofibrillar pathology, distal weakness, structural muscle abnormalities (bouchard2023limb–girdlemusculardystrophies pages 2-4, politano2024iscardiactransplantation pages 2-4)
Excluded from revised LGMD classification LGMD1H Unknown Unknown Unknown Not confirmed in retrieved evidence Not confirmed in retrieved evidence Historical subtype with unresolved/unknown genetic basis; excluded from refined classification (bouchard2023limb–girdlemusculardystrophies pages 5-6, jeong2023tripartitemotifcontainingprotein pages 10-11)

Table: This table summarizes recognized autosomal dominant limb-girdle muscular dystrophy subtypes and historically named/excluded forms, with genes, loci, OMIM identifiers when available from retrieved evidence, onset, and hallmark clinical features. It is useful for mapping old and new nomenclature during knowledge-base curation.

2. Etiology

Disease Causal Factors

AD-LGMDs are exclusively genetic (Mendelian) disorders. Each subtype is caused by heterozygous pathogenic variants in a specific gene. The disease is inherited in an autosomal dominant pattern, meaning a single mutant allele is sufficient to cause disease (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

Genetic Risk Factors (Causal Genes)

The currently recognized AD-LGMD subtypes and their causal genes are:

  • LGMDD1 (formerly LGMD1D): DNAJB6 (7q36.3) — encodes a co-chaperone of the HSP70 system involved in Z-disc organization and protein quality control. Mutations are primarily clustered in the G/F region and J domain (sun2025recentinsightsinto pages 5-7, sarparanta2020neuromusculardiseasesdue pages 9-11).
  • LGMDD2 (formerly LGMD1F): TNPO3 (7q32.1) — encodes transportin-3, a nuclear carrier for serine/arginine-rich (SR) proteins essential for mRNA splicing (rodia2025novelinsightsinto pages 1-2, costa2022lgmdd2tnpo3related pages 7-8).
  • LGMDD3 (formerly LGMD1G): HNRNPDL (4p21) — encodes heterogeneous nuclear ribonucleoprotein D-like, involved in RNA binding and transcription regulation (sun2025recentinsightsinto pages 5-7, jeong2023tripartitemotifcontainingprotein pages 10-11).
  • LGMDD4 (formerly LGMD1I): CAPN3 — encodes calpain-3, a cysteine protease involved in sarcomeric remodeling (sun2025recentinsightsinto pages 5-7, jeong2023tripartitemotifcontainingprotein pages 10-11).
  • LGMDD5 (Bethlem myopathy): COL6A1, COL6A2, COL6A3 — encode collagen type VI subunits, components of the extracellular matrix (bouchard2023limb–girdlemusculardystrophies pages 5-6, jeong2023tripartitemotifcontainingprotein pages 10-11).

Historically classified but excluded from the revised LGMD classification are MYOT (LGMD1A), LMNA (LGMD1B), CAV3 (LGMD1C), DES (LGMD1E), and LGMD1H (gene unknown) (bouchard2023limb–girdlemusculardystrophies pages 2-4, politano2024iscardiactransplantation pages 2-4, jeong2023tripartitemotifcontainingprotein pages 10-11).

Environmental and Protective Factors

AD-LGMDs are monogenic disorders and are not significantly influenced by environmental risk factors. However, exercise interventions including aerobic and resistance training have demonstrated improvements in muscle strength and cardiorespiratory function across various LGMD subtypes (sun2025recentinsightsinto pages 18-21). No specific genetic protective factors or gene–environment interactions have been identified for AD-LGMD.

3. Phenotypes

Core Clinical Features

The hallmark phenotype shared across AD-LGMD subtypes includes progressive proximal muscle weakness, elevated serum creatine kinase (CK) levels, and muscle fiber atrophy (sun2025recentinsightsinto pages 5-7). Individual subtypes exhibit distinct phenotypic patterns:

LGMDD1 (DNAJB6-related): Slowly progressive proximal limb weakness with onset from the 2nd decade to upper middle age, with distal involvement. MRI shows fat infiltration, and biopsies reveal rimmed vacuoles and increased internal nuclei (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

LGMDD2 (TNPO3-related): Highly variable presentation from infancy to late adulthood. Features include weakness of the pelvic and shoulder girdle muscles, generalized muscle atrophy, scapular winging, rigid spine, scoliosis, possible wheelchair dependence and respiratory insufficiency. Phenotypic variation is notable even within families (costa2022lgmdd2tnpo3related pages 1-2, sun2025recentinsightsinto pages 5-7).

LGMDD3 (HNRNPDL-related): Slowly progressive proximal limb weakness with adult onset. Rimmed vacuoles on muscle biopsy (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

LGMDD4 (CAPN3 dominant): Progressive scapular and pelvic girdle degeneration with onset at 8–15 years. Severity depends on mutation type, with missense mutations causing milder phenotypes than null mutations (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

LGMDD5 (Bethlem myopathy): Progressive weakness with proximal muscle atrophy, onset 10–30 years. Characteristic findings include ankle contractures and distinctive MRI signs ("target sign" and "sandwich sign") (bouchard2023limb–girdlemusculardystrophies pages 2-4, sun2025recentinsightsinto pages 5-7).

Caveolinopathy (CAV3, formerly LGMD1C): HyperCKemia in all patients, ankle contracture, calf hypertrophy, exercise intolerance, muscular cramps. May overlap with rippling muscle disease, familial hypertrophic cardiomyopathy, and distal myopathy phenotypes (bouchard2023limb–girdlemusculardystrophies pages 2-4).

Suggested HPO Terms

  • HP:0003202 — Skeletal muscle atrophy
  • HP:0003560 — Muscular dystrophy
  • HP:0003325 — Limb-girdle muscle weakness
  • HP:0003236 — Elevated circulating creatine kinase concentration
  • HP:0001371 — Flexion contracture
  • HP:0002355 — Difficulty walking
  • HP:0003701 — Proximal muscle weakness
  • HP:0003557 — Increased variability in muscle fiber diameter
  • HP:0003198 — Myopathy
  • HP:0001644 — Dilated cardiomyopathy (LMNA-related)
  • HP:0001638 — Cardiomyopathy
  • HP:0002093 — Respiratory insufficiency

Diagnostic Criteria

Diagnostic criteria for LGMD include: proximal or non-proximal muscle dystrophy, muscle fiber degeneration and necrosis, elevated serum CK levels, and muscle degenerative changes with fibrofatty infiltration (sun2025recentinsightsinto pages 5-7). The combination of clinical examination, muscle MRI, CK levels, muscle biopsy, and genetic testing constitutes the standard diagnostic approach. Cardiac involvement (22% of patients) and respiratory insufficiency (15.4%) should be assessed (lin2023clinicalfeaturesimaging pages 1-2).

Diagnostic Testing

Genetic Testing: Next-generation sequencing (NGS) gene panels and whole exome sequencing (WES) have become the primary diagnostic tools. A definitive molecular diagnosis was obtained in 20% of a cohort of over 25,000 individuals with neuromuscular disorders, with diagnostic yields of up to 33% for muscular dystrophies specifically (doody2024definingclinicalendpoints pages 1-2). Multigene analysis is recommended over single-gene testing given significant phenotypic overlap (doody2024definingclinicalendpoints pages 1-2).

Biomarkers: Circulating miR-206 is a potential biomarker for disease progression, with significant elevation in LGMD patients compared to controls and 50–80-fold overexpression in severe cases (lin2023clinicalfeaturesimaging pages 1-2). MiR-1, miR-133a, and miR-206 are differentially expressed in serum and muscle, changing according to degrees of inflammation, fibrosis, and dystrophic progression (lin2023clinicalfeaturesimaging pages 1-2).

Muscle Imaging: MRI reveals fatty infiltration and replacement in affected muscles. Each subtype has characteristic patterns of muscle involvement on imaging (bouchard2023limb–girdlemusculardystrophies pages 2-4).

4. Genetic/Molecular Information

Causal Genes and Pathogenic Variants

The following table provides a comprehensive overview of the molecular mechanisms underlying each AD-LGMD subtype:

Subtype Gene/Protein Mechanism Type Key Molecular Pathways Affected Cellular Processes Disrupted Key References
LGMDD1 (formerly LGMD1D) DNAJB6 / DnaJ heat shock protein family member B6 Toxic gain-of-function Hsp70 chaperone cycle dysregulation; proteostasis network; Z-disc protein quality control; autophagy-related stress pathways Unregulated DNAJB6-Hsp70 binding, Hsp70 sequestration/depletion, protein misfolding, myofibrillar/Z-disc aggregation, vacuolar myopathy (bengoechea2025inhibitionofdnajhsp70 pages 1-2, abayevavraham2023dnajb6mutantsdisplay pages 9-9, abayevavraham2023dnajb6mutantsdisplay pages 1-2, bengoechea2025inhibitionofdnajhsp70 pages 7-8, sarparanta2020neuromusculardiseasesdue pages 9-11, sarparanta2020neuromusculardiseasesdue pages 7-9)
LGMDD2 (formerly LGMD1F) TNPO3 / Transportin-3 Likely dominant toxic / loss-of-function mechanism Nuclear import of SR proteins; RNA metabolism and alternative splicing; myogenic regulatory factor signaling; autophagy Impaired nuclear transport of splicing factors (e.g., SRSF1/SRSF2/RBM4/CPSF6), altered transcript processing, abnormal myogenic commitment, myofibrillar disarray, myofiber atrophy (rodia2025novelinsightsinto pages 1-2, rodia2025novelinsightsinto pages 18-19, rodia2025novelinsightsinto pages 8-13, rodia2025novelinsightsinto pages 5-8, costa2022lgmdd2tnpo3related pages 7-8, costa2022lgmdd2tnpo3related pages 5-7)
LGMD1C / caveolinopathy (excluded from revised LGMD classification) CAV3 / Caveolin-3 Dominant negative with functional Caveolin-3 deficiency Caveolae biology; mTORC1 signaling; lysosomal cholesterol trafficking; mitochondrial homeostasis; Akt/p38 signaling Caveolin-3 loss, reduced anabolic signaling, impaired protein synthesis, mitochondrial fragmentation and respiratory failure, altered cholesterol distribution, defective myoblast differentiation/fusion (shah2023caveolin‐3losslinked pages 1-2, shah2020caveolin‐3deficiencyassociated pages 1-2, shah2020caveolin‐3deficiencyassociated pages 7-9, shah2020caveolin‐3deficiencyassociated pages 20-20, shah2020caveolin‐3deficiencyassociated pages 16-17, shah2020caveolin‐3deficiencyassociated pages 19-20)
LGMD1A / myotilinopathy (excluded from revised LGMD classification) MYOT / Myotilin Unclear; dominant structural/protein-aggregation mechanism Sarcomere assembly; actin filament cross-linking; Z-disc organization Disrupted actin cross-linking, impaired sarcomere assembly, myofibrillar instability, protein aggregate formation (bouchard2023limb–girdlemusculardystrophies pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 5-6)
LGMD1B / laminopathy (excluded from revised LGMD classification) LMNA / Lamin A/C Predominantly dominant negative / structural nuclear envelope dysfunction Nuclear lamina integrity; mechanotransduction; genome organization and transcriptional regulation Nuclear envelope disruption, abnormal nuclear morphology, muscle fiber fragility, conduction-system/cardiac involvement in many patients (bouchard2023limb–girdlemusculardystrophies pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 5-6)
LGMD1E / desminopathy (excluded from revised LGMD classification) DES / Desmin Dominant protein-aggregation / filament disorganization mechanism Intermediate filament network; cytoskeletal organization; myofibril integrity Desmin aggregation, irregular muscle fiber architecture, cytoskeletal collapse, myofibrillar degeneration (bouchard2023limb–girdlemusculardystrophies pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 5-6)
LGMDD3 (formerly LGMD1G) HNRNPDL / hnRNP D-like Likely dominant toxic protein/RNA-processing mechanism RNA binding and transcription/splicing regulation Abnormal RNA handling, rimmed-vacuolar myopathy, progressive proximal weakness (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 5-6, jeong2023tripartitemotifcontainingprotein pages 10-11)
LGMDD4 (formerly LGMD1I) CAPN3 / Calpain-3 Mutation-dependent; dominant pathogenic mechanism recognized but incompletely defined Sarcomere remodeling; muscle proteolysis; myofibrillar maintenance Scapular/pelvic girdle degeneration, impaired sarcomeric maintenance, progressive muscle fiber loss (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4, bouchard2023limb–girdlemusculardystrophies pages 5-6, jeong2023tripartitemotifcontainingprotein pages 10-11)
LGMDD5 (Bethlem myopathy spectrum) COL6A1/COL6A2/COL6A3 / Collagen VI Usually dominant structural extracellular-matrix mechanism Extracellular matrix organization; basement membrane-matrix interactions; muscle regeneration support Matrix instability, impaired muscle fiber support, proximal weakness, contractures/ankle contracture, progressive fatty replacement (bouchard2023limb–girdlemusculardystrophies pages 5-6, jeong2023tripartitemotifcontainingprotein pages 10-11, bouchard2023limb–girdlemusculardystrophies pages 2-4, sun2025recentinsightsinto pages 5-7)

Table: This table summarizes the main pathogenic mechanisms reported for autosomal dominant limb-girdle muscular dystrophy subtypes and historically associated dominant LGMD entities. It is useful for comparing whether disease biology is driven primarily by proteostasis failure, nuclear transport defects, membrane/caveola dysfunction, cytoskeletal aggregation, or extracellular matrix disruption.

LGMDD1 (DNAJB6) — Detailed Molecular Mechanism

DNAJB6 exists as two isoforms: the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, with the latter being the primary pathogenic isoform (findlay2023dnajb6isoformspecific pages 1-3). Disease-causing mutations are clustered in the G/F region near the α5 helix and in the J domain (sarparanta2020neuromusculardiseasesdue pages 9-11, sarparanta2020neuromusculardiseasesdue pages 7-9).

The pathogenic mechanism is a toxic gain-of-function dependent on DNAJB6-HSP70 interaction. Wild-type DNAJB6 possesses an autoinhibitory mechanism in its G/F domain that regulates J-domain interaction with HSP70. LGMDD1 mutations disrupt this autoinhibition, making the J-domain constitutively accessible for HSP70 binding (inoue2025moleculargeneticsof pages 6-8). The mutant DNAJB6 can thus "recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis" (abayevavraham2023dnajb6mutantsdisplay pages 1-2). This aberrant interaction leads to abnormal trapping of HSP70 at the Z-disc, impairing its normal rapid diffusion (bengoechea2025inhibitionofdnajhsp70 pages 1-2). Accumulated proteins include structural Z-disc proteins, RNA-binding stress-granule proteins, TDP-43, and various chaperones and cochaperones (HSPA8, CRYAB, HSPB8, SQSTM1, BAG3, STUB1), indicating widespread proteostasis disruption (sarparanta2020neuromusculardiseasesdue pages 7-9).

LGMDD2 (TNPO3) — Detailed Molecular Mechanism

TNPO3 mutations produce a protein with an extended C-terminal domain that impairs nuclear transport of SR proteins essential for mRNA splicing and metabolism (rodia2025novelinsightsinto pages 1-2). Mutated TNPO3 fails to properly transport cargo proteins (SRSF1, SRSF2, RBM4, CPSF6) through the nuclear membrane, disrupting alternative splicing and protein synthesis. This leads to myofibrillar protein accumulation and disarray (costa2022lgmdd2tnpo3related pages 7-8). Recent zebrafish studies demonstrated that mutant TNPO3 caused myofibrillar disarray with perpendicularly oriented fibers resembling LGMDD2 patient muscle architecture (rodia2025novelinsightsinto pages 8-13). The mutation disrupts normal myogenic commitment and affects myogenic regulatory factor expression, representing impaired myogenesis as a core disease mechanism (rodia2025novelinsightsinto pages 18-19, rodia2025novelinsightsinto pages 5-8).

CAV3 (Caveolinopathy) — Detailed Molecular Mechanism

The P104L mutation causes dramatic loss of Cav3 protein through a dominant negative mechanism, with the mutant protein being retained in the Golgi complex and subjected to proteasomal degradation rather than trafficking to the plasma membrane (shah2020caveolin‐3deficiencyassociated pages 7-9). Cav3 deficiency impairs mTORC1 signaling by disrupting lysosomal cholesterol trafficking, increasing lysosomal cholesterol content by 26% and suppressing mTORC1 activation, with phosphorylation of S6K1 and 4EBP1 reduced by 75–90% (shah2023caveolin‐3losslinked pages 1-2). Additionally, the P104L mutation causes mitochondrial fragmentation, shifting from predominantly tubular/elongated mitochondria (~65%) to fragmented/spheroid forms (>60%), with significant reductions in oxygen consumption rates (shah2020caveolin‐3deficiencyassociated pages 7-9). Loss of Cav3 also reduces cardiolipin content, increases mitochondrial cholesterol, elevates ROS production, and impairs myoblast differentiation through reduced Akt and p38 signaling (shah2020caveolin‐3deficiencyassociated pages 1-2, shah2020caveolin‐3deficiencyassociated pages 20-20, shah2020caveolin‐3deficiencyassociated pages 16-17).

Suggested GO Terms

  • GO:0006457 — Protein folding
  • GO:0051085 — Chaperone cofactor-dependent protein refolding
  • GO:0006606 — Protein import into nucleus
  • GO:0000398 — mRNA splicing, via spliceosome
  • GO:0007517 — Muscle organ development
  • GO:0030240 — Skeletal muscle thin filament assembly
  • GO:0045214 — Sarcomere organization
  • GO:0031529 — Ruffle organization (caveolae)
  • GO:0006914 — Autophagy

5. Anatomical Structures Affected

Organ Level

  • Primary: Skeletal muscle (UBERON:0001134), particularly proximal limb muscles
  • Secondary: Heart (UBERON:0000948) — cardiac involvement in LMNA-related and some CAV3-related forms; respiratory system (UBERON:0001004) — restrictive respiratory insufficiency in ~15.4% of patients (lin2023clinicalfeaturesimaging pages 1-2)

Tissue and Cell Level

  • Skeletal muscle tissue (UBERON:0001134)
  • Skeletal muscle fibers (CL:0000187 — skeletal muscle fiber)
  • Myoblasts (CL:0000056 — myoblast)
  • Satellite cells (CL:0000594 — skeletal muscle satellite cell)

Subcellular Level

  • Z-disc (GO:0030018) — aggregation of Z-disc proteins in LGMDD1
  • Sarcomere (GO:0030017)
  • Nucleus (GO:0005634) — nuclear transport disruption in LGMDD2
  • Mitochondria (GO:0005739) — dysfunction in CAV3-related disease
  • Caveolae (GO:0005901) — disrupted in CAV3-related disease
  • Sarcoplasmic reticulum and plasma membrane

6. Temporal Development

Onset

  • LGMDD1: 2nd decade to upper middle age (sun2025recentinsightsinto pages 5-7)
  • LGMDD2: Infancy to late adulthood, highly variable (costa2022lgmdd2tnpo3related pages 1-2, sun2025recentinsightsinto pages 5-7)
  • LGMDD3: Adult onset (sun2025recentinsightsinto pages 5-7)
  • LGMDD4: 8–15 years (sun2025recentinsightsinto pages 5-7)
  • LGMDD5: 10–30 years (sun2025recentinsightsinto pages 5-7)

Progression

Disease course is chronic and progressive, though the rate of progression varies substantially among subtypes and even within families. Some subtypes show stability until adulthood followed by slow progression, while others demonstrate early-onset disease with more rapid deterioration (costa2022lgmdd2tnpo3related pages 1-2). Cardiac involvement may present as sudden cardiac death, as documented in a patient with LMNA-related muscular dystrophy at age 37 (lin2023clinicalfeaturesimaging pages 1-2).

7. Epidemiology and Inheritance

Epidemiology

LGMD collectively has a global incidence of approximately 0.7 per 100,000 and variable prevalence by region (doody2024definingclinicalendpoints pages 1-2). AD-LGMDs represent approximately 10–15% of all LGMDs (costa2022lgmdd2tnpo3related pages 1-2). In a US population-based study (MD STARnet, 2008–2016), LGMD was the most common diagnosis among 243 individuals with muscular dystrophy (138 cases), with a higher proportion of male individuals compared with female individuals (lin2023clinicalfeaturesimaging pages 1-2).

Inheritance Pattern

All AD-LGMD subtypes follow an autosomal dominant inheritance pattern with variable expressivity and incomplete penetrance in some subtypes (sun2025recentinsightsinto pages 5-7, costa2022lgmdd2tnpo3related pages 1-2). The expressivity varies significantly even within the same family carrying the same pathogenic variant, as documented for TNPO3 and CAV3 mutations (costa2022lgmdd2tnpo3related pages 1-2). Somatic mosaicism has been documented in parents of LMNA-related muscular dystrophy probands (lin2023clinicalfeaturesimaging pages 1-2). De novo mutations are recognized, particularly in LMNA and DNAJB6 (lin2023clinicalfeaturesimaging pages 1-2).

8. Treatment

Current Treatment — Symptomatic Management

Currently, only symptomatic treatments are available for AD-LGMD patients. Symptomatic therapy manages symptoms through interventions including nocturnal ventilation for respiratory impairment, β-blockers for cardiac involvement, nutritional adjustments, and physical rehabilitation, though it does not slow disease progression (sun2025recentinsightsinto pages 18-21). Exercise interventions, including aerobic and resistance training, have demonstrated improvements in muscle strength and cardiorespiratory function (sun2025recentinsightsinto pages 18-21). Suggested MAXO terms: MAXO:0000950 — Supportive care; MAXO:0001001 — Respiratory support.

Experimental Therapeutics

Small Molecule DNAJ-HSP70 Inhibitors (LGMDD1): Treatment with a small-molecule inhibitor (JG231) of the DNAJ-HSP70 complex restored HSP70 mobility, improved muscle strength, and corrected myopathological features in LGMDD1 mouse models (bengoechea2025inhibitionofdnajhsp70 pages 1-2). This represents a promising therapeutic avenue as "interfering with DNAJB6-Hsp70 binding reverses the disease phenotype" (abayevavraham2023dnajb6mutantsdisplay pages 9-9).

Isoform-Specific Knockdown (LGMDD1): Morpholino antisense oligonucleotides targeting the DNAJB6b isoform (BPAS morpholinos) have shown therapeutic potential. Selective DNAJB6b reduction corrected 57% of disease-related proteins toward wild-type levels in F90I+/- myotubes, including HSP70 (findlay2023dnajb6isoformspecific pages 4-5). This approach was validated in primary mouse myotubes, human LGMDD1 myoblasts, and mouse skeletal muscle in vivo (findlay2022dnajb6isoformspecific pages 1-7, findlay2022dnajb6isoformspecific pages 13-17). Future clinical translation may involve peptide-conjugated phosphorodiamidate morpholinos or AAV-delivered U7-snRNA approaches (findlay2022dnajb6isoformspecific pages 7-13).

RNAi Approaches: RNAi approaches to knock down dominant mutations, such as myotilin mutations in LGMD1A, are under investigation (bouchard2023limb–girdlemusculardystrophies pages 9-11).

Gene Editing: CRISPR-Cas systems, base editing, and prime editing approaches have been explored, with some in vitro experiments successfully correcting mutations in LGMD models (bouchard2023limb–girdlemusculardystrophies pages 9-11).

Clinical Trial Readiness: The GRASP-LGMD Research Consortium (NCT03981289) is a multi-center study of 188 LGMD patients across 13 sites, including DNAJB6/LGMDD1 patients, designed to validate clinical outcome assessments for future clinical trials (doody2024definingclinicalendpoints pages 1-2).

9. Model Organisms

LGMDD1 (DNAJB6) Models

Transgenic Mouse Model: Overexpression of mutant DNAJB6b-F93L under the MCK promoter produces an aggressive myopathy with 40% mortality by 2 months, desmin inclusions, and hnRNPA1/A2B1 aggregates recapitulating human LGMDD1 pathology (bengoechea2025inhibitionofdnajhsp70 pages 8-13).

Knock-in Mouse Model: A more physiologically relevant knock-in model expressing the LGMDD1 F90I mutation at endogenous levels develops progressive myopathy and has been used for preclinical therapeutic testing, including the DNAJ-HSP70 inhibitor JG231 (inoue2025moleculargeneticsof pages 8-10, bengoechea2025inhibitionofdnajhsp70 pages 8-13).

C. elegans Model: Blocking mutant DNAJB6-Hsp70 interaction rescues normal muscle morphology, and Hsp70 overexpression partially rescues disease phenotypes in C. elegans (abayevavraham2023dnajb6mutantsdisplay pages 9-9).

Zebrafish Model: Among the first in vivo models providing evidence that DNAJB6 mutations are pathogenic, demonstrating distinct muscle defects and implicating the cytoplasmic DNAJB6b isoform (inoue2025moleculargeneticsof pages 8-10).

LGMDD2 (TNPO3) Models

Zebrafish Model: Microinjection of zebrafish embryos with mutant human TNPO3 mRNA caused body shortening, myofibrillar disarray, altered myosin patterning, and disrupted expression of myogenic regulatory factors (rodia2025novelinsightsinto pages 8-13, rodia2025novelinsightsinto pages 2-4). The model validates that TNPO3 mutations disrupt normal myogenic commitment and provides a platform for drug testing (rodia2025novelinsightsinto pages 18-19).

C2C12 Cell Model: Transfection of C2C12 cells with mutant TNPO3 demonstrated effects on muscle regulatory factor expression, p62 (autophagy marker), MuRF-1 (muscle atrophy marker), and desmin expression (rodia2025novelinsightsinto pages 5-8, rodia2025novelinsightsinto pages 4-5).

10. Prognosis and Outcomes

Disease Course

AD-LGMDs generally follow a chronic progressive course, though the rate and severity vary markedly by subtype. LGMDD1 presents with slowly progressive proximal weakness, while LGMDD2 shows wide variability from childhood-onset with wheelchair dependence to adult-onset stable disease (costa2022lgmdd2tnpo3related pages 1-2, sun2025recentinsightsinto pages 5-7).

Complications

Cardiac abnormalities were present in 22% of patients in one cohort, and one patient with LMNA-related muscular dystrophy experienced sudden cardiac death at age 37 (lin2023clinicalfeaturesimaging pages 1-2). Restrictive respiratory insufficiency was documented in 15.4% of patients (lin2023clinicalfeaturesimaging pages 1-2). Joint contractures, scoliosis, and scapular winging are common skeletal complications (costa2022lgmdd2tnpo3related pages 1-2, bouchard2023limb–girdlemusculardystrophies pages 2-4).

Life Expectancy

Life expectancy varies by subtype. Most AD-LGMD forms have near-normal lifespan when cardiac involvement is monitored and managed, though LMNA-related forms carry risk of life-threatening cardiac arrhythmias. Specific longevity data for individual AD-LGMD subtypes remain limited.

11. Prevention

Primary Prevention

As monogenic disorders, AD-LGMDs cannot be prevented through lifestyle modification. Primary prevention relies on genetic counseling and family planning.

Genetic Counseling and Screening

Given autosomal dominant inheritance, affected individuals have a 50% risk of transmitting the disease to offspring. Genetic counseling is recommended for all affected families. Preimplantation genetic diagnosis (PGD) and prenatal testing are available when the familial mutation is known. Cascade genetic testing of at-risk family members is recommended.

Secondary Prevention

Cardiac surveillance is essential for LMNA-related forms due to high risk of arrhythmias and sudden death. Regular respiratory function monitoring is recommended for all subtypes given the ~15% rate of restrictive pulmonary insufficiency (lin2023clinicalfeaturesimaging pages 1-2).

12. Summary and Current Challenges

AD-LGMD remains a diagnostic and therapeutic challenge due to its genetic heterogeneity, phenotypic variability, and rarity. The 2018 reclassification streamlined the nomenclature to five recognized subtypes (LGMDD1–D5), though several historically classified forms (MYOT, LMNA, CAV3, DES) remain clinically important entities that have been reclassified to other disease categories (jeong2023tripartitemotifcontainingprotein pages 10-11). The most promising therapeutic advances center on LGMDD1 (DNAJB6-related), where both small molecule inhibitors of the DNAJ-HSP70 interaction and isoform-specific antisense oligonucleotide knockdown approaches have shown preclinical efficacy (bengoechea2025inhibitionofdnajhsp70 pages 1-2, findlay2023dnajb6isoformspecific pages 4-5, findlay2023dnajb6isoformspecific pages 1-3). The GRASP-LGMD consortium represents a critical infrastructure development for clinical trial readiness (doody2024definingclinicalendpoints pages 1-2). Despite these advances, no disease-modifying therapies are yet available for human patients with any AD-LGMD subtype, and treatment remains supportive.

References

  1. (costa2022lgmdd2tnpo3related pages 1-2): Roberta Costa, Maria Teresa Rodia, Serafina Pacilio, Corrado Angelini, and Giovanna Cenacchi. Lgmd d2 tnpo3-related: from clinical spectrum to pathogenetic mechanism. Frontiers in Neurology, Mar 2022. URL: https://doi.org/10.3389/fneur.2022.840683, doi:10.3389/fneur.2022.840683. This article has 27 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. (politano2024iscardiactransplantation pages 2-4): Luisa Politano. Is cardiac transplantation still a contraindication in patients with muscular dystrophy-related end-stage dilated cardiomyopathy? a systematic review. International Journal of Molecular Sciences, 25:5289, May 2024. URL: https://doi.org/10.3390/ijms25105289, doi:10.3390/ijms25105289. This article has 12 citations.

  4. (rodia2025novelinsightsinto pages 1-2): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

  5. (jeong2023tripartitemotifcontainingprotein pages 10-11): Seung Yeon Jeong, Jun Hee Choi, Jooho Kim, Jin Seok Woo, and Eun Hui Lee. Tripartite motif-containing protein 32 (trim32): what does it do for skeletal muscle? Cells, 12:2104, Aug 2023. URL: https://doi.org/10.3390/cells12162104, doi:10.3390/cells12162104. This article has 14 citations.

  6. (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.

  7. (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.

  8. (sarparanta2020neuromusculardiseasesdue pages 9-11): J. Sarparanta, P. Jonson, S. Kawan, and B. Udd. Neuromuscular diseases due to chaperone mutations: a review and some new results. International Journal of Molecular Sciences, Feb 2020. URL: https://doi.org/10.3390/ijms21041409, doi:10.3390/ijms21041409. This article has 91 citations.

  9. (costa2022lgmdd2tnpo3related pages 7-8): Roberta Costa, Maria Teresa Rodia, Serafina Pacilio, Corrado Angelini, and Giovanna Cenacchi. Lgmd d2 tnpo3-related: from clinical spectrum to pathogenetic mechanism. Frontiers in Neurology, Mar 2022. URL: https://doi.org/10.3389/fneur.2022.840683, doi:10.3389/fneur.2022.840683. This article has 27 citations and is from a peer-reviewed journal.

  10. (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.

  11. (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.

  12. (doody2024definingclinicalendpoints pages 1-2): Amy Doody, Lindsay N. Alfano, Jordi Díaz-Manera, Linda P Lowes, T. Mozaffar, Kathy Mathews, Conrad C. Weihl, Matthew Wicklund, Man Hung, J. Statland, Nicholas E. Johnson, Kathy Doris Peter Urvi John Carla Stacy Mathews Leung Kang Desai Vissing Zingariello Dixon, Kathy Mathews, Doris Leung, Peter Kang, Urvi Desai, J. Vissing, Carla Zingariello, and Stacy Dixon. Defining clinical endpoints in limb girdle muscular dystrophy: a grasp-lgmd study. BMC Neurology, Mar 2024. URL: https://doi.org/10.1186/s12883-024-03588-1, doi:10.1186/s12883-024-03588-1. This article has 10 citations and is from a peer-reviewed journal.

  13. (bengoechea2025inhibitionofdnajhsp70 pages 1-2): R. Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, S. Pittman, J. Daw, Jason E. Gestwicki, Heather L. True, and Conrad C. Weihl. Inhibition of dnaj-hsp70 interaction improves strength in muscular dystrophy. The Journal of Clinical Investigation, May 2025. URL: https://doi.org/10.1172/jci194757, doi:10.1172/jci194757. This article has 48 citations.

  14. (abayevavraham2023dnajb6mutantsdisplay pages 9-9): Meital Abayev-Avraham, Yehuda Salzberg, Dar Gliksberg, Meital Oren-Suissa, and Rina Rosenzweig. Dnajb6 mutants display toxic gain of function through unregulated interaction with hsp70 chaperones. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-42735-z, doi:10.1038/s41467-023-42735-z. This article has 47 citations and is from a highest quality peer-reviewed journal.

  15. (abayevavraham2023dnajb6mutantsdisplay pages 1-2): Meital Abayev-Avraham, Yehuda Salzberg, Dar Gliksberg, Meital Oren-Suissa, and Rina Rosenzweig. Dnajb6 mutants display toxic gain of function through unregulated interaction with hsp70 chaperones. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-42735-z, doi:10.1038/s41467-023-42735-z. This article has 47 citations and is from a highest quality peer-reviewed journal.

  16. (bengoechea2025inhibitionofdnajhsp70 pages 7-8): R. Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, S. Pittman, J. Daw, Jason E. Gestwicki, Heather L. True, and Conrad C. Weihl. Inhibition of dnaj-hsp70 interaction improves strength in muscular dystrophy. The Journal of Clinical Investigation, May 2025. URL: https://doi.org/10.1172/jci194757, doi:10.1172/jci194757. This article has 48 citations.

  17. (sarparanta2020neuromusculardiseasesdue pages 7-9): J. Sarparanta, P. Jonson, S. Kawan, and B. Udd. Neuromuscular diseases due to chaperone mutations: a review and some new results. International Journal of Molecular Sciences, Feb 2020. URL: https://doi.org/10.3390/ijms21041409, doi:10.3390/ijms21041409. This article has 91 citations.

  18. (rodia2025novelinsightsinto pages 18-19): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

  19. (rodia2025novelinsightsinto pages 8-13): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

  20. (rodia2025novelinsightsinto pages 5-8): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

  21. (costa2022lgmdd2tnpo3related pages 5-7): Roberta Costa, Maria Teresa Rodia, Serafina Pacilio, Corrado Angelini, and Giovanna Cenacchi. Lgmd d2 tnpo3-related: from clinical spectrum to pathogenetic mechanism. Frontiers in Neurology, Mar 2022. URL: https://doi.org/10.3389/fneur.2022.840683, doi:10.3389/fneur.2022.840683. This article has 27 citations and is from a peer-reviewed journal.

  22. (shah2023caveolin‐3losslinked pages 1-2): Dinesh S. Shah, Raid B. Nisr, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 loss linked with the p104l lgmd‐1c mutation modulates skeletal muscle mtorc1 signalling and cholesterol homeostasis. Journal of Cachexia, Sarcopenia and Muscle, 14:2310-2326, Sep 2023. URL: https://doi.org/10.1002/jcsm.13317, doi:10.1002/jcsm.13317. This article has 6 citations and is from a domain leading peer-reviewed journal.

  23. (shah2020caveolin‐3deficiencyassociated pages 1-2): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

  24. (shah2020caveolin‐3deficiencyassociated pages 7-9): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

  25. (shah2020caveolin‐3deficiencyassociated pages 20-20): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

  26. (shah2020caveolin‐3deficiencyassociated pages 16-17): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

  27. (shah2020caveolin‐3deficiencyassociated pages 19-20): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

  28. (findlay2023dnajb6isoformspecific pages 1-3): Andrew R. Findlay, May M. Paing, Jil A. Daw, Meade Haller, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for limb girdle muscular dystrophy d1. Molecular Therapy - Nucleic Acids, 32:937-948, Jun 2023. URL: https://doi.org/10.1016/j.omtn.2023.05.017, doi:10.1016/j.omtn.2023.05.017. This article has 10 citations.

  29. (inoue2025moleculargeneticsof pages 6-8): Michio Inoue. Molecular genetics of j-domain protein-related chaperonopathies in skeletal muscle. Journal of human genetics, Jul 2025. URL: https://doi.org/10.1038/s10038-025-01372-8, doi:10.1038/s10038-025-01372-8. This article has 0 citations and is from a peer-reviewed journal.

  30. (findlay2023dnajb6isoformspecific pages 4-5): Andrew R. Findlay, May M. Paing, Jil A. Daw, Meade Haller, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for limb girdle muscular dystrophy d1. Molecular Therapy - Nucleic Acids, 32:937-948, Jun 2023. URL: https://doi.org/10.1016/j.omtn.2023.05.017, doi:10.1016/j.omtn.2023.05.017. This article has 10 citations.

  31. (findlay2022dnajb6isoformspecific pages 1-7): Andrew R. Findlay, May M. Paing, Jil A. Daw, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for lgmdd1. bioRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.17.516920, doi:10.1101/2022.11.17.516920. This article has 1 citations.

  32. (findlay2022dnajb6isoformspecific pages 13-17): Andrew R. Findlay, May M. Paing, Jil A. Daw, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for lgmdd1. bioRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.17.516920, doi:10.1101/2022.11.17.516920. This article has 1 citations.

  33. (findlay2022dnajb6isoformspecific pages 7-13): Andrew R. Findlay, May M. Paing, Jil A. Daw, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for lgmdd1. bioRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.17.516920, doi:10.1101/2022.11.17.516920. This article has 1 citations.

  34. (bouchard2023limb–girdlemusculardystrophies pages 9-11): 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.

  35. (bengoechea2025inhibitionofdnajhsp70 pages 8-13): R. Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, S. Pittman, J. Daw, Jason E. Gestwicki, Heather L. True, and Conrad C. Weihl. Inhibition of dnaj-hsp70 interaction improves strength in muscular dystrophy. The Journal of Clinical Investigation, May 2025. URL: https://doi.org/10.1172/jci194757, doi:10.1172/jci194757. This article has 48 citations.

  36. (inoue2025moleculargeneticsof pages 8-10): Michio Inoue. Molecular genetics of j-domain protein-related chaperonopathies in skeletal muscle. Journal of human genetics, Jul 2025. URL: https://doi.org/10.1038/s10038-025-01372-8, doi:10.1038/s10038-025-01372-8. This article has 0 citations and is from a peer-reviewed journal.

  37. (rodia2025novelinsightsinto pages 2-4): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

  38. (rodia2025novelinsightsinto pages 4-5): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

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