Autosomal Recessive Limb-Girdle Muscular Dystrophy

Mendelian MONDO:0015152 Pathograph 28 Show in embeddings browser Limb-Girdle Muscular Dystrophy Muscular Dystrophy Neuromuscular Disease

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

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Inheritance
10
Pathophys.
10
Phenotypes
28
Pathograph
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Genes
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Medical Actions
15
Subtypes
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Trials
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References
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Deep Research
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Inheritance

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

15
LGMD R1 (calpainopathy, LGMD2A; CAPN3) MONDO:0009675
CAPN3 hgnc:1480 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CAPN3 (hgnc:1480). hgnc:1480 is a gene from the HUGO Gene Nomenclature Committee.
Calpainopathy, caused by biallelic CAPN3 variants. The most common LGMD-R subtype in many cohorts (~30-40% of LGMD). Characterized by symmetric progressive proximal weakness, scapular winging, tiptoe walking, Achilles tendon shortening, and scoliosis, typically without cardiac involvement.
LGMD R2 (dysferlinopathy, LGMD2B; DYSF)
DYSF hgnc:3097 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in DYSF (hgnc:3097). hgnc:3097 is a gene from the HUGO Gene Nomenclature Committee.
Dysferlinopathy, caused by biallelic DYSF variants encoding the membrane-repair protein dysferlin. Onset usually in the late teens to thirties, with very high serum CK (50-200x normal) and a phenotypic spectrum that also includes Miyoshi distal myopathy. Cardiac involvement is rare.
LGMD R3 (alpha-sarcoglycanopathy, LGMD2D; SGCA)
SGCA hgnc:10805 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SGCA (hgnc:10805). hgnc:10805 is a gene from the HUGO Gene Nomenclature Committee.
Alpha-sarcoglycanopathy, caused by biallelic SGCA variants. Usually childhood onset with proximal weakness, calf hypertrophy, and risk of cardiomyopathy.
LGMD R4 (beta-sarcoglycanopathy, LGMD2E; SGCB)
SGCB hgnc:10806 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SGCB (hgnc:10806). hgnc:10806 is a gene from the HUGO Gene Nomenclature Committee.
Beta-sarcoglycanopathy, caused by biallelic SGCB variants. Often a severe childhood-onset sarcoglycanopathy with cardiac and respiratory involvement.
LGMD R5 (gamma-sarcoglycanopathy, LGMD2C; SGCG)
SGCG hgnc:10809 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SGCG (hgnc:10809). hgnc:10809 is a gene from the HUGO Gene Nomenclature Committee.
Gamma-sarcoglycanopathy, caused by biallelic SGCG variants. Variable severity including a severe childhood form with early loss of ambulation, calf hypertrophy, and high CK.
LGMD R6 (delta-sarcoglycanopathy, LGMD2F; SGCD)
SGCD hgnc:10807 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SGCD (hgnc:10807). hgnc:10807 is a gene from the HUGO Gene Nomenclature Committee.
Delta-sarcoglycanopathy, caused by biallelic SGCD variants. A typically severe childhood-to-adolescence sarcoglycanopathy with risk of cardiomyopathy and respiratory complications.
LGMD R9 (FKRP-related dystroglycanopathy, LGMD2I; FKRP)
FKRP hgnc:17997 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FKRP (hgnc:17997). hgnc:17997 is a gene from the HUGO Gene Nomenclature Committee.
FKRP-related dystroglycanopathy, caused by biallelic FKRP variants that impair glycosylation of alpha-dystroglycan. Variable onset; the common founder variant c.826C>A is associated with a later median loss of ambulation; respiratory decline and cardiomyopathy may occur.
LGMD R12 (anoctaminopathy, LGMD2L; ANO5) MONDO:0012652
ANO5 hgnc:27337 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ANO5 (hgnc:27337). hgnc:27337 is a gene from the HUGO Gene Nomenclature Committee.
Anoctaminopathy, caused by biallelic ANO5 variants. Typically adult-onset proximal weakness, sometimes asymmetric or with a mixed proximal/distal pattern, with elevated CK and slower progression than the childhood sarcoglycanopathies.
LGMD2P (primary dystroglycanopathy; DAG1) MONDO:0013440
DAG1 hgnc:2666 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in DAG1 (hgnc:2666). hgnc:2666 is a gene from the HUGO Gene Nomenclature Committee.
Primary dystroglycanopathy: limb-girdle weakness with cognitive impairment caused by a missense variant in DAG1 itself rather than in one of the glycosyltransferases that modify alpha-dystroglycan. The reported Thr192Met substitution blocks LARGE-dependent maturation of the phosphorylated O-mannosyl glycans that alpha-dystroglycan needs for high-affinity laminin binding.
Show evidence (1 reference)
PMID:21388311 SUPPORT Human Clinical
"We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment."
Establishes the DAG1 missense variant as the cause of limb-girdle muscular dystrophy with cognitive impairment.
LGMD2Z / LGMD R21 (POGLUT1-related) MONDO:0014977
POGLUT1 hgnc:22954 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in POGLUT1 (hgnc:22954). hgnc:22954 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive limb-girdle muscular dystrophy caused by a missense variant in POGLUT1, the protein O-glucosyltransferase that modifies Notch. Patient muscle shows decreased Notch signalling, a markedly reduced satellite cell pool, and muscle-specific alpha-dystroglycan hypoglycosylation that is absent from the same patients' fibroblasts. MONDO's primary label for this concept reads "type 2R1", which matches none of its own exact synonyms; those give "autosomal recessive limb-girdle muscular dystrophy type 2Z" and "muscular dystrophy, limb-girdle, autosomal recessive 21", and this row follows them.
Show evidence (2 references)
PMID:27807076 SUPPORT Human Clinical
"In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function."
Establishes the POGLUT1 missense variant as the cause of this autosomal recessive limb-girdle muscular dystrophy.
PMID:27807076 SUPPORT Human Clinical
"Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts."
Sources the muscle findings described for this subtype, including the tissue-restricted alpha-dystroglycan hypoglycosylation.
LGMD2X / LGMD R25 (POPDC1-related, with cardiac arrhythmia) MONDO:0014782
POPDC1 hgnc:1152 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in POPDC1, annotated with BVES (hgnc:1152). hgnc:1152 is a gene from the HUGO Gene Nomenclature Committee.
Adult-onset proximal limb-girdle weakness with cardiac arrhythmia, caused by a homozygous POPDC1 missense variant. POPDC1 (previous symbol BVES) encodes a plasma membrane cAMP-binding protein of striated muscle; the reported S201F substitution halves cAMP affinity and impairs membrane trafficking of both POPDC1 and POPDC2 in patient muscle.
Show evidence (1 reference)
PMID:26642364 SUPPORT Human Clinical
"Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD)."
Establishes the homozygous POPDC1 variant as the cause of combined arrhythmia and limb-girdle muscular dystrophy.
LGMD R18 (TRAPPC11-related) MONDO:0014144
TRAPPC11 hgnc:25751 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TRAPPC11 (hgnc:25751). hgnc:25751 is a gene from the HUGO Gene Nomenclature Committee.
Recessive TRAPPC11 variants cause a spectrum from pure limb-girdle muscular dystrophy to a syndromic myopathy with infantile hyperkinetic movements, ataxia and intellectual disability, depending on the allele: a gryzun-domain missense variant segregated with LGMD in one consanguineous family, while a splice variant producing an in-frame deletion in the foie gras domain segregated with the syndromic form in Hutterite families.
Show evidence (1 reference)
PMID:23830518 SUPPORT Human Clinical
"Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and..."
Establishes recessive TRAPPC11 variants as the cause of both ends of this subtype's phenotypic spectrum.
Limb-girdle muscular dystrophy due to POMK deficiency MONDO:0014489
POMK hgnc:26267 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in POMK (hgnc:26267). hgnc:26267 is a gene from the HUGO Gene Nomenclature Committee.
The mild end of the POMK dystroglycanopathy spectrum: limb-girdle weakness with cognitive defects, as opposed to Walker-Warburg syndrome at the severe end. POMK phosphorylates the O-mannosyl glycan on alpha-dystroglycan, a step required for extracellular matrix binding, so this is a dystroglycanopathy caused by a kinase rather than by a glycosyltransferase.
Show evidence (1 reference)
PMID:24925318 SUPPORT Human Clinical
"Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects."
Establishes the limb-girdle end of the POMK phenotypic spectrum that this subtype names.
LGMD R26 (POPDC3-related) MONDO:0030014
POPDC3 hgnc:17649 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in POPDC3 (hgnc:17649). hgnc:17649 is a gene from the HUGO Gene Nomenclature Committee.
Homozygous POPDC3 missense variants cause a limb-girdle muscular dystrophy with mostly adult-onset proximal weakness affecting the lower limbs before the upper, high creatine kinase, dystrophic biopsies, and fat replacement of paraspinal and proximal leg muscles on MRI. Unlike its paralogue POPDC1, cardiac investigations in the reported patients were unremarkable.
Show evidence (2 references)
PMID:31610034 SUPPORT Human Clinical
"We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families."
Establishes homozygous POPDC3 variants as the cause of this subtype in three unrelated families.
PMID:31610034 SUPPORT Human Clinical
"Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable."
Sources the clinical pattern and the absence of cardiac involvement described for this subtype.
LGMD R27 (JAG2-related) MONDO:0030456
JAG2 hgnc:6189 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in JAG2 (hgnc:6189). hgnc:6189 is a gene from the HUGO Gene Nomenclature Committee.
Biallelic JAG2 variants cause a muscular dystrophy with onset from infancy to young adulthood, normal or only mildly raised creatine kinase, and a distinctive slightly asymmetric MRI pattern with cores of preserved and affected muscle in quadriceps and tibialis anterior that can resemble POGLUT1-associated disease. JAG2 encodes the Notch ligand Jagged2, placing this subtype with POGLUT1 in the Notch/satellite-cell group rather than with the sarcolemmal ones.
Show evidence (2 references)
PMID:33861953 SUPPORT Human Clinical
"Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families."
Establishes biallelic JAG2 variants across 13 unrelated families as the cause of this subtype.
PMID:33861953 SUPPORT Human Clinical
"MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy."
Sources the MRI pattern and its resemblance to POGLUT1 disease described for this subtype.
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Pathophysiology

10
Alpha-Dystroglycan Hypoglycosylation and Loss of Laminin Binding
Alpha-dystroglycan reaches the extracellular matrix only after an O-mannosyl glycan is phosphorylated and then extended by LARGE; the mature glycan is what binds laminin with high affinity. Two of the LGMD-R genes act inside this pathway rather than on the sarcolemmal complex itself. DAG1 is the substrate: the Thr192Met variant blocks LARGE-dependent maturation of the phosphorylated O-mannosyl glycan, so the receptor loses laminin binding despite being present. POMK is the kinase that performs the phosphorylation step, and truncating alleles that remove its kinase domain produce dystroglycanopathy ranging from Walker-Warburg syndrome to limb-girdle weakness with cognitive defects. This node is the primary-dystroglycanopathy counterpart of the FKRP-driven secondary dystroglycanopathy recorded on the sarcolemmal node below.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
DAG1 hgnc:2666 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DAG1 (hgnc:2666). hgnc:2666 is a gene from the HUGO Gene Nomenclature Committee. POMK hgnc:26267 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POMK (hgnc:26267). hgnc:26267 is a gene from the HUGO Gene Nomenclature Committee.
laminin binding GO:0043236 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased laminin binding (GO:0043236). GO:0043236 is a molecular function from the Gene Ontology.
Downstream
Sarcolemmal Instability and Failed Membrane Repair An alpha-dystroglycan that cannot bind laminin severs the link between the myofiber cytoskeleton and the basement membrane, the same lesion the sarcoglycan and FKRP subtypes reach by other routes.
Show evidence (3 references)
PMID:21388311 SUPPORT Model Organism
"In vitro and in vivo studies showed that the mutation impairs the receptor function of dystroglycan in skeletal muscle and brain by inhibiting the post-translational modification, mediated by the glycosyltransferase LARGE, of the phosphorylated O-mannosyl glycans on α-dystroglycan that is..."
Supports loss of high-affinity laminin binding by alpha-dystroglycan as the molecular lesion in the DAG1 form. Graded MODEL_ORGANISM because the "in vivo" half of this sentence is the T190M knock-in mouse described earlier in the same paper, which is where the laminin-overlay and histology results come from; the human proband contributes the genotype and phenotype, covered by the other evidence on this record.
PMID:24925318 SUPPORT BACKGROUND Other
"POMK, which was found mutated in two dystroglycanopathy cases, is instead involved in a glycan phosphorylation reaction critical for ECM binding, but little is known about the clinical presentation of POMK mutations or of the function of this protein in the muscle."
States the glycan-phosphorylation step that POMK performs and that this node asserts is lost.
PMID:24925318 SUPPORT Model Organism
"Analysis of loss of function in the zebrafish embryo and larva showed that pomk function is necessary for normal muscle development, leading to locomotor dysfuction in the embryo and signs of muscular dystrophy in the larva."
Model-organism support that loss of POMK function produces muscular dystrophy.
Calpain-3 Deficiency and Impaired Sarcomere Remodelling
Calpain-3 is the muscle-specific calcium-dependent protease, held at the N2A region of titin in the sarcomere and activated by sustained modest rises in cytoplasmic calcium such as those following eccentric contraction. Loss of calpain-3 expression causes LGMDR1, and its pathogenic mechanism is understood as impaired sarcomere remodelling rather than as sarcolemmal fragility, which is why this subtype is wired to a separate node from the sarcoglycanopathies and dysferlinopathy.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
CAPN3 hgnc:1480 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CAPN3 (hgnc:1480). hgnc:1480 is a gene from the HUGO Gene Nomenclature Committee.
sarcomere organization GO:0045214 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology.
Downstream
Myofiber Degeneration and Necrosis Failure to remodel the sarcomere after contraction-induced damage feeds the same cycles of myofiber degeneration and regeneration that the sarcolemmal subtypes reach through membrane injury.
Show evidence (3 references)
PMID:19793101 SUPPORT Other
"The physiological roles of the calpains are not well understood, although ubiquitous calpains have been associated with apoptosis and myogenesis and calpain-3 is likely involved in sarcomeric remodelling. A defect in the expression of calpain-3 results in limb-girdle muscular dystrophy Type 2A."
Links loss of calpain-3 expression to LGMD2A and states the sarcomeric remodelling role this node asserts, with the hedging the source itself uses.
PMID:19793101 SUPPORT Other
"Calpain-3 is tightly bound in skeletal muscle fibres at the N2A line of the large elastic protein titin."
Sources the sarcomeric localization of calpain-3 recorded in this node.
PMID:23414389 SUPPORT Human Clinical
"The peculiar clinical features and the pathogenic mechanism related to calpain-3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin-proteasome degradation pathway may have a crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A)."
A human LGMD2A study stating impaired sarcomere remodelling as the pathogenic mechanism of calpain-3 deficiency.
Reduced Notch Signalling in Muscle Progenitors
Two LGMD-R genes act on the Notch pathway rather than on the sarcolemma: POGLUT1 O-glucosylates Notch, and JAG2 encodes the Notch ligand Jagged2. Muscle from POGLUT1 patients shows reduced Notch signalling, and restoring Notch signalling rescues the myogenic defect in their primary myoblasts. JAG2 muscle shows misregulation of myogenesis genes including PAX7. This node holds the pathway state; its cellular consequence is recorded separately on the satellite cell node it points at, because the sources treat the two as cause and effect.
POGLUT1 hgnc:22954 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POGLUT1 (hgnc:22954). hgnc:22954 is a gene from the HUGO Gene Nomenclature Committee. JAG2 hgnc:6189 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAG2 (hgnc:6189). hgnc:6189 is a gene from the HUGO Gene Nomenclature Committee.
Notch signaling pathway GO:0007219 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology.
Downstream
Satellite Cell Pool Depletion Notch signalling maintains satellite cell quiescence and self-renewal, so reduced signalling depletes the pool the sources measure.
Show evidence (3 references)
PMID:27807076 SUPPORT Human Clinical
"Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts."
Direct patient-muscle evidence for the reduced Notch signalling this node asserts.
PMID:33861953 SUPPORT Human Clinical
"In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction."
Places the JAG2 subtype in the same Notch-pathway mechanism as POGLUT1.
PMID:33861953 SUPPORT Human Clinical
"Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7."
Supports the myogenic-program disturbance, including PAX7, recorded for the JAG2 form.
Satellite Cell Pool Depletion
Skeletal muscle regeneration depends on satellite cells, whose quiescence and self-renewal are controlled by Notch signalling. POGLUT1 patients' muscle holds a dramatically reduced satellite cell pool, and their primary myoblasts proliferate slowly, differentiate too readily, and hold a smaller pool of quiescent PAX7-positive cells. The authors name Notch-dependent loss of satellite cells as the pathomechanism, which is why this node sits downstream of the pathway node rather than beside it.
skeletal muscle satellite cell CL:0000594 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle satellite cell (CL:0000594). CL:0000594 is a cell type from the Cell Ontology.
Downstream
Chronic Inflammation and Fibrofatty Replacement A depleted satellite cell pool cannot sustain repair, so repeated injury exhausts regenerative capacity and muscle is replaced by fibrotic and fatty tissue.
Show evidence (1 reference)
PMID:27807076 SUPPORT Human Clinical
"These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells."
The authors' own statement that satellite cell loss is Notch-dependent, which is the edge into this node.
POPDC1 cAMP-Effector Membrane Trafficking Defect
POPDC1 is a plasma-membrane cAMP-binding protein abundant in striated muscle. The LGMD2X variant POPDC1 S201F halves cAMP affinity and, in patient skeletal muscle, leaves both mutant POPDC1 and wild-type POPDC2 stranded short of the membrane. POPDC1 disease carries cardiac arrhythmia. The paralogue POPDC3 is modelled separately: no source reports a trafficking defect for it, so it is not listed on this node.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
POPDC1 hgnc:1152 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POPDC1, annotated with BVES (hgnc:1152). hgnc:1152 is a gene from the HUGO Gene Nomenclature Committee.
protein localization to plasma membrane GO:0072659 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to plasma membrane (GO:0072659). GO:0072659 is a biological process from the Gene Ontology.
Downstream
Sarcolemmal Instability and Failed Membrane Repair Failure to deliver and hold POPDC1 at the sarcolemma degrades the membrane's response to mechanical and adrenergic stress, converging on the shared sarcolemmal lesion.
Show evidence (1 reference)
PMID:26642364 SUPPORT Human Clinical
"Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking."
Direct patient-muscle evidence for the impaired membrane trafficking this node asserts.
Aberrant POPDC3 Modulation of TREK-1
POPDC3 is the POPDC1 paralogue, also a plasma-membrane cAMP-binding protein of striated muscle. The only functional readout reported for the three LGMD R26 variants is aberrant modulation of the mechano-gated potassium channel TREK-1 in Xenopus oocytes. No source reports a membrane-trafficking defect for POPDC3, and the path from altered TREK-1 modulation to the sarcolemmal lesion is not established, so this node is kept separate from the POPDC1 trafficking node and its downstream link names no intermediate step. POPDC3 disease, in the reported patients, did not involve the heart.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
POPDC3 hgnc:17649 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POPDC3 (hgnc:17649). hgnc:17649 is a gene from the HUGO Gene Nomenclature Committee.
potassium channel regulator activity GO:0015459 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal potassium channel regulator activity (GO:0015459). GO:0015459 is a molecular function from the Gene Ontology.
Downstream
Sarcolemmal Instability and Failed Membrane Repair Altered POPDC3 modulation of TREK-1 is the only reported functional consequence of these variants; how it reaches the sarcolemmal lesion is not established.
Show evidence (1 reference)
PMID:31610034 SUPPORT In Vitro
"All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1."
The only functional abnormality reported for the POPDC3 variants, and the sole basis for this node.
Golgi Trafficking Defect
TRAPPC11 is a subunit of the multiprotein TRAPP membrane-trafficking complex. Both reported LGMD R18 alleles weaken TRAPPC11 binding to other TRAPP components and disrupt Golgi architecture. Endoplasmic-reticulum-to-Golgi transport remains normal while exit from the Golgi to the cell surface is dramatically delayed, and the lysosomal membrane glycoproteins LAMP1 and LAMP2 are altered as a consequence, so the defect is in secretory-pathway transit rather than in the sarcolemmal complex.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
TRAPPC11 hgnc:25751 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRAPPC11 (hgnc:25751). hgnc:25751 is a gene from the HUGO Gene Nomenclature Committee.
Golgi organization GO:0007030 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi organization (GO:0007030). GO:0007030 is a biological process from the Gene Ontology.
Downstream
Myofiber Degeneration and Necrosis Delayed delivery of secretory and lysosomal proteins to the myofiber surface and to the lysosome degrades the fiber's capacity to maintain and repair itself, feeding the shared degeneration cycle.
Show evidence (2 references)
PMID:23830518 SUPPORT In Vitro
"We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture."
Supports disrupted Golgi architecture as the molecular lesion in this node.
PMID:23830518 SUPPORT In Vitro
"Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface."
Localizes the transport block to Golgi exit rather than to ER-to-Golgi transit, as described here.
Sarcolemmal Instability and Failed Membrane Repair
Across LGMD-R subtypes the proximate defect destabilizes the myofiber plasma membrane (sarcolemma). Sarcoglycanopathies (SGCA-D) and dystroglycanopathies (FKRP) disrupt the dystrophin-glycoprotein complex that links the cytoskeleton to the extracellular matrix, while dysferlin (DYSF) deficiency impairs calcium-triggered resealing of membrane microtears. The result is a fragile sarcolemma that cannot withstand or repair contraction-induced injury.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
DYSF hgnc:3097 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DYSF (hgnc:3097). hgnc:3097 is a gene from the HUGO Gene Nomenclature Committee. FKRP hgnc:17997 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FKRP (hgnc:17997). hgnc:17997 is a gene from the HUGO Gene Nomenclature Committee. SGCA hgnc:10805 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SGCA (hgnc:10805). hgnc:10805 is a gene from the HUGO Gene Nomenclature Committee. SGCB hgnc:10806 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SGCB (hgnc:10806). hgnc:10806 is a gene from the HUGO Gene Nomenclature Committee. SGCG hgnc:10809 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SGCG (hgnc:10809). hgnc:10809 is a gene from the HUGO Gene Nomenclature Committee. SGCD hgnc:10807 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SGCD (hgnc:10807). hgnc:10807 is a gene from the HUGO Gene Nomenclature Committee. ANO5 hgnc:27337 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANO5 (hgnc:27337). hgnc:27337 is a gene from the HUGO Gene Nomenclature Committee.
plasma membrane repair GO:0001778 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased plasma membrane repair (GO:0001778). GO:0001778 is a biological process from the Gene Ontology.
Downstream
Myofiber Degeneration and Necrosis A fragile, poorly repaired sarcolemma cannot withstand contraction-induced stress, leading to repeated myofiber injury and necrosis.
Show evidence (4 references)
PMID:40422224 SUPPORT Human Clinical
"A specific subgroup of muscular dystrophies is associated with genetic defects in components of the dystrophin-glycoprotein complex (DGC), which plays a crucial role in linking the cytosol to the skeletal muscle basement membrane. In these cases, dystrophin-associated proteins fail to correctly..."
Establishes that DGC defects (e.g., sarcoglycanopathies, dystroglycanopathies) destabilize the sarcolemma, the shared upstream lesion in this node.
PMID:38540676 SUPPORT Human Clinical
"They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes."
Establishes that dysferlin deficiency impairs membrane repair, the complementary mechanism of sarcolemmal instability in LGMDR2.
PMID:20096397 SUPPORT Human Clinical
"With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes."
Ultrastructural sarcolemmal lesions in ANO5 patients place anoctaminopathy on this node alongside the sarcoglycanopathies and dysferlinopathy.
+ 1 more reference
Myofiber Degeneration and Necrosis
Sarcolemmal instability permits pathological calcium influx and uncontrolled activation of degradative pathways (calpain proteolysis, the ubiquitin-proteasome system, and dysregulated autophagy), driving cycles of myofiber degeneration, necrosis, and regeneration. Centralized nuclei, necrotic fibers, and inflammatory cytokine release are characteristic histological features.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
muscle cell apoptotic process GO:0010657 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased muscle cell apoptotic process (GO:0010657). GO:0010657 is a biological process from the Gene Ontology. calcium ion transport GO:0006816 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal calcium ion transport (GO:0006816). GO:0006816 is a biological process from the Gene Ontology. autophagy GO:0006914 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology.
Downstream
Chronic Inflammation and Fibrofatty Replacement Repeated necrosis releases inflammatory cytokines and eventually exhausts regenerative capacity, leading to chronic inflammation and replacement of muscle with fibrotic and fatty tissue.
Show evidence (1 reference)
PMID:40422224 SUPPORT Human Clinical
"These are characterized by the centralization of skeletal muscle syncytial nuclei, the replacement of muscle fibers with fibrotic tissue, the release of inflammatory cytokines, and the disruption of muscle protein homeostasis, ultimately leading to necrosis and loss of muscle functionality."
Documents myofiber necrosis, disrupted protein homeostasis, and inflammatory cytokine release downstream of sarcolemmal destabilization.
Chronic Inflammation and Fibrofatty Replacement
Sustained injury drives chronic inflammation (with impaired macrophage M1-to-M2 switching) and progressive replacement of contractile muscle by fibrotic and adipose tissue, which is detectable as subtype-specific fatty infiltration patterns on muscle MRI and as fibrosis on biopsy. This is the structural substrate of permanent weakness.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. tissue remodeling GO:0048771 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal tissue remodeling (GO:0048771). GO:0048771 is a biological process from the Gene Ontology.
Downstream
Progressive proximal muscle weakness Loss of functional contractile muscle and its replacement by fibrofatty tissue manifests clinically as progressive proximal limb-girdle weakness.
Calf muscle hypertrophy In the sarcoglycanopathies, fibrofatty replacement and reactive enlargement of the calf musculature produce calf (pseudo)hypertrophy, a characteristic sign.
Show evidence (1 reference)
PMID:37974208 SUPPORT Human Clinical
"Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B."
Documents fibrofatty (fatty infiltration) replacement of muscle, with subtype-specific MRI patterns, as a downstream consequence of repeated degeneration.
⬡

Pathograph

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

Phenotypes

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

Genetic Associations

16
CAPN3 (calpainopathy / LGMDR1)
Gene: CAPN3 hgnc:1480 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CAPN3 (hgnc:1480). hgnc:1480 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:38045992 SUPPORT Human Clinical
"The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
The US MD STARnet population-based surveillance study identifies CAPN3 among the most common genes associated with LGMD.
DYSF (dysferlinopathy / LGMDR2)
Gene: DYSF hgnc:3097 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DYSF (hgnc:3097). hgnc:3097 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:38540676 SUPPORT Human Clinical
"They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes."
Identifies DYSF/dysferlin as the cause of dysferlinopathy and its membrane-repair role.
SGCA (alpha-sarcoglycanopathy / LGMDR3)
Gene: SGCA hgnc:10805 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SGCA (hgnc:10805). hgnc:10805 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including the sarcoglycanopathies, arise from mutations in multiple distinct genes.
SGCB (beta-sarcoglycanopathy / LGMDR4)
Gene: SGCB hgnc:10806 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SGCB (hgnc:10806). hgnc:10806 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including beta-sarcoglycanopathy, arise from mutations in multiple distinct genes.
SGCG (gamma-sarcoglycanopathy / LGMDR5)
Gene: SGCG hgnc:10809 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SGCG (hgnc:10809). hgnc:10809 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including gamma-sarcoglycanopathy, arise from mutations in multiple distinct genes.
SGCD (delta-sarcoglycanopathy / LGMDR6)
Gene: SGCD hgnc:10807 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SGCD (hgnc:10807). hgnc:10807 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
The classification review establishes that LGMDs, including delta-sarcoglycanopathy, arise from mutations in multiple distinct genes.
ANO5 (anoctaminopathy / LGMDR12)
Gene: ANO5 hgnc:27337 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANO5 (hgnc:27337). hgnc:27337 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:38045992 SUPPORT Human Clinical
"The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
ANO5 is among the most common LGMD-associated genes in the US MD STARnet cohort.
DAG1 (primary dystroglycanopathy / LGMD2P)
Gene: DAG1 hgnc:2666 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DAG1 (hgnc:2666). hgnc:2666 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:21388311 SUPPORT Human Clinical
"We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment."
Establishes a DAG1 missense variant as the cause of limb-girdle muscular dystrophy with cognitive impairment.
CGGV:assertion_61b73fd7-5578-447b-9482-ea64d62dae1d-2024-08-13T190000.000Z SUPPORT Other
"DAG1 | HGNC:2666 | qualitative or quantitative defects of alpha-dystroglycan | MONDO:0018282 | AR | Definitive"
ClinGen classifies DAG1 as Definitive with autosomal recessive inheritance, but against the dystroglycanopathy concept rather than against LGMD-R.
POGLUT1 (LGMD2Z / LGMD R21)
Gene: POGLUT1 hgnc:22954 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POGLUT1 (hgnc:22954). hgnc:22954 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:27807076 SUPPORT Human Clinical
"In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function."
Establishes the POGLUT1 missense variant as the cause in the index family.
PMID:27807076 SUPPORT Model Organism
"In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development."
Functional support for the loss of enzymatic activity recorded in these notes. Graded MODEL_ORGANISM rather than IN_VITRO because the "in vivo" half is the transgenic Drosophila rescue experiment, in which human POGLUT1 D233E fails to rescue the muscle phenotype of fly Poglut1 loss; the enzymatic assays and the patient primary myoblasts are the in vitro half, and the sentence covers both.
CGGV:assertion_c3396945-a664-4ada-bb7f-c123ec50b849-2024-08-14T190000.000Z SUPPORT Other
"POGLUT1 | HGNC:22954 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
ClinGen classifies the POGLUT1 LGMD-R relationship as definitive with autosomal recessive inheritance.
POPDC1 (LGMD2X / LGMDR25)
Gene: POPDC1 hgnc:1152 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POPDC1, annotated with BVES (hgnc:1152). hgnc:1152 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:26642364 SUPPORT Human Clinical
"Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases."
Establishes POPDC1 as an autosomal recessive cause of combined arrhythmia and LGMD.
CGGV:assertion_31a0db34-cad3-4746-a40f-2912318dfbd2-2024-08-29T190000.000Z SUPPORT Other
"BVES | HGNC:1152 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
ClinGen classifies the relationship as definitive, under the previous gene symbol BVES but against the same HGNC identifier as POPDC1.
TRAPPC11 (LGMD R18)
Gene: TRAPPC11 hgnc:25751 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRAPPC11 (hgnc:25751). hgnc:25751 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:23830518 SUPPORT Human Clinical
"By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino..."
Identifies the two TRAPPC11 alleles behind the two ends of the phenotypic spectrum.
CGGV:assertion_8b835ba1-afbd-48ac-afec-b9396acc5521-2024-08-14T190000.000Z SUPPORT Other
"TRAPPC11 | HGNC:25751 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
ClinGen classifies the TRAPPC11-LGMD-R relationship as definitive with autosomal recessive inheritance.
POMK (POMK-deficiency LGMD)
Gene: POMK hgnc:26267 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POMK (hgnc:26267). hgnc:26267 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:24925318 SUPPORT Human Clinical
"Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects."
Establishes POMK truncating alleles as a cause of limb-girdle muscular dystrophy with cognitive defects.
POPDC3 (LGMD R26)
Gene: POPDC3 hgnc:17649 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POPDC3 (hgnc:17649). hgnc:17649 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:31610034 SUPPORT Human Clinical
"We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families."
Establishes the three homozygous POPDC3 variants and the families they were found in.
CGGV:assertion_bb7755df-a1e3-4398-a771-cd6c2d112b68-2025-02-11T170000.000Z SUPPORT Other
"POPDC3 | HGNC:17649 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
ClinGen classifies the POPDC3-LGMD-R relationship as definitive with autosomal recessive inheritance.
JAG2 (LGMD R27)
Gene: JAG2 hgnc:6189 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAG2 (hgnc:6189). hgnc:6189 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33861953 SUPPORT Human Clinical
"Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families."
Establishes biallelic JAG2 variants across the whole reported cohort.
CGGV:assertion_16f43ce9-05b5-437d-a35e-b1c379c0ba7a-2024-08-27T160000.000Z SUPPORT Other
"JAG2 | HGNC:6189 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Moderate"
ClinGen classifies the JAG2-LGMD-R relationship as Moderate, the strength recorded in these notes.
LIMS2 (disputed)
Gene: LIMS2 hgnc:16084 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LIMS2 (hgnc:16084). hgnc:16084 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (3 references)
PMID:25589244 SUPPORT Human Clinical
"Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2."
The single original report proposing LIMS2 as a muscular dystrophy gene.
CGGV:assertion_00284b9e-fc0e-4667-ad1b-fd68f2cdc490-2024-11-12T200000.000Z REFUTE Other
"In summary, the evidence supporting the relationship between LIMS2 and autosomal recessive limb-girdle muscular dystrophy has been disputed and no valid evidence remains to support the claim."
ClinGen's expert-panel conclusion that no valid evidence remains for the LIMS2-LGMD-R relationship, which is why this record is typed DISPUTED.
CGGV:assertion_00284b9e-fc0e-4667-ad1b-fd68f2cdc490-2024-11-12T200000.000Z REFUTE Model Organism
"The resulting LIMS2 deficient mice showed no apparent phenotype when compared to their wild-type and heterozygous littermates (PMID:16317048)."
The model-organism negative result ClinGen cites among its reasons for disputing the relationship.
💊

Medical Actions

6
Physical therapy and rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
No curative therapy is approved; management is supportive. Physical therapy and stretching promote mobility and prevent contractures, with mobility aids as needed.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Physical therapy and stretching exercises to promote mobility and prevent contractures; supervised strengthening and gentle low-impact aerobic exercise"
The Calpainopathy GeneReviews recommends physical therapy and stretching as mainstay supportive management.
Noninvasive ventilation
Action: noninvasive ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is noninvasive ventilation, annotated with Non-Invasive Mechanical Ventilation (NCIT:C171457). NCIT:C171457 is a clinical intervention from the NCI Thesaurus. Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457
Nocturnal and chronic noninvasive ventilatory support is used as respiratory muscle weakness progresses to respiratory insufficiency.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"nocturnal ventilator assistance as needed; respiratory aids to treat chronic respiratory insufficiency in late stages of the disease"
The Calpainopathy GeneReviews recommends ventilatory support for respiratory insufficiency in advanced disease.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling is essential for carrier identification, recurrence-risk assessment, and reproductive planning given autosomal recessive inheritance.
Show evidence (1 reference)
PMID:20301480 SUPPORT Human Clinical
"Once the DYSF pathogenic variants have been identified in an affected family member, carrier testing for at-risk"
The Dysferlinopathy GeneReviews describes carrier testing and genetic counseling following identification of family pathogenic variants.
AAV gene replacement therapy (investigational)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Adeno-associated virus (AAV) gene replacement therapies are in clinical development for the sarcoglycanopathies, including bidridistrogene xeboparvovec (SRP-9003) for beta-sarcoglycanopathy/LGMDR4, which has progressed to a Phase 3 trial.
Show evidence (1 reference)
PMID:37510884 SUPPORT Human Clinical
"In the last decade, multiple other potential treatments were developed and studied, such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene editing."
The classification/therapy review documents gene delivery (gene replacement) among the molecular therapies in development for LGMD.
Cardiac management for LGMD-associated cardiomyopathy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus. beta-blocker NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses beta-blocker, annotated with Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus.
Cardiac surveillance and standard heart-failure pharmacotherapy are indicated in the subtypes with cardiac involvement (sarcoglycanopathies LGMDR3-R6 and FKRP-related LGMDR9). Guideline-directed medical therapy for dilated cardiomyopathy uses angiotensin-converting-enzyme (ACE) inhibitors and beta-adrenergic antagonists (beta-blockers) to reduce afterload and neurohormonal activation.
Show evidence (1 reference)
PMID:20301582 SUPPORT Human Clinical
"monitoring for cardiomyopathy in LGMD types with cardiac involvement"
The Limb-Girdle Muscular Dystrophy Overview GeneReviews recommends monitoring for cardiomyopathy in the LGMD subtypes with cardiac involvement, which underpins the ACE-inhibitor/beta-blocker heart-failure management standard of care.
Agents and circumstances to avoid
Action: avoidance of myotoxic and anesthetic triggersNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is avoidance of myotoxic and anesthetic triggers, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Because of a malignant-hyperthermia-like anesthetic risk and drug-induced myotoxicity, succinylcholine and halogenated (volatile) anesthetic agents should be avoided when possible, and cholesterol-lowering statins should be avoided when possible in calpainopathy and related LGMD-R subtypes.
Show evidence (1 reference)
PMID:20301490 SUPPORT Human Clinical
"Avoid succinylcholine and halogenated anesthetic agents when possible; avoid cholesterol-lowering agents (e.g., statins) when possible."
The Calpainopathy GeneReviews lists succinylcholine, halogenated anesthetics, and statins among the agents/circumstances to avoid.
🔬

Diagnosis

1
Next-generation sequencing gene panel / exome
Diagnosis is confirmed by identifying biallelic pathogenic variants via targeted neuromuscular NGS gene panels, whole-exome, or whole-genome sequencing, supported by muscle biopsy with immunohistochemistry showing the specific protein deficiency.
Show evidence (1 reference)
PMID:20301480 SUPPORT Human Clinical
"The diagnosis of dysferlinopathy is established in a proband with suggestive findings and biallelic pathogenic variants in DYSF identified by molecular genetic testing."
Confirms molecular genetic testing as the diagnostic standard, exemplified for DYSF.
📊

Prevalence

1
Southeast China LGMD cohort (subtype distribution)
In a genetically confirmed Southeast Chinese LGMD cohort, dysferlinopathy (LGMD-R2) and calpainopathy (LGMD-R1) were the two most common subtypes.
Show evidence (1 reference)
PMID:37974208 SUPPORT Human Clinical
"Among 50 patients (41 families) with LGMDs, the most common subtypes were LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%)."
Provides the relative subtype frequencies in a population-defined LGMD cohort.
🔬

Clinical Trials

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

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

references:
- reference: PMID:20301582
  title: "Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301490
  title: "Calpainopathy."
  tags:
  - GeneReviews
- reference: PMID:20301480
  title: "Dysferlinopathy."
  tags:
  - GeneReviews

has_subtypes:
- name: LGMDR1
  display_name: LGMD R1 (calpainopathy, LGMD2A; CAPN3)
  subtype_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2A
    term:
      id: MONDO:0009675
      label: autosomal recessive limb-girdle muscular dystrophy type 2A
  description: >-
    Calpainopathy, caused by biallelic CAPN3 variants. The most common LGMD-R subtype
    in many cohorts (~30-40% of LGMD). Characterized by symmetric progressive proximal
    weakness, scapular winging, tiptoe walking, Achilles tendon shortening, and scoliosis,
    typically without cardiac involvement.
  genes:
  - preferred_term: CAPN3
    term:
      id: hgnc:1480
      label: CAPN3
- name: LGMDR2
  display_name: LGMD R2 (dysferlinopathy, LGMD2B; DYSF)
  description: >-
    Dysferlinopathy, caused by biallelic DYSF variants encoding the membrane-repair
    protein dysferlin. Onset usually in the late teens to thirties, with very high
    serum CK (50-200x normal) and a phenotypic spectrum that also includes Miyoshi
    distal myopathy. Cardiac involvement is rare.
  genes:
  - preferred_term: DYSF
    term:
      id: hgnc:3097
      label: DYSF
- name: LGMDR3
  display_name: LGMD R3 (alpha-sarcoglycanopathy, LGMD2D; SGCA)
  description: >-
    Alpha-sarcoglycanopathy, caused by biallelic SGCA variants. Usually childhood
    onset with proximal weakness, calf hypertrophy, and risk of cardiomyopathy.
  genes:
  - preferred_term: SGCA
    term:
      id: hgnc:10805
      label: SGCA
- name: LGMDR4
  display_name: LGMD R4 (beta-sarcoglycanopathy, LGMD2E; SGCB)
  description: >-
    Beta-sarcoglycanopathy, caused by biallelic SGCB variants. Often a severe
    childhood-onset sarcoglycanopathy with cardiac and respiratory involvement.
  genes:
  - preferred_term: SGCB
    term:
      id: hgnc:10806
      label: SGCB
- name: LGMDR5
  display_name: LGMD R5 (gamma-sarcoglycanopathy, LGMD2C; SGCG)
  description: >-
    Gamma-sarcoglycanopathy, caused by biallelic SGCG variants. Variable severity
    including a severe childhood form with early loss of ambulation, calf hypertrophy,
    and high CK.
  genes:
  - preferred_term: SGCG
    term:
      id: hgnc:10809
      label: SGCG
- name: LGMDR6
  display_name: LGMD R6 (delta-sarcoglycanopathy, LGMD2F; SGCD)
  description: >-
    Delta-sarcoglycanopathy, caused by biallelic SGCD variants. A typically severe
    childhood-to-adolescence sarcoglycanopathy with risk of cardiomyopathy and
    respiratory complications.
  genes:
  - preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
- name: LGMDR9
  display_name: LGMD R9 (FKRP-related dystroglycanopathy, LGMD2I; FKRP)
  description: >-
    FKRP-related dystroglycanopathy, caused by biallelic FKRP variants that impair
    glycosylation of alpha-dystroglycan. Variable onset; the common founder variant
    c.826C>A is associated with a later median loss of ambulation; respiratory decline
    and cardiomyopathy may occur.
  genes:
  - preferred_term: FKRP
    term:
      id: hgnc:17997
      label: FKRP
- name: LGMDR12
  display_name: LGMD R12 (anoctaminopathy, LGMD2L; ANO5)
  subtype_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2L
    term:
      id: MONDO:0012652
      label: autosomal recessive limb-girdle muscular dystrophy type 2L
  description: >-
    Anoctaminopathy, caused by biallelic ANO5 variants. Typically adult-onset proximal
    weakness, sometimes asymmetric or with a mixed proximal/distal pattern, with
    elevated CK and slower progression than the childhood sarcoglycanopathies.
  genes:
  - preferred_term: ANO5
    term:
      id: hgnc:27337
      label: ANO5
- name: LGMD2P
  display_name: LGMD2P (primary dystroglycanopathy; DAG1)
  subtype_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2P
    term:
      id: MONDO:0013440
      label: autosomal recessive limb-girdle muscular dystrophy type 2P
  description: >-
    Primary dystroglycanopathy: limb-girdle weakness with cognitive impairment caused
    by a missense variant in DAG1 itself rather than in one of the glycosyltransferases
    that modify alpha-dystroglycan. The reported Thr192Met substitution blocks
    LARGE-dependent maturation of the phosphorylated O-mannosyl glycans that
    alpha-dystroglycan needs for high-affinity laminin binding.
  genes:
  - preferred_term: DAG1
    term:
      id: hgnc:2666
      label: DAG1
  evidence:
  - reference: PMID:21388311
    reference_title: "A dystroglycan mutation associated with limb-girdle muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment."
    explanation: Establishes the DAG1 missense variant as the cause of limb-girdle muscular dystrophy with cognitive impairment.
- name: LGMD2Z
  display_name: LGMD2Z / LGMD R21 (POGLUT1-related)
  subtype_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2Z
    term:
      id: MONDO:0014977
      label: autosomal recessive limb-girdle muscular dystrophy type 2R1
  description: >-
    Autosomal recessive limb-girdle muscular dystrophy caused by a missense variant
    in POGLUT1, the protein O-glucosyltransferase that modifies Notch. Patient
    muscle shows decreased Notch signalling, a markedly reduced satellite cell pool,
    and muscle-specific alpha-dystroglycan hypoglycosylation that is absent from the
    same patients' fibroblasts. MONDO's primary label for this concept reads "type
    2R1", which matches none of its own exact synonyms; those give "autosomal
    recessive limb-girdle muscular dystrophy type 2Z" and "muscular dystrophy,
    limb-girdle, autosomal recessive 21", and this row follows them.
  genes:
  - preferred_term: POGLUT1
    term:
      id: hgnc:22954
      label: POGLUT1
  evidence:
  - reference: PMID:27807076
    reference_title: "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function."
    explanation: Establishes the POGLUT1 missense variant as the cause of this autosomal recessive limb-girdle muscular dystrophy.
  - reference: PMID:27807076
    reference_title: "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts."
    explanation: Sources the muscle findings described for this subtype, including the tissue-restricted alpha-dystroglycan hypoglycosylation.
- name: LGMD2X
  display_name: LGMD2X / LGMD R25 (POPDC1-related, with cardiac arrhythmia)
  subtype_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2X
    term:
      id: MONDO:0014782
      label: autosomal recessive limb-girdle muscular dystrophy type 2X
  description: >-
    Adult-onset proximal limb-girdle weakness with cardiac arrhythmia, caused by a
    homozygous POPDC1 missense variant. POPDC1 (previous symbol BVES) encodes a
    plasma membrane cAMP-binding protein of striated muscle; the reported S201F
    substitution halves cAMP affinity and impairs membrane trafficking of both
    POPDC1 and POPDC2 in patient muscle.
  genes:
  - preferred_term: POPDC1
    term:
      id: hgnc:1152
      label: BVES
  evidence:
  - reference: PMID:26642364
    reference_title: "POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD)."
    explanation: Establishes the homozygous POPDC1 variant as the cause of combined arrhythmia and limb-girdle muscular dystrophy.
- name: LGMDR18
  display_name: LGMD R18 (TRAPPC11-related)
  subtype_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type R18
    term:
      id: MONDO:0014144
      label: autosomal recessive limb-girdle muscular dystrophy type R18
  description: >-
    Recessive TRAPPC11 variants cause a spectrum from pure limb-girdle muscular
    dystrophy to a syndromic myopathy with infantile hyperkinetic movements, ataxia
    and intellectual disability, depending on the allele: a gryzun-domain missense
    variant segregated with LGMD in one consanguineous family, while a splice
    variant producing an in-frame deletion in the foie gras domain segregated with
    the syndromic form in Hutterite families.
  genes:
  - preferred_term: TRAPPC11
    term:
      id: hgnc:25751
      label: TRAPPC11
  evidence:
  - reference: PMID:23830518
    reference_title: "Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability."
    explanation: Establishes recessive TRAPPC11 variants as the cause of both ends of this subtype's phenotypic spectrum.
- name: POMK-LGMD
  display_name: Limb-girdle muscular dystrophy due to POMK deficiency
  subtype_term:
    preferred_term: limb-girdle muscular dystrophy due to POMK deficiency
    term:
      id: MONDO:0014489
      label: limb-girdle muscular dystrophy due to POMK deficiency
  description: >-
    The mild end of the POMK dystroglycanopathy spectrum: limb-girdle weakness with
    cognitive defects, as opposed to Walker-Warburg syndrome at the severe end.
    POMK phosphorylates the O-mannosyl glycan on alpha-dystroglycan, a step required
    for extracellular matrix binding, so this is a dystroglycanopathy caused by a
    kinase rather than by a glycosyltransferase.
  genes:
  - preferred_term: POMK
    term:
      id: hgnc:26267
      label: POMK
  evidence:
  - reference: PMID:24925318
    reference_title: "POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects."
    explanation: Establishes the limb-girdle end of the POMK phenotypic spectrum that this subtype names.
- name: LGMDR26
  display_name: LGMD R26 (POPDC3-related)
  subtype_term:
    preferred_term: muscular dystrophy, limb-girdle, autosomal recessive 26
    term:
      id: MONDO:0030014
      label: "muscular dystrophy, limb-girdle, autosomal recessive 26"
  description: >-
    Homozygous POPDC3 missense variants cause a limb-girdle muscular dystrophy with
    mostly adult-onset proximal weakness affecting the lower limbs before the upper,
    high creatine kinase, dystrophic biopsies, and fat replacement of paraspinal and
    proximal leg muscles on MRI. Unlike its paralogue POPDC1, cardiac investigations
    in the reported patients were unremarkable.
  genes:
  - preferred_term: POPDC3
    term:
      id: hgnc:17649
      label: POPDC3
  evidence:
  - reference: PMID:31610034
    reference_title: "POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families."
    explanation: Establishes homozygous POPDC3 variants as the cause of this subtype in three unrelated families.
  - reference: PMID:31610034
    reference_title: "POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable."
    explanation: Sources the clinical pattern and the absence of cardiac involvement described for this subtype.
- name: LGMDR27
  display_name: LGMD R27 (JAG2-related)
  subtype_term:
    preferred_term: muscular dystrophy, limb-girdle, autosomal recessive 27
    term:
      id: MONDO:0030456
      label: "muscular dystrophy, limb-girdle, autosomal recessive 27"
  description: >-
    Biallelic JAG2 variants cause a muscular dystrophy with onset from infancy to
    young adulthood, normal or only mildly raised creatine kinase, and a distinctive
    slightly asymmetric MRI pattern with cores of preserved and affected muscle in
    quadriceps and tibialis anterior that can resemble POGLUT1-associated disease.
    JAG2 encodes the Notch ligand Jagged2, placing this subtype with POGLUT1 in the
    Notch/satellite-cell group rather than with the sarcolemmal ones.
  genes:
  - preferred_term: JAG2
    term:
      id: hgnc:6189
      label: JAG2
  evidence:
  - reference: PMID:33861953
    reference_title: "A form of muscular dystrophy associated with pathogenic variants in JAG2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families."
    explanation: Establishes biallelic JAG2 variants across 13 unrelated families as the cause of this subtype.
  - reference: PMID:33861953
    reference_title: "A form of muscular dystrophy associated with pathogenic variants in JAG2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy."
    explanation: Sources the MRI pattern and its resemblance to POGLUT1 disease described for this subtype.

genetic:
- name: CAPN3 (calpainopathy / LGMDR1)
  subtype: LGMDR1
  notes: >-
    Biallelic pathogenic variants in CAPN3 (calpain-3, a muscle-specific calcium-activated
    protease) cause calpainopathy/LGMDR1, the most common LGMD-R subtype.
  gene_term:
    preferred_term: CAPN3
    term:
      id: hgnc:1480
      label: CAPN3
  evidence:
  - reference: PMID:38045992
    reference_title: "Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
    explanation: >-
      The US MD STARnet population-based surveillance study identifies CAPN3 among the
      most common genes associated with LGMD.
- name: DYSF (dysferlinopathy / LGMDR2)
  subtype: LGMDR2
  notes: >-
    Biallelic pathogenic variants in DYSF (dysferlin, a sarcolemmal membrane-repair
    protein) cause dysferlinopathy/LGMDR2.
  gene_term:
    preferred_term: DYSF
    term:
      id: hgnc:3097
      label: DYSF
  evidence:
  - reference: PMID:38540676
    reference_title: "The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are caused by mutations in the DYSF gene, which encodes the dysferlin protein
      that is crucial for repairing muscle membranes.
    explanation: >-
      Identifies DYSF/dysferlin as the cause of dysferlinopathy and its membrane-repair role.
- name: SGCA (alpha-sarcoglycanopathy / LGMDR3)
  subtype: LGMDR3
  notes: >-
    Biallelic pathogenic variants in the sarcoglycan genes (SGCA, SGCB, SGCG, SGCD)
    destabilize the sarcoglycan subcomplex of the dystrophin-glycoprotein complex,
    causing the sarcoglycanopathies (LGMDR3-R6).
  gene_term:
    preferred_term: SGCA
    term:
      id: hgnc:10805
      label: SGCA
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including the sarcoglycanopathies,
      arise from mutations in multiple distinct genes.
- name: SGCB (beta-sarcoglycanopathy / LGMDR4)
  subtype: LGMDR4
  notes: >-
    Biallelic pathogenic variants in SGCB (beta-sarcoglycan) destabilize the sarcoglycan
    subcomplex of the dystrophin-glycoprotein complex, causing beta-sarcoglycanopathy
    (LGMDR4), often a severe childhood-onset form with cardiac and respiratory involvement.
  gene_term:
    preferred_term: SGCB
    term:
      id: hgnc:10806
      label: SGCB
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including beta-sarcoglycanopathy,
      arise from mutations in multiple distinct genes.
- name: SGCG (gamma-sarcoglycanopathy / LGMDR5)
  subtype: LGMDR5
  notes: >-
    Biallelic pathogenic variants in SGCG (gamma-sarcoglycan) destabilize the sarcoglycan
    subcomplex of the dystrophin-glycoprotein complex, causing gamma-sarcoglycanopathy
    (LGMDR5), which includes a severe childhood form with early loss of ambulation.
  gene_term:
    preferred_term: SGCG
    term:
      id: hgnc:10809
      label: SGCG
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including gamma-sarcoglycanopathy,
      arise from mutations in multiple distinct genes.
- name: SGCD (delta-sarcoglycanopathy / LGMDR6)
  subtype: LGMDR6
  notes: >-
    Biallelic pathogenic variants in SGCD (delta-sarcoglycan) destabilize the sarcoglycan
    subcomplex of the dystrophin-glycoprotein complex, causing delta-sarcoglycanopathy
    (LGMDR6), a typically severe childhood-to-adolescence form with risk of cardiomyopathy.
  gene_term:
    preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes."
    explanation: >-
      The classification review establishes that LGMDs, including delta-sarcoglycanopathy,
      arise from mutations in multiple distinct genes.
- name: FKRP (FKRP-related dystroglycanopathy / LGMDR9)
  subtype: LGMDR9
  notes: >-
    Biallelic pathogenic variants in FKRP (fukutin-related protein) impair glycosylation
    of alpha-dystroglycan, causing the dystroglycanopathy LGMDR9; the c.826C>A founder
    variant is common in European populations.
  gene_term:
    preferred_term: FKRP
    term:
      id: hgnc:17997
      label: FKRP
  evidence:
  - reference: PMID:38045992
    reference_title: "Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
    explanation: >-
      FKRP is the most common LGMD-associated gene in the US MD STARnet surveillance cohort.
- name: ANO5 (anoctaminopathy / LGMDR12)
  subtype: LGMDR12
  notes: >-
    Biallelic pathogenic variants in ANO5 (anoctamin-5) cause the typically adult-onset
    anoctaminopathy LGMDR12.
  gene_term:
    preferred_term: ANO5
    term:
      id: hgnc:27337
      label: ANO5
  evidence:
  - reference: PMID:38045992
    reference_title: "Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common associated genes were FKRP, CAPN3, ANO5, and DYSF."
    explanation: >-
      ANO5 is among the most common LGMD-associated genes in the US MD STARnet cohort.
- name: DAG1 (primary dystroglycanopathy / LGMD2P)
  subtype: LGMD2P
  relationship_type: CAUSATIVE
  notes: >-
    DAG1 encodes dystroglycan itself, so a pathogenic DAG1 variant produces a
    primary dystroglycanopathy rather than the secondary form caused by the
    glycosyltransferase genes. ClinGen's Muscular Dystrophies and Myopathies Gene
    Curation Expert Panel classifies DAG1 as Definitive, but files the assertion
    against the dystroglycanopathy concept (MONDO:0018282) rather than against
    autosomal recessive limb-girdle muscular dystrophy, which is why a search
    restricted to the LGMD-R concept does not return it.
  gene_term:
    preferred_term: DAG1
    term:
      id: hgnc:2666
      label: DAG1
  evidence:
  - reference: PMID:21388311
    reference_title: "A dystroglycan mutation associated with limb-girdle muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment."
    explanation: Establishes a DAG1 missense variant as the cause of limb-girdle muscular dystrophy with cognitive impairment.
  - reference: CGGV:assertion_61b73fd7-5578-447b-9482-ea64d62dae1d-2024-08-13T190000.000Z
    reference_title: "DAG1 / qualitative or quantitative defects of alpha-dystroglycan (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DAG1 | HGNC:2666 | qualitative or quantitative defects of alpha-dystroglycan | MONDO:0018282 | AR | Definitive"
    explanation: >-
      ClinGen classifies DAG1 as Definitive with autosomal recessive inheritance, but
      against the dystroglycanopathy concept rather than against LGMD-R.
- name: POGLUT1 (LGMD2Z / LGMD R21)
  subtype: LGMD2Z
  relationship_type: CAUSATIVE
  notes: >-
    POGLUT1 is the protein O-glucosyltransferase that modifies the Notch
    extracellular domain. A homozygous missense variant reduces its
    O-glucosyltransferase activity on Notch and impairs muscle development, and
    ClinGen classifies the gene as Definitive for autosomal recessive limb-girdle
    muscular dystrophy.
  gene_term:
    preferred_term: POGLUT1
    term:
      id: hgnc:22954
      label: POGLUT1
  evidence:
  - reference: PMID:27807076
    reference_title: "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function."
    explanation: Establishes the POGLUT1 missense variant as the cause in the index family.
  - reference: PMID:27807076
    reference_title: "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development."
    explanation: >-
      Functional support for the loss of enzymatic activity recorded in these notes.
      Graded MODEL_ORGANISM rather than IN_VITRO because the "in vivo" half is the
      transgenic Drosophila rescue experiment, in which human POGLUT1 D233E fails to
      rescue the muscle phenotype of fly Poglut1 loss; the enzymatic assays and the
      patient primary myoblasts are the in vitro half, and the sentence covers both.
  - reference: CGGV:assertion_c3396945-a664-4ada-bb7f-c123ec50b849-2024-08-14T190000.000Z
    reference_title: "POGLUT1 / autosomal recessive limb-girdle muscular dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "POGLUT1 | HGNC:22954 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
    explanation: ClinGen classifies the POGLUT1 LGMD-R relationship as definitive with autosomal recessive inheritance.
- name: POPDC1 (LGMD2X / LGMDR25)
  subtype: LGMD2X
  relationship_type: CAUSATIVE
  notes: >-
    POPDC1 carries the previous HGNC symbol BVES, and ClinGen's Definitive
    assertion is filed under that previous symbol; a search of the approved symbol
    POPDC1 in the Gene-Disease Validity CSV (snapshot 2026-08-13) returns no row
    while a search of BVES returns the Definitive LGMD-R assertion. The bound
    term.label is likewise BVES: a live query of the HGNC REST API for HGNC:1152
    returns the approved symbol POPDC1 with BVES as a previous symbol, but the OBO
    HGNC build this repository validates against still carries BVES, so the label
    follows the build and preferred_term carries the approved symbol. The disease
    combines limb-girdle weakness with cardiac arrhythmia, which separates it from
    the POPDC3 subtype, where cardiac investigations in the reported patients were
    unremarkable.
  gene_term:
    preferred_term: POPDC1
    term:
      id: hgnc:1152
      label: BVES
  evidence:
  - reference: PMID:26642364
    reference_title: "POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases."
    explanation: Establishes POPDC1 as an autosomal recessive cause of combined arrhythmia and LGMD.
  - reference: CGGV:assertion_31a0db34-cad3-4746-a40f-2912318dfbd2-2024-08-29T190000.000Z
    reference_title: "BVES / autosomal recessive limb-girdle muscular dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BVES | HGNC:1152 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
    explanation: >-
      ClinGen classifies the relationship as definitive, under the previous gene
      symbol BVES but against the same HGNC identifier as POPDC1.
- name: TRAPPC11 (LGMD R18)
  subtype: LGMDR18
  relationship_type: CAUSATIVE
  notes: >-
    Recessive TRAPPC11 variants produce a spectrum whose severe end adds infantile
    hyperkinetic movements, ataxia and intellectual disability to the limb-girdle
    weakness. ClinGen classifies TRAPPC11 as Definitive for autosomal recessive
    limb-girdle muscular dystrophy.
  gene_term:
    preferred_term: TRAPPC11
    term:
      id: hgnc:25751
      label: TRAPPC11
  evidence:
  - reference: PMID:23830518
    reference_title: "Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families."
    explanation: Identifies the two TRAPPC11 alleles behind the two ends of the phenotypic spectrum.
  - reference: CGGV:assertion_8b835ba1-afbd-48ac-afec-b9396acc5521-2024-08-14T190000.000Z
    reference_title: "TRAPPC11 / autosomal recessive limb-girdle muscular dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TRAPPC11 | HGNC:25751 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
    explanation: ClinGen classifies the TRAPPC11-LGMD-R relationship as definitive with autosomal recessive inheritance.
- name: POMK (POMK-deficiency LGMD)
  subtype: POMK-LGMD
  relationship_type: CAUSATIVE
  notes: >-
    POMK phosphorylates the O-mannosyl glycan of alpha-dystroglycan, the step that
    LARGE-dependent extension and therefore laminin binding depends on. Truncating
    alleles removing the kinase domain span Walker-Warburg syndrome to limb-girdle
    weakness with cognitive defects, so the limb-girdle presentation is the mild end
    of a dystroglycanopathy spectrum rather than a separate mechanism. A search of
    the approved symbol POMK in the ClinGen Gene-Disease Validity CSV (snapshot
    2026-08-13) returns no row.
  gene_term:
    preferred_term: POMK
    term:
      id: hgnc:26267
      label: POMK
  evidence:
  - reference: PMID:24925318
    reference_title: "POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects."
    explanation: Establishes POMK truncating alleles as a cause of limb-girdle muscular dystrophy with cognitive defects.
- name: POPDC3 (LGMD R26)
  subtype: LGMDR26
  relationship_type: CAUSATIVE
  notes: >-
    Homozygous POPDC3 missense variants in three ethnically distinct families cause
    an adult-onset limb-girdle muscular dystrophy without cardiac involvement in the
    reported patients, distinguishing it from the POPDC1 subtype. ClinGen classifies
    POPDC3 as Definitive for autosomal recessive limb-girdle muscular dystrophy.
  gene_term:
    preferred_term: POPDC3
    term:
      id: hgnc:17649
      label: POPDC3
  evidence:
  - reference: PMID:31610034
    reference_title: "POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families."
    explanation: Establishes the three homozygous POPDC3 variants and the families they were found in.
  - reference: CGGV:assertion_bb7755df-a1e3-4398-a771-cd6c2d112b68-2025-02-11T170000.000Z
    reference_title: "POPDC3 / autosomal recessive limb-girdle muscular dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "POPDC3 | HGNC:17649 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Definitive"
    explanation: ClinGen classifies the POPDC3-LGMD-R relationship as definitive with autosomal recessive inheritance.
- name: JAG2 (LGMD R27)
  subtype: LGMDR27
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic JAG2 variants were found in all 13 families of an international cohort
    of 23 individuals with previously unsolved muscular dystrophy. ClinGen's
    Muscular Dystrophies and Myopathies Gene Curation Expert Panel classifies the
    relationship as Moderate rather than Definitive, so it is supported but not
    established at Definitive strength.
  gene_term:
    preferred_term: JAG2
    term:
      id: hgnc:6189
      label: JAG2
  evidence:
  - reference: PMID:33861953
    reference_title: "A form of muscular dystrophy associated with pathogenic variants in JAG2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families."
    explanation: Establishes biallelic JAG2 variants across the whole reported cohort.
  - reference: CGGV:assertion_16f43ce9-05b5-437d-a35e-b1c379c0ba7a-2024-08-27T160000.000Z
    reference_title: "JAG2 / autosomal recessive limb-girdle muscular dystrophy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JAG2 | HGNC:6189 | autosomal recessive limb-girdle muscular dystrophy | MONDO:0015152 | AR | Moderate"
    explanation: ClinGen classifies the JAG2-LGMD-R relationship as Moderate, the strength recorded in these notes.
- name: LIMS2 (disputed)
  relationship_type: DISPUTED
  notes: >-
    LIMS2 (also called PINCH2) was proposed as an LGMD gene in 2015 on the strength
    of compound heterozygous missense variants in one sibling pair with childhood-onset
    weakness, triangular tongues and biventricular cardiac dysfunction. ClinGen's
    Muscular Dystrophies and Myopathies Gene Curation Expert Panel disputed the
    relationship in November 2024: that report remains the only published one, none
    of the variants has functional support, contacting ClinVar submitters produced no
    further evidence, and a Lims2 knockout mouse had no apparent phenotype. This
    record is deliberately not wired to a pathophysiology node and carries no
    has_subtypes row, because dismech should not assert a mechanism for a
    gene-disease relationship an expert panel has disputed. MONDO nonetheless
    records LIMS2 as the causal gene of MONDO:0014788 (autosomal recessive
    limb-girdle muscular dystrophy type 2W); that disagreement is recorded here
    rather than resolved.
  gene_term:
    preferred_term: LIMS2
    term:
      id: hgnc:16084
      label: LIMS2
  evidence:
  - reference: PMID:25589244
    reference_title: "LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2."
    explanation: The single original report proposing LIMS2 as a muscular dystrophy gene.
  - reference: CGGV:assertion_00284b9e-fc0e-4667-ad1b-fd68f2cdc490-2024-11-12T200000.000Z
    reference_title: "LIMS2 / autosomal recessive limb-girdle muscular dystrophy (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "In summary, the evidence supporting the relationship between LIMS2 and autosomal recessive limb-girdle muscular dystrophy has been disputed and no valid evidence remains to support the claim."
    explanation: >-
      ClinGen's expert-panel conclusion that no valid evidence remains for the
      LIMS2-LGMD-R relationship, which is why this record is typed DISPUTED.
  - reference: CGGV:assertion_00284b9e-fc0e-4667-ad1b-fd68f2cdc490-2024-11-12T200000.000Z
    reference_title: "LIMS2 / autosomal recessive limb-girdle muscular dystrophy (Disputed)"
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "The resulting LIMS2 deficient mice showed no apparent phenotype when compared to their wild-type and heterozygous littermates (PMID:16317048)."
    explanation: The model-organism negative result ClinGen cites among its reasons for disputing the relationship.

pathophysiology:
- name: Alpha-Dystroglycan Hypoglycosylation and Loss of Laminin Binding
  biological_scale: MOLECULAR
  description: >-
    Alpha-dystroglycan reaches the extracellular matrix only after an O-mannosyl
    glycan is phosphorylated and then extended by LARGE; the mature glycan is what
    binds laminin with high affinity. Two of the LGMD-R genes act inside this
    pathway rather than on the sarcolemmal complex itself. DAG1 is the substrate:
    the Thr192Met variant blocks LARGE-dependent maturation of the phosphorylated
    O-mannosyl glycan, so the receptor loses laminin binding despite being present.
    POMK is the kinase that performs the phosphorylation step, and truncating
    alleles that remove its kinase domain produce dystroglycanopathy ranging from
    Walker-Warburg syndrome to limb-girdle weakness with cognitive defects. This
    node is the primary-dystroglycanopathy counterpart of the FKRP-driven secondary
    dystroglycanopathy recorded on the sarcolemmal node below.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  molecular_functions:
  - preferred_term: laminin binding
    term:
      id: GO:0043236
      label: laminin binding
    modifier: DECREASED
  genes:
  - preferred_term: DAG1
    term:
      id: hgnc:2666
      label: DAG1
  - preferred_term: POMK
    term:
      id: hgnc:26267
      label: POMK
  evidence:
  - reference: PMID:21388311
    reference_title: "A dystroglycan mutation associated with limb-girdle muscular dystrophy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vitro and in vivo studies showed that the mutation impairs the receptor function of dystroglycan in skeletal muscle and brain by inhibiting the post-translational modification, mediated by the glycosyltransferase LARGE, of the phosphorylated O-mannosyl glycans on α-dystroglycan that is required for high-affinity binding to laminin."
    explanation: >-
      Supports loss of high-affinity laminin binding by alpha-dystroglycan as the
      molecular lesion in the DAG1 form. Graded MODEL_ORGANISM because the "in vivo"
      half of this sentence is the T190M knock-in mouse described earlier in the same
      paper, which is where the laminin-overlay and histology results come from; the
      human proband contributes the genotype and phenotype, covered by the other
      evidence on this record.
  - reference: PMID:24925318
    reference_title: "POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "POMK, which was found mutated in two dystroglycanopathy cases, is instead involved in a glycan phosphorylation reaction critical for ECM binding, but little is known about the clinical presentation of POMK mutations or of the function of this protein in the muscle."
    quote_role: BACKGROUND
    explanation: States the glycan-phosphorylation step that POMK performs and that this node asserts is lost.
  - reference: PMID:24925318
    reference_title: "POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of loss of function in the zebrafish embryo and larva showed that pomk function is necessary for normal muscle development, leading to locomotor dysfuction in the embryo and signs of muscular dystrophy in the larva."
    explanation: Model-organism support that loss of POMK function produces muscular dystrophy.
  downstream:
  - target: Sarcolemmal Instability and Failed Membrane Repair
    description: >-
      An alpha-dystroglycan that cannot bind laminin severs the link between the
      myofiber cytoskeleton and the basement membrane, the same lesion the
      sarcoglycan and FKRP subtypes reach by other routes.
    causal_link_type: DIRECT
- name: Calpain-3 Deficiency and Impaired Sarcomere Remodelling
  biological_scale: MOLECULAR
  description: >-
    Calpain-3 is the muscle-specific calcium-dependent protease, held at the N2A
    region of titin in the sarcomere and activated by sustained modest rises in
    cytoplasmic calcium such as those following eccentric contraction. Loss of
    calpain-3 expression causes LGMDR1, and its pathogenic mechanism is understood
    as impaired sarcomere remodelling rather than as sarcolemmal fragility, which is
    why this subtype is wired to a separate node from the sarcoglycanopathies and
    dysferlinopathy.
  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: ABNORMAL
  genes:
  - preferred_term: CAPN3
    term:
      id: hgnc:1480
      label: CAPN3
  evidence:
  - reference: PMID:19793101
    reference_title: "Calpains, skeletal muscle function and exercise."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The physiological roles of the calpains are not well understood, although ubiquitous calpains have been associated with apoptosis and myogenesis and calpain-3 is likely involved in sarcomeric remodelling. A defect in the expression of calpain-3 results in limb-girdle muscular dystrophy Type 2A."
    explanation: >-
      Links loss of calpain-3 expression to LGMD2A and states the sarcomeric
      remodelling role this node asserts, with the hedging the source itself uses.
  - reference: PMID:19793101
    reference_title: "Calpains, skeletal muscle function and exercise."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Calpain-3 is tightly bound in skeletal muscle fibres at the N2A line of the large elastic protein titin."
    explanation: Sources the sarcomeric localization of calpain-3 recorded in this node.
  - reference: PMID:23414389
    reference_title: "Muscle atrophy in Limb Girdle Muscular Dystrophy 2A: a morphometric and molecular study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The peculiar clinical features and the pathogenic mechanism related to calpain-3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin-proteasome degradation pathway may have a crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A)."
    explanation: A human LGMD2A study stating impaired sarcomere remodelling as the pathogenic mechanism of calpain-3 deficiency.
  downstream:
  - target: Myofiber Degeneration and Necrosis
    description: >-
      Failure to remodel the sarcomere after contraction-induced damage feeds the
      same cycles of myofiber degeneration and regeneration that the sarcolemmal
      subtypes reach through membrane injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced Notch Signalling in Muscle Progenitors
  biological_scale: MOLECULAR
  description: >-
    Two LGMD-R genes act on the Notch pathway rather than on the sarcolemma:
    POGLUT1 O-glucosylates Notch, and JAG2 encodes the Notch ligand Jagged2. Muscle
    from POGLUT1 patients shows reduced Notch signalling, and restoring Notch
    signalling rescues the myogenic defect in their primary myoblasts. JAG2 muscle
    shows misregulation of myogenesis genes including PAX7. This node holds the
    pathway state; its cellular consequence is recorded separately on the satellite
    cell node it points at, because the sources treat the two as cause and effect.
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: DECREASED
  genes:
  - preferred_term: POGLUT1
    term:
      id: hgnc:22954
      label: POGLUT1
  - preferred_term: JAG2
    term:
      id: hgnc:6189
      label: JAG2
  evidence:
  - reference: PMID:27807076
    reference_title: "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts."
    explanation: Direct patient-muscle evidence for the reduced Notch signalling this node asserts.
  - reference: PMID:33861953
    reference_title: "A form of muscular dystrophy associated with pathogenic variants in JAG2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction."
    explanation: Places the JAG2 subtype in the same Notch-pathway mechanism as POGLUT1.
  - reference: PMID:33861953
    reference_title: "A form of muscular dystrophy associated with pathogenic variants in JAG2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7."
    explanation: Supports the myogenic-program disturbance, including PAX7, recorded for the JAG2 form.
  downstream:
  - target: Satellite Cell Pool Depletion
    description: >-
      Notch signalling maintains satellite cell quiescence and self-renewal, so
      reduced signalling depletes the pool the sources measure.
    causal_link_type: DIRECT
- name: Satellite Cell Pool Depletion
  biological_scale: CELLULAR
  description: >-
    Skeletal muscle regeneration depends on satellite cells, whose quiescence and
    self-renewal are controlled by Notch signalling. POGLUT1 patients' muscle holds a
    dramatically reduced satellite cell pool, and their primary myoblasts proliferate
    slowly, differentiate too readily, and hold a smaller pool of quiescent
    PAX7-positive cells. The authors name Notch-dependent loss of satellite cells as
    the pathomechanism, which is why this node sits downstream of the pathway node
    rather than beside it.
  cell_types:
  - preferred_term: skeletal muscle satellite cell
    term:
      id: CL:0000594
      label: skeletal muscle satellite cell
  evidence:
  - reference: PMID:27807076
    reference_title: "A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells."
    explanation: The authors' own statement that satellite cell loss is Notch-dependent, which is the edge into this node.
  downstream:
  - target: Chronic Inflammation and Fibrofatty Replacement
    description: >-
      A depleted satellite cell pool cannot sustain repair, so repeated injury
      exhausts regenerative capacity and muscle is replaced by fibrotic and fatty
      tissue.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: POPDC1 cAMP-Effector Membrane Trafficking Defect
  biological_scale: MOLECULAR
  description: >-
    POPDC1 is a plasma-membrane cAMP-binding protein abundant in striated muscle.
    The LGMD2X variant POPDC1 S201F halves cAMP affinity and, in patient skeletal
    muscle, leaves both mutant POPDC1 and wild-type POPDC2 stranded short of the
    membrane. POPDC1 disease carries cardiac arrhythmia. The paralogue POPDC3 is
    modelled separately: no source reports a trafficking defect for it, so it is not
    listed on this node.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: DECREASED
  genes:
  - preferred_term: POPDC1
    term:
      id: hgnc:1152
      label: BVES
  evidence:
  - reference: PMID:26642364
    reference_title: "POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking."
    explanation: Direct patient-muscle evidence for the impaired membrane trafficking this node asserts.
  downstream:
  - target: Sarcolemmal Instability and Failed Membrane Repair
    description: >-
      Failure to deliver and hold POPDC1 at the sarcolemma degrades the membrane's
      response to mechanical and adrenergic stress, converging on the shared
      sarcolemmal lesion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Aberrant POPDC3 Modulation of TREK-1
  biological_scale: MOLECULAR
  description: >-
    POPDC3 is the POPDC1 paralogue, also a plasma-membrane cAMP-binding protein of
    striated muscle. The only functional readout reported for the three LGMD R26
    variants is aberrant modulation of the mechano-gated potassium channel TREK-1 in
    Xenopus oocytes. No source reports a membrane-trafficking defect for POPDC3, and
    the path from altered TREK-1 modulation to the sarcolemmal lesion is not
    established, so this node is kept separate from the POPDC1 trafficking node and
    its downstream link names no intermediate step. POPDC3 disease, in the reported
    patients, did not involve the heart.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  molecular_functions:
  - preferred_term: potassium channel regulator activity
    term:
      id: GO:0015459
      label: potassium channel regulator activity
    modifier: ABNORMAL
  genes:
  - preferred_term: POPDC3
    term:
      id: hgnc:17649
      label: POPDC3
  evidence:
  - reference: PMID:31610034
    reference_title: "POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1."
    explanation: The only functional abnormality reported for the POPDC3 variants, and the sole basis for this node.
  downstream:
  - target: Sarcolemmal Instability and Failed Membrane Repair
    description: >-
      Altered POPDC3 modulation of TREK-1 is the only reported functional consequence
      of these variants; how it reaches the sarcolemmal lesion is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Golgi Trafficking Defect
  biological_scale: MOLECULAR
  description: >-
    TRAPPC11 is a subunit of the multiprotein TRAPP membrane-trafficking complex.
    Both reported LGMD R18 alleles weaken TRAPPC11 binding to other TRAPP components
    and disrupt Golgi architecture. Endoplasmic-reticulum-to-Golgi transport remains
    normal while exit from the Golgi to the cell surface is dramatically delayed, and
    the lysosomal membrane glycoproteins LAMP1 and LAMP2 are altered as a
    consequence, so the defect is in secretory-pathway transit rather than in the
    sarcolemmal complex.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Golgi organization
    term:
      id: GO:0007030
      label: Golgi organization
    modifier: ABNORMAL
  genes:
  - preferred_term: TRAPPC11
    term:
      id: hgnc:25751
      label: TRAPPC11
  evidence:
  - reference: PMID:23830518
    reference_title: "Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture."
    explanation: Supports disrupted Golgi architecture as the molecular lesion in this node.
  - reference: PMID:23830518
    reference_title: "Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface."
    explanation: Localizes the transport block to Golgi exit rather than to ER-to-Golgi transit, as described here.
  downstream:
  - target: Myofiber Degeneration and Necrosis
    description: >-
      Delayed delivery of secretory and lysosomal proteins to the myofiber surface
      and to the lysosome degrades the fiber's capacity to maintain and repair
      itself, feeding the shared degeneration cycle.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Sarcolemmal Instability and Failed Membrane Repair
  conforms_to: "sarcolemmal_fragility_myofiber_necrosis#Sarcolemmal Membrane Repair Failure"
  description: >-
    Across LGMD-R subtypes the proximate defect destabilizes the myofiber plasma
    membrane (sarcolemma). Sarcoglycanopathies (SGCA-D) and dystroglycanopathies
    (FKRP) disrupt the dystrophin-glycoprotein complex that links the cytoskeleton
    to the extracellular matrix, while dysferlin (DYSF) deficiency impairs
    calcium-triggered resealing of membrane microtears. The result is a fragile
    sarcolemma that cannot withstand or repair contraction-induced injury.
  genes:
  - preferred_term: DYSF
    term:
      id: hgnc:3097
      label: DYSF
  - preferred_term: FKRP
    term:
      id: hgnc:17997
      label: FKRP
  - preferred_term: SGCA
    term:
      id: hgnc:10805
      label: SGCA
  - preferred_term: SGCB
    term:
      id: hgnc:10806
      label: SGCB
  - preferred_term: SGCG
    term:
      id: hgnc:10809
      label: SGCG
  - preferred_term: SGCD
    term:
      id: hgnc:10807
      label: SGCD
  - preferred_term: ANO5
    term:
      id: hgnc:27337
      label: ANO5
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: plasma membrane repair
    term:
      id: GO:0001778
      label: plasma membrane repair
    modifier: DECREASED
  evidence:
  - reference: PMID:40422224
    reference_title: "Misregulation of the Ubiquitin-Proteasome System and Autophagy in Muscular Dystrophies Associated with the Dystrophin-Glycoprotein Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A specific subgroup of muscular dystrophies is associated with genetic defects in
      components of the dystrophin-glycoprotein complex (DGC), which plays a crucial role
      in linking the cytosol to the skeletal muscle basement membrane. In these cases,
      dystrophin-associated proteins fail to correctly localize to the sarcolemma
    explanation: >-
      Establishes that DGC defects (e.g., sarcoglycanopathies, dystroglycanopathies)
      destabilize the sarcolemma, the shared upstream lesion in this node.
  - reference: PMID:38540676
    reference_title: "The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They are caused by mutations in the DYSF gene, which encodes the dysferlin protein
      that is crucial for repairing muscle membranes.
    explanation: >-
      Establishes that dysferlin deficiency impairs membrane repair, the complementary
      mechanism of sarcolemmal instability in LGMDR2.
  - reference: PMID:20096397
    reference_title: "Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes."
    explanation: >-
      Ultrastructural sarcolemmal lesions in ANO5 patients place anoctaminopathy on
      this node alongside the sarcoglycanopathies and dysferlinopathy.
  - reference: PMID:20096397
    reference_title: "Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies."
    explanation: >-
      Direct membrane-resealing evidence for the ANO5 repair defect, in a single
      individual with the allelic distal phenotype rather than in an LGMD2L patient,
      which is the strength of the evidence for placing ANO5 on this node.
  downstream:
  - target: Myofiber Degeneration and Necrosis
    description: >-
      A fragile, poorly repaired sarcolemma cannot withstand contraction-induced stress,
      leading to repeated myofiber injury and necrosis.
    causal_link_type: DIRECT
- name: Myofiber Degeneration and Necrosis
  conforms_to: "sarcolemmal_fragility_myofiber_necrosis#Myofiber Necrosis"
  description: >-
    Sarcolemmal instability permits pathological calcium influx and uncontrolled
    activation of degradative pathways (calpain proteolysis, the ubiquitin-proteasome
    system, and dysregulated autophagy), driving cycles of myofiber degeneration,
    necrosis, and regeneration. Centralized nuclei, necrotic fibers, and inflammatory
    cytokine release are characteristic histological features.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: muscle cell apoptotic process
    term:
      id: GO:0010657
      label: muscle cell apoptotic process
    modifier: INCREASED
  - preferred_term: calcium ion transport
    term:
      id: GO:0006816
      label: calcium ion transport
    modifier: ABNORMAL
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40422224
    reference_title: "Misregulation of the Ubiquitin-Proteasome System and Autophagy in Muscular Dystrophies Associated with the Dystrophin-Glycoprotein Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These are characterized by the centralization of skeletal muscle syncytial nuclei,
      the replacement of muscle fibers with fibrotic tissue, the release of inflammatory
      cytokines, and the disruption of muscle protein homeostasis, ultimately leading to
      necrosis and loss of muscle functionality.
    explanation: >-
      Documents myofiber necrosis, disrupted protein homeostasis, and inflammatory
      cytokine release downstream of sarcolemmal destabilization.
  downstream:
  - target: Chronic Inflammation and Fibrofatty Replacement
    description: >-
      Repeated necrosis releases inflammatory cytokines and eventually exhausts
      regenerative capacity, leading to chronic inflammation and replacement of
      muscle with fibrotic and fatty tissue.
    causal_link_type: DIRECT
- name: Chronic Inflammation and Fibrofatty Replacement
  description: >-
    Sustained injury drives chronic inflammation (with impaired macrophage M1-to-M2
    switching) and progressive replacement of contractile muscle by fibrotic and
    adipose tissue, which is detectable as subtype-specific fatty infiltration patterns
    on muscle MRI and as fibrosis on biopsy. This is the structural substrate of
    permanent weakness.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37974208
    reference_title: "Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle
      differences, including more severe fatty infiltration of the posterior thigh
      muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those
      with LGMD-R2/LGMD2B.
    explanation: >-
      Documents fibrofatty (fatty infiltration) replacement of muscle, with subtype-specific
      MRI patterns, as a downstream consequence of repeated degeneration.
  downstream:
  - target: Progressive proximal muscle weakness
    description: >-
      Loss of functional contractile muscle and its replacement by fibrofatty tissue
      manifests clinically as progressive proximal limb-girdle weakness.
    causal_link_type: DIRECT
  - target: Calf muscle hypertrophy
    description: >-
      In the sarcoglycanopathies, fibrofatty replacement and reactive enlargement of
      the calf musculature produce calf (pseudo)hypertrophy, a characteristic sign.
    causal_link_type: DIRECT

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

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

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

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

treatments:
- name: Physical therapy and rehabilitation
  description: >-
    No curative therapy is approved; management is supportive. Physical therapy and
    stretching promote mobility and prevent contractures, with mobility aids as needed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical therapy and stretching exercises to promote mobility and prevent
      contractures; supervised strengthening and gentle low-impact aerobic exercise
    explanation: >-
      The Calpainopathy GeneReviews recommends physical therapy and stretching as
      mainstay supportive management.
- name: Noninvasive ventilation
  description: >-
    Nocturnal and chronic noninvasive ventilatory support is used as respiratory muscle
    weakness progresses to respiratory insufficiency.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nocturnal ventilator assistance as needed; respiratory aids to treat chronic
      respiratory insufficiency in late stages of the disease
    explanation: >-
      The Calpainopathy GeneReviews recommends ventilatory support for respiratory
      insufficiency in advanced disease.
- name: Genetic counseling
  description: >-
    Genetic counseling is essential for carrier identification, recurrence-risk
    assessment, and reproductive planning given autosomal recessive inheritance.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301480
    reference_title: "Dysferlinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the DYSF pathogenic variants have been identified in an affected family
      member, carrier testing for at-risk
    explanation: >-
      The Dysferlinopathy GeneReviews describes carrier testing and genetic counseling
      following identification of family pathogenic variants.
- name: AAV gene replacement therapy (investigational)
  description: >-
    Adeno-associated virus (AAV) gene replacement therapies are in clinical development
    for the sarcoglycanopathies, including bidridistrogene xeboparvovec (SRP-9003) for
    beta-sarcoglycanopathy/LGMDR4, which has progressed to a Phase 3 trial.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  therapeutic_modality: GENE_THERAPY
  evidence:
  - reference: PMID:37510884
    reference_title: "Limb-Girdle Muscular Dystrophies Classification and Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the last decade, multiple other potential treatments were developed and studied,
      such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene
      editing.
    explanation: >-
      The classification/therapy review documents gene delivery (gene replacement) among
      the molecular therapies in development for LGMD.
- name: Cardiac management for LGMD-associated cardiomyopathy
  description: >-
    Cardiac surveillance and standard heart-failure pharmacotherapy are indicated in the
    subtypes with cardiac involvement (sarcoglycanopathies LGMDR3-R6 and FKRP-related
    LGMDR9). Guideline-directed medical therapy for dilated cardiomyopathy uses
    angiotensin-converting-enzyme (ACE) inhibitors and beta-adrenergic antagonists
    (beta-blockers) to reduce afterload and neurohormonal activation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  evidence:
  - reference: PMID:20301582
    reference_title: "Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitoring for cardiomyopathy in LGMD types with cardiac involvement"
    explanation: >-
      The Limb-Girdle Muscular Dystrophy Overview GeneReviews recommends monitoring for
      cardiomyopathy in the LGMD subtypes with cardiac involvement, which underpins the
      ACE-inhibitor/beta-blocker heart-failure management standard of care.
- name: Agents and circumstances to avoid
  description: >-
    Because of a malignant-hyperthermia-like anesthetic risk and drug-induced myotoxicity,
    succinylcholine and halogenated (volatile) anesthetic agents should be avoided when
    possible, and cholesterol-lowering statins should be avoided when possible in
    calpainopathy and related LGMD-R subtypes.
  treatment_term:
    preferred_term: avoidance of myotoxic and anesthetic triggers
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301490
    reference_title: "Calpainopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoid succinylcholine and halogenated anesthetic agents when possible; avoid
      cholesterol-lowering agents (e.g., statins) when possible.
    explanation: >-
      The Calpainopathy GeneReviews lists succinylcholine, halogenated anesthetics, and
      statins among the agents/circumstances to avoid.

datasets: []
📚

References & Deep Research

References

3
PMID:20301582
Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.
PMID:20301490
Calpainopathy.
No top-level findings curated for this source.
PMID:20301480
Dysferlinopathy.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

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

1. Disease Information

Overview

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

Key Identifiers

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

Synonyms

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

2. Etiology

Disease Causal Factors

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

Genetic Risk Factors

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

Gene-Environment Interactions

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

3. Phenotypes

Core Phenotypes

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

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

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

Subtype-Specific Features

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

Quality of Life Impact

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

Suggested HPO Terms

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

4. Genetic/Molecular Information

Causal Genes and Pathogenic Variants

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

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

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

Variant Types and Classification

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

Founder Effects

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

OpenTargets Disease-Target Associations

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

5. Mechanism / Pathophysiology

Molecular Pathways

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

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

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

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

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

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

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

Subtype-Specific Mechanisms

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

Suggested GO Terms

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

Suggested Cell Ontology Terms

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

6. Anatomical Structures Affected

Primary Organs

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

Tissue and Cell Level

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

Subcellular Level

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

7. Temporal Development

Onset

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

Progression

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

Patterns

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

8. Inheritance and Population

Epidemiology

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

Inheritance Pattern

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

Population Demographics

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

9. Diagnostics

Clinical Tests

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

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

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

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

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

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

Genetic Testing

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

Differential Diagnosis

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

Biomarkers

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

10. Outcome/Prognosis

Survival and Morbidity

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

Complications

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

11. Treatment

Current Symptomatic Management

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

Gene Therapy (Experimental)

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

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

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

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

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

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

The following table summarizes key clinical trials:

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

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

12. Prevention

Primary Prevention

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

Genetic Screening

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

Tertiary Prevention

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

13. Model Organisms

Mouse Models

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

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

Zebrafish Models

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

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

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

14. Environmental Information and Lifestyle Factors

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

15. Summary

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

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