Emery-Dreifuss Muscular Dystrophy

Mendelian MONDO:0016830 Pathograph 29 Show in embeddings browser

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous, primarily Mendelian neuromuscular disorder within the spectrum of nuclear-envelope diseases (laminopathies / nuclear envelopathies). It is classically defined by a clinical triad of (i) early joint contractures (typically elbows, Achilles tendons, and posterior cervical/paraspinal muscles producing a rigid spine); (ii) slowly progressive skeletal muscle weakness and wasting in a humeroperoneal (later scapular and pelvic-girdle) distribution; and (iii) cardiac involvement dominated by atrial disease, conduction-system disease, and arrhythmia, with risk of thromboembolism, cardiomyopathy/heart failure, and sudden cardiac death. EDMD is caused by pathogenic variants in genes encoding nuclear lamina, inner-nuclear-membrane, and LINC-complex proteins that couple the nucleoskeleton to the cytoskeleton: X-linked EMD (emerin; EDMD1), autosomal dominant/recessive LMNA (lamin A/C; EDMD2/EDMD3), and additional nuclear-envelope genes SYNE1/SYNE2 (nesprin-1/-2), FHL1, and TMEM43 (LUMA). Convergent pathophysiology involves failure of nucleo-cytoskeletal coupling and mechanotransduction, mechanical-stress-induced nuclear damage and DNA-damage responses, and maladaptive transcriptional reprogramming (fibrosis, metabolism, splicing).

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3
Inheritance
6
Pathophys.
16
Phenotypes
29
Pathograph
7
Genes
9
Medical Actions
7
Subtypes
1
Trials
5
References
1
Deep Research
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Inheritance

3
X-linked recessive inheritance HP:0001419
EDMD1 (EMD) and EDMD6 (FHL1) are inherited in an X-linked manner. Males are primarily affected; heterozygous female carriers are usually asymptomatic but are at risk of developing cardiac disease.
X-linked recessive inheritance
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"EDMD is inherited in an X-linked (XL), autosomal dominant (AD), or (rarely) autosomal recessive (AR) manner."
GeneReviews documents X-linked, autosomal dominant, and rare autosomal recessive inheritance.
Autosomal dominant inheritance HP:0000006
EDMD2 (LMNA) and EDMD4/5/7 (SYNE1/SYNE2/TMEM43) are inherited in an autosomal dominant manner; a high proportion of LMNA-related AD-EDMD cases arise de novo.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Sixty-five percent of individuals with LMNA-related AD-EDMD have a de novo pathogenic variant."
GeneReviews documents autosomal dominant inheritance with a high de novo rate for LMNA-related EDMD.
Autosomal recessive inheritance HP:0000007
Rare autosomal recessive EDMD3 results from biallelic LMNA variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"(more rarely) biallelic pathogenic variants in LMNA or SUN1"
GeneReviews documents rare autosomal recessive EDMD from biallelic LMNA variants.
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Subtypes

7
EDMD1 (X-linked, EMD / emerin) MONDO:0100531
EMD hgnc:3331 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in EMD (hgnc:3331). hgnc:3331 is a gene from the HUGO Gene Nomenclature Committee.
Classical X-linked EDMD caused by hemizygous pathogenic variants in EMD, encoding emerin, an inner-nuclear-membrane protein (OMIM #310300). Males are primarily affected; heterozygous female carriers are usually asymptomatic but are at risk of later-onset cardiac disease. Cardiac phenotype is dominated by atrial arrhythmia, conduction disease, and a substantial risk of malignant ventricular arrhythmia and end-stage heart failure.
Show evidence (1 reference)
PMID:7894480 SUPPORT Human Clinical
"Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive disorder characterized by slowly progressing contractures, wasting of skeletal muscle and cardiomyopathy."
Original identification of the EMD gene (emerin) as the cause of X-linked EDMD.
EDMD2 (autosomal dominant, LMNA / lamin A/C) MONDO:0021569
LMNA hgnc:6636 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal dominant EDMD caused by heterozygous LMNA pathogenic variants, encoding lamin A/C, a nuclear lamina intermediate filament protein (OMIM #181350). Clinically identical to X-linked EDMD but with frequent de novo variants and a more malignant cardiac trajectory (dilated cardiomyopathy, end-stage heart failure, malignant ventricular arrhythmias). Biallelic LMNA variants cause the rare autosomal recessive form, recorded separately as the EDMD3 row below.
Show evidence (1 reference)
PMID:10080180 SUPPORT Human Clinical
"We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations."
Original identification of LMNA mutations as the cause of autosomal dominant EDMD.
EDMD3 (autosomal recessive, LMNA / lamin A/C) MONDO:0014676
LMNA hgnc:6636 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee.
Rare autosomal recessive EDMD caused by biallelic LMNA variants - the same gene as dominant EDMD2, so the two subtypes are distinguished by inheritance and allele dose rather than by locus. The originally reported proband was homozygous for a missense change and the heterozygous first-cousin parents were clinically and cardiologically unaffected, which separates this recessive form from the dominant one in which a single allele suffices. In that single reported case the phenotype was severe and skeletal-muscle-predominant: contractures left him unable to stand at age five and he was wheelchair-bound with diffuse wasting at 40, with no cardiac problems on careful cardiological examination at that age.
Show evidence (2 references)
PMID:10739764 SUPPORT Human Clinical
"Our results show that LMNA mutations are also responsible for the recessive form of the disease."
Original demonstration that LMNA variants cause the autosomal recessive as well as the autosomal dominant form of EDMD, the basis of the EDMD3 class.
PMID:10739764 SUPPORT Human Clinical
"Sequence analysis of the rest of the LMNA gene in the patient demonstrated that C664T was the only mutation. His parents, who were first cousins, were heterozygotes."
Records the recessive segregation this row rests on: a single homozygous LMNA change in the proband with unaffected heterozygous consanguineous parents.
EDMD4 (autosomal dominant, SYNE1 / nesprin-1) MONDO:0013071
SYNE1 hgnc:17089 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SYNE1 (hgnc:17089). hgnc:17089 is a gene from the HUGO Gene Nomenclature Committee.
EDMD caused by heterozygous variants in SYNE1, encoding nesprin-1, a spectrin-repeat protein of the outer nuclear membrane that binds emerin and lamin A/C and links the nucleoskeleton to the cytoskeleton as part of the LINC complex. Fibroblasts from the reported nesprin-mutant patients show nuclear morphology defects and mislocalization of emerin and SUN2, changes that siRNA knockdown of either nesprin reproduces in normal fibroblasts. The sibling SYNE2 subtype is EDMD5.
Show evidence (1 reference)
PMID:17761684 SUPPORT Human Clinical
"Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
Identifies heterozygous missense variants in the two nesprin genes across a screen of 190 EDMD and EDMD-like probands. The reported mutations are not apportioned between SYNE1 and SYNE2 in this sentence, so it supports the pair rather than either gene alone.
EDMD5 (autosomal dominant, SYNE2 / nesprin-2) MONDO:0013072
SYNE2 hgnc:17084 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SYNE2 (hgnc:17084). hgnc:17084 is a gene from the HUGO Gene Nomenclature Committee.
EDMD caused by heterozygous variants in SYNE2, encoding nesprin-2, the other outer-nuclear-membrane spectrin-repeat LINC-complex protein that binds emerin and lamin A/C. EDMD5 departs from the classical triad: joint contractures are not a feature, and the usual presentation is muscle weakness with cardiomyopathy in late childhood. A reported infant presented instead with persistently raised transaminases judged to be of non-hepatic origin, calf pseudohypertrophy and a markedly raised creatine phosphokinase, with a normal electrocardiogram and echocardiogram and no contractures.
Show evidence (2 references)
PMID:41136957 SUPPORT Human Clinical
"The whole exome sequencing detected a missense splice region heterozygous variant of the SYNE2 gene, confirming Emery-Dreifuss muscular dystrophy 5."
Attributes EDMD5 to a heterozygous SYNE2 variant in the report's own proband, which is the gene-to-subtype assignment this row asserts.
PMID:17761684 SUPPORT Human Clinical
"Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
Identifies heterozygous missense variants in the two nesprin genes across a screen of 190 EDMD and EDMD-like probands. The reported mutations are not apportioned between SYNE1 and SYNE2 in this sentence, so it supports the pair rather than either gene alone.
EDMD6 (X-linked, FHL1) MONDO:0800318
FHL1 hgnc:3702 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FHL1 (hgnc:3702). hgnc:3702 is a gene from the HUGO Gene Nomenclature Committee.
X-linked EDMD caused by FHL1 variants. The predominant phenotype is myopathy with scapulo-peroneal and/or axial distribution plus joint contractures, associated with a cardiac disease that includes conduction defects, arrhythmias, and hypertrophic cardiomyopathy.
Show evidence (1 reference)
PMID:19716112 SUPPORT Human Clinical
"In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy."
Establishes FHL1 as a cause of X-linked EDMD with hypertrophic cardiomyopathy.
EDMD7 (autosomal dominant, TMEM43 / LUMA) MONDO:0013677
TMEM43 hgnc:28472 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TMEM43 (hgnc:28472). hgnc:28472 is a gene from the HUGO Gene Nomenclature Committee.
EDMD-related myopathy caused by heterozygous TMEM43 variants, encoding LUMA, a nuclear-membrane protein and binding partner of emerin and lamins (OMIM #612048). Mutant LUMA fails to oligomerize and causes reduced nuclear staining of emerin and SUN2 with abnormally shaped nuclei.
Show evidence (1 reference)
PMID:21391237 SUPPORT Human Clinical
"We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients."
Identification of TMEM43 (LUMA) mutations in EDMD-related myopathy.
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Pathophysiology

6
Nuclear Envelope and LINC Complex Dysfunction
EDMD is caused by loss or dysfunction of nuclear-envelope proteins (emerin, lamin A/C) and LINC-complex components (nesprins, SUN proteins, LUMA) that physically couple the nucleoskeleton to the cytoskeleton. These proteins form an interacting network spanning the nuclear lamina, inner nuclear membrane, and outer nuclear membrane. Pathogenic variants disrupt nesprin/emerin/lamin binding, mislocalize emerin and SUN2, and compromise nuclear envelope integrity, which is the upstream defect shared by the nuclear-envelope subtypes (EDMD1-5 and EDMD7). FHL1-related EDMD6 is the exception: FHL1 is a sarcomeric and sarcolemmal protein, and its lesion is modelled as a separate node.
skeletal muscle myoblast CL:0000056 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle myoblast, annotated with myoblast (CL:0000056). CL:0000056 is a cell type from the Cell Ontology.
EMD hgnc:3331 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EMD (hgnc:3331). hgnc:3331 is a gene from the HUGO Gene Nomenclature Committee. LMNA hgnc:6636 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee. SYNE1 hgnc:17089 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SYNE1 (hgnc:17089). hgnc:17089 is a gene from the HUGO Gene Nomenclature Committee. SYNE2 hgnc:17084 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SYNE2 (hgnc:17084). hgnc:17084 is a gene from the HUGO Gene Nomenclature Committee. TMEM43 hgnc:28472 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM43 (hgnc:28472). hgnc:28472 is a gene from the HUGO Gene Nomenclature Committee.
nuclear envelope organization GO:0006998 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nuclear envelope organization (GO:0006998). GO:0006998 is a biological process from the Gene Ontology.
nuclear envelope GO:0005635 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear envelope (GO:0005635). GO:0005635 is a cellular component from the Gene Ontology. nuclear lamina GO:0005652 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear lamina (GO:0005652). GO:0005652 is a cellular component from the Gene Ontology. inner nuclear membrane GO:0005637 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves inner nuclear membrane, annotated with nuclear inner membrane (GO:0005637). GO:0005637 is a cellular component from the Gene Ontology.
Downstream
Impaired Mechanotransduction and Nuclear Mechanical Fragility
Show evidence (2 references)
PMID:17761684 SUPPORT In Vitro
"diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts."
Demonstrates that disrupted nesprin/emerin/lamin interactions and nuclear envelope localization are a common feature across EDMD patient cells, establishing nuclear-envelope/LINC-complex dysfunction as the shared upstream defect.
PMID:21391237 SUPPORT In Vitro
"Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei."
Shows mutant LUMA (TMEM43) disrupts emerin and SUN2 localization and nuclear shape, illustrating convergent nuclear-envelope dysfunction.
Impaired Mechanotransduction and Nuclear Mechanical Fragility
Striated muscle nuclei are continuously exposed to mechanical strain. A functional nuclear envelope / LINC complex transmits and buffers these forces. In EDMD, defective nucleo-cytoskeletal coupling impairs mechanotransduction and renders nuclei mechanically fragile. In LMNA-mutant (EDMD2) myoblasts under cyclic stretch, lamin A/C fails to recruit desmin and plectin to the nuclear periphery and nuclei fail to reorient properly, directly linking the molecular defect to defective mechanosignaling.
skeletal muscle myoblast CL:0000056 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle myoblast, annotated with myoblast (CL:0000056). CL:0000056 is a cell type from the Cell Ontology.
LMNA hgnc:6636 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee.
cellular response to mechanical stimulus GO:0071260 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cellular response to mechanical stimulus (GO:0071260). GO:0071260 is a biological process from the Gene Ontology.
Downstream
Mechanical-Stress-Induced Nuclear Damage and DNA Damage Response
Show evidence (1 reference)
PMID:38247853 SUPPORT In Vitro
"in Emery-Dreifuss Muscular Dystrophy (EDMD2) myoblasts exposed to mechanical stretching, the recruitment of desmin and plectin to the nucleus and nuclear orientation were impaired, suggesting that a functional lamin A/C is crucial for the response to mechanical strain."
Directly demonstrates impaired mechanotransduction in EDMD2 myoblasts: lamin A/C dysfunction prevents recruitment of cytoskeletal proteins to the nucleus and proper nuclear reorientation under mechanical strain.
FHL1 Deficiency and Impaired Sarcomere Assembly
FHL1 (four and a half LIM domains 1) is the one EDMD gene product that does not reside at the nuclear envelope; it localizes to the sarcomere and the sarcolemma and contributes to sarcomere assembly. Pathogenic FHL1 variants in X-linked EDMD6 sit in the distal exons and severely reduce FHL1 protein levels in patient muscle, and patient myoblasts show a severe delay in myotube formation. The resulting myopathy has a scapulo-peroneal and/or axial distribution with joint contractures, and the cardiac disease characteristically includes hypertrophic cardiomyopathy alongside conduction defects and arrhythmias. How FHL1 loss produces the cardiac phenotype is not established by the cited sources, so the cardiac edge is left without named intermediates.
skeletal muscle myoblast CL:0000515 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle myoblast (CL:0000515). CL:0000515 is a cell type from the Cell Ontology.
FHL1 hgnc:3702 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FHL1 (hgnc:3702). hgnc:3702 is a gene from the HUGO Gene Nomenclature Committee.
myotube differentiation GO:0014902 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myotube differentiation (GO:0014902). GO:0014902 is a biological process from the Gene Ontology.
sarcomere GO:0030017 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcomere (GO:0030017). GO:0030017 is a cellular component from the Gene Ontology. sarcolemma GO:0042383 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcolemma (GO:0042383). GO:0042383 is a cellular component from the Gene Ontology.
Downstream
Muscle weakness Reduced FHL1 and delayed myotube formation are followed in FHL1-mutated families by a myopathy of scapulo-peroneal and/or axial distribution; the steps from defective sarcomere assembly to clinical weakness are not described in the cited source.
Joint contractures Joint contractures are part of the predominant phenotype of FHL1-related EDMD6; how FHL1 loss produces them is not established by the cited source.
Hypertrophic cardiomyopathy Every index case of the FHL1 families had cardiac disease that included hypertrophic cardiomyopathy; the mechanism linking FHL1 loss to cardiac hypertrophy is not described in the cited source.
Show evidence (2 references)
PMID:31840275 SUPPORT REVIEW SYNTHESIS Other
"An exception is FHL1, a protein encoded by the gene of the same name, which localizes to the sarcomere and the sarcolemma; at the former, it contributes to sarcomere assembly."
Review establishing that FHL1, unlike the other EDMD proteins, acts at the sarcomere and sarcolemma rather than the nuclear envelope, which is why its lesion is a separate node from the nuclear-envelope/LINC node.
PMID:19716112 SUPPORT In Vitro
"Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available."
Patient-derived evidence that EDMD6 FHL1 variants reduce FHL1 protein and impair myotube formation, the cellular defect this node records.
Mechanical-Stress-Induced Nuclear Damage and DNA Damage Response
Mechanically fragile EDMD nuclei accumulate damage under physiologic strain, including stretch-induced DNA damage and activation of DNA-damage responses (e.g., gamma-H2A.X foci, p53 signaling). Muscle-specific loss of the nuclear-envelope protein NET39 in mice recapitulates EDMD-like muscle wasting with abnormal myonuclei and DNA damage, and renders myoblasts hypersensitive to mechanical stretch, establishing a mechanical-stress to DNA-damage axis as a contributor to muscle degeneration.
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.
DNA damage response GO:0006974 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology.
Downstream
Maladaptive Transcriptional Reprogramming and Fibro-Fatty Remodeling
Show evidence (1 reference)
PMID:37395273 SUPPORT Model Organism
"cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage."
Mouse model evidence that nuclear-envelope dysfunction causes mechanical-stress-induced DNA damage and EDMD-like muscle pathology.
Maladaptive Transcriptional Reprogramming and Fibro-Fatty Remodeling
Nuclear-envelope dysfunction alters chromatin organization and gene expression programs. Transcriptomic analysis of EDMD-spectrum patient myotubes across seven causal genes shows convergent dysregulation of fibrosis/ECM, metabolism, myogenic signaling, and splicing pathways. This maladaptive reprogramming drives muscle fiber degeneration with fibro-fatty remodeling in skeletal muscle and contributes to fibrosis and electrical instability in 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.
extracellular matrix organization GO:0030198 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. RNA splicing GO:0008380 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal RNA splicing (GO:0008380). GO:0008380 is a biological process from the Gene Ontology. muscle cell differentiation GO:0042692 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal muscle cell differentiation (GO:0042692). GO:0042692 is a biological process from the Gene Ontology.
Downstream
Cardiac Conduction Disease and Arrhythmogenesis
Joint contractures
Elbow contracture
Achilles tendon contracture
Spinal rigidity
Muscle weakness
Peroneal muscle weakness
Muscle atrophy and wasting
Respiratory insufficiency
Show evidence (1 reference)
PMID:36282542 SUPPORT In Vitro
"the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling and splicing were affected in all patients."
RNA-seq across EDMD-spectrum patient cells (seven causal genes) shows convergent dysregulation of fibrosis, metabolism, myogenic signaling, and splicing pathways downstream of nuclear-envelope dysfunction.
Cardiac Conduction Disease and Arrhythmogenesis
Cardiac involvement is the principal determinant of morbidity and mortality in EDMD. Nuclear-envelope dysfunction in atrial and conduction-system cardiomyocytes produces an atrial myopathy with progressive conduction disease (AV block, sinus node dysfunction), atrial arrhythmia (atrial fibrillation/flutter), and atrial standstill, with attendant thromboembolic risk. EMD and especially LMNA variants additionally confer a high risk of malignant ventricular arrhythmia and progression to dilated cardiomyopathy, end-stage heart failure, and sudden cardiac death. Pacing alone does not prevent sudden death from ventricular arrhythmia, so ICD therapy is often required.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. cardiac Purkinje conduction myocyte CL:0002068 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac Purkinje conduction myocyte, annotated with Purkinje myocyte (CL:0002068). CL:0002068 is a cell type from the Cell Ontology. nodal (pacemaker/conduction) myocyte CL:0002072 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves nodal (pacemaker/conduction) myocyte, annotated with nodal myocyte (CL:0002072). CL:0002072 is a cell type from the Cell Ontology.
EMD hgnc:3331 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EMD (hgnc:3331). hgnc:3331 is a gene from the HUGO Gene Nomenclature Committee.
cardiac conduction GO:0061337 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology.
Downstream
Atrioventricular block
Atrial fibrillation
Atrial standstill
Dilated cardiomyopathy
Ventricular arrhythmia
Sudden cardiac death
Thromboembolism
Hypertrophic cardiomyopathy
Show evidence (2 references)
PMID:37639473 SUPPORT Human Clinical
"Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA)."
Establishes conduction disease and atrial arrhythmia as common to EDMD1 and EDMD2, with LMNA additionally causing end-stage heart failure and malignant ventricular arrhythmia.
PMID:35453731 SUPPORT Human Clinical
"The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias."
Systematic review summarizing the cardiac manifestation spectrum of EDMD/cardiolaminopathies.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Emery-Dreifuss 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.
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Phenotypes

16
Blood 1
Thromboembolism HP:0001907 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thromboembolism (HP:0001907). HP:0001907 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35453731 SUPPORT Human Clinical
"The IR of thromboembolic events reached up to 8.9 events/100 pts-year."
Systematic review quantifies thromboembolic event incidence in EDMD/cardiolaminopathy cohorts.
Cardiovascular 7
Atrioventricular block HP:0001678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular block (HP:0001678). HP:0001678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10080180 SUPPORT Human Clinical
"a cardiomyopathy with conduction blocks which is life-threatening"
Documents life-threatening conduction block as a defining cardiac feature of EDMD.
Atrial fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35453731 SUPPORT Human Clinical
"The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year."
Systematic review quantifies the incidence of atrial fibrillation/flutter/tachycardia in EDMD cohorts.
Atrial standstill HP:0025478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial standstill (HP:0025478). HP:0025478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35453731 SUPPORT Human Clinical
"The IR of atrial standstill ranged between 0 and 2 events/100 pts-year."
Systematic review reports atrial standstill incidence in EDMD/cardiolaminopathy cohorts.
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36968203 SUPPORT Human Clinical
"Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM)"
Pediatric LMNA cohort documents dilated cardiomyopathy as a frequent outcome.
Ventricular arrhythmia HP:0004308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular arrhythmia (HP:0004308). HP:0004308 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37639473 SUPPORT Human Clinical
"Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months."
Documents the substantial risk of malignant ventricular arrhythmia in male EMD variant carriers.
PMID:35453731 SUPPORT Human Clinical
"The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation."
Systematic review concludes that pacing for conduction disease does not address the competing malignant-ventricular-arrhythmia risk, justifying ICD over pacemaker implantation.
Sudden cardiac death HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
A quantitative sudden-cardiac-death or all-cause/cardiovascular mortality rate for EDMD/cardiolaminopathy cohorts is still needed; PMID:35453731's abstract does not report one.
Show evidence (1 reference)
PMID:35453731 SUPPORT Human Clinical
"studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality)"
This is the review's search/inclusion-criteria list naming sudden cardiac death as a searched-for outcome, not a reported SCD incidence or mortality rate; the review's abstract does not give a quantitative SCD figure (only arrhythmia/thromboembolic incidence rates), so this only partially supports the node's mortality claim.
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19716112 SUPPORT Human Clinical
"associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families."
FHL1-related EDMD is associated with hypertrophic cardiomyopathy.
Limbs 2
Achilles tendon contracture HP:0001771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Achilles tendon contracture (HP:0001771). HP:0001771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10080180 SUPPORT Human Clinical
"Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons"
Directly documents early Achilles tendon contractures as characteristic of EDMD.
Peroneal muscle weakness HP:0011727 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peroneal muscle weakness (HP:0011727). HP:0011727 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"humeroperoneal (or more rarely limb-girdle) muscle weakness and wasting"
GeneReviews documents humeroperoneal weakness, of which peroneal involvement is a component.
Musculoskeletal 6
Joint contractures HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392), qualified as childhood onset. HP:0034392 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"the clinical triad of joint contractures that begin in early childhood"
GeneReviews documents early-childhood joint contractures as part of the defining triad.
Elbow contracture HP:0034391 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elbow contracture (HP:0034391). HP:0034391 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10080180 SUPPORT Human Clinical
"Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons"
Directly documents early elbow contractures as characteristic of EDMD.
Spinal rigidity HP:0003306 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spinal rigidity (HP:0003306). HP:0003306 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Assess joints for contractures and mobility, and spine for rigidity, posture, flexibility"
GeneReviews surveillance recommendations specifically reference spinal rigidity as a feature to monitor.
Muscle weakness Proximal muscle weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Humeroperoneal muscle weakness, annotated with Proximal muscle weakness (HP:0003701), qualified as course progressive. HP:0003701 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
HP:0003701 (Proximal muscle weakness) is broader than the EDMD distribution: the characteristic humeroperoneal pattern includes both a proximal upper-limb (humeral/biceps-triceps) component and a distal lower-limb (peroneal) component. The distal peroneal component is captured separately in the dedicated "Peroneal muscle weakness" phenotype (HP:0011727).
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"slowly progressive muscle weakness and wasting initially in a humeroperoneal distribution that later extends to the scapular and pelvic girdle muscles"
GeneReviews documents the characteristic humeroperoneal pattern of progressive weakness.
Muscle atrophy and wasting 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:20301609 SUPPORT Human Clinical
"slowly progressive muscle weakness and wasting initially in a humeroperoneal distribution that later extends to the scapular and pelvic girdle muscles"
GeneReviews documents progressive muscle wasting (atrophy) accompanying the weakness in EDMD.
Respiratory insufficiency 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). HP:0002747 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"respiratory function may be impaired in some individuals"
GeneReviews documents respiratory impairment in some individuals with EDMD.
🧬

Genetic Associations

7
EMD (Loss-of-function variants (X-linked recessive))
Gene: EMD hgnc:3331 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EMD (hgnc:3331). hgnc:3331 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:7894480 SUPPORT Human Clinical
"these mutations result in the loss of all or part of the protein. The EDMD gene encodes a novel serine-rich protein termed emerin"
Original identification of loss-of-function EMD (emerin) mutations in X-linked EDMD.
LMNA (Heterozygous (dominant) variants)
Gene: LMNA hgnc:6636 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:10080180 SUPPORT Human Clinical
"These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder."
Establishes LMNA (lamin A/C, a nuclear lamina component) as a cause of EDMD.
LMNA biallelic (Biallelic (recessive) variants)
Gene: LMNA hgnc:6636 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:10739764 SUPPORT Human Clinical
"Our results show that LMNA mutations are also responsible for the recessive form of the disease."
Original demonstration that LMNA variants cause autosomal recessive EDMD in addition to the dominant form.
SYNE1 (Heterozygous (dominant) variants)
Gene: SYNE1 hgnc:17089 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYNE1 (hgnc:17089). hgnc:17089 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:17761684 SUPPORT Human Clinical
"Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
Identification of SYNE1 (nesprin-1) mutations in EDMD probands.
SYNE2 (Heterozygous (dominant) variants)
Gene: SYNE2 hgnc:17084 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYNE2 (hgnc:17084). hgnc:17084 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:41136957 SUPPORT Human Clinical
"The whole exome sequencing detected a missense splice region heterozygous variant of the SYNE2 gene, confirming Emery-Dreifuss muscular dystrophy 5."
SYNE2-specific attribution of EDMD5 in the report's own proband, which the shared nesprin screening sentence below cannot supply on its own.
PMID:17761684 SUPPORT Human Clinical
"Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
Identification of SYNE2 (nesprin-2) mutations in EDMD probands.
FHL1 (Hemizygous variants (X-linked))
Gene: FHL1 hgnc:3702 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FHL1 (hgnc:3702). hgnc:3702 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:19716112 SUPPORT Human Clinical
"In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy."
Establishes FHL1 as a cause of X-linked EDMD with hypertrophic cardiomyopathy.
TMEM43 (Heterozygous (dominant) variants)
Gene: TMEM43 hgnc:28472 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM43 (hgnc:28472). hgnc:28472 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:21391237 SUPPORT Human Clinical
"We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients."
Identification of TMEM43 (LUMA) mutations in EDMD-related myopathy.
💊

Medical Actions

9
Cardiac pacemaker implantation
Action: pacemaker implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pacemaker implantation, annotated with Pacemaker Placement (NCIT:C80434). NCIT:C80434 is a clinical intervention from the NCI Thesaurus. Ontology label: Pacemaker Placement NCIT:C80434
Pacemaker implantation is indicated for advanced conduction disturbances (e.g., high-grade AV block, sinus node dysfunction). Note that pacing alone does not prevent sudden death from ventricular arrhythmia.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Treatment for cardiac disease can include antiarrhythmic drugs, oral anticoagulation, ablation procedures, cardiac pacemaker, implantable cardioverter-defibrillator"
GeneReviews lists cardiac pacemaker among standard cardiac treatments for EDMD.
Implantable cardioverter-defibrillator placement
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
ICD implantation is considered, particularly in LMNA-related disease and when pacing is needed, because pacemakers alone do not prevent sudden death from malignant ventricular arrhythmia. Early ICD implantation and heart failure drug therapy are recommended in male EMD variant carriers with cardiac disease.
Show evidence (1 reference)
PMID:37639473 SUPPORT Human Clinical
"Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease."
Recommends early ICD implantation in EMD variant carriers with cardiac disease.
Anticoagulant therapy
Action: anticoagulant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticoagulant agent therapy, annotated with Anticoagulation Therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticoagulation Therapy NCIT:C63341
Oral anticoagulation is used when atrial fibrillation/flutter or atrial standstill is present, given the high thromboembolic risk.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Treatment for cardiac disease can include antiarrhythmic drugs, oral anticoagulation"
GeneReviews lists oral anticoagulation among standard cardiac treatments for EDMD.
Physical therapy and stretching
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
Physical therapy and stretching are used to prevent and manage contractures, with orthopedic surgery to release contractures or manage scoliosis as needed.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"physical therapy and stretching to prevent contractures"
GeneReviews recommends physical therapy and stretching to prevent contractures.
Orthopedic surgery for contractures and scoliosis
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgery to release contractures and to manage scoliosis is performed as needed.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Surgery to release contractures and manage scoliosis as needed"
GeneReviews recommends surgery for contracture release and scoliosis management.
Heart transplantation
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
Heart transplantation is appropriate for the end stages of heart failure.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"heart transplantation for the end stages of heart failure as appropriate"
GeneReviews recommends heart transplantation for end-stage heart failure.
Respiratory support
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
Respiratory aids — including respiratory muscle training, assisted coughing techniques, and mechanical (noninvasive) ventilation — are used as needed in those with respiratory compromise.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"respiratory aids (respiratory muscle training, assisted coughing techniques, mechanical ventilation) as needed"
GeneReviews recommends respiratory aids including mechanical ventilation as needed.
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. NCIT:C15240
Genetic counseling addresses the X-linked, autosomal dominant, or rare autosomal recessive inheritance, recurrence risk, cascade testing of relatives at risk, and reproductive options including prenatal and preimplantation genetic testing.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Once the EDMD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible."
GeneReviews documents the role of genetic testing and counseling for at-risk relatives and reproduction.
Peri-operative anesthetic precautions (malignant hyperthermia avoidance)
Action: anesthesia procedure (malignant hyperthermia trigger avoidance)NCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anesthesia procedure (malignant hyperthermia trigger avoidance), annotated with Anesthesia Procedure (NCIT:C15181). NCIT:C15181 is a clinical intervention from the NCI Thesaurus. Ontology label: Anesthesia Procedure NCIT:C15181
GeneReviews identifies safety-critical agents and circumstances to avoid in EDMD. Triggering agents for malignant hyperthermia — depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (e.g., halothane, isoflurane) — should be avoided during anesthesia, and obesity should be avoided. Anesthetic plans should also account for cardiac conduction disease and arrhythmia risk in affected individuals.
Show evidence (1 reference)
PMID:20301609 SUPPORT Human Clinical
"Triggering agents for malignant hyperthermia, such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane); obesity."
GeneReviews lists malignant-hyperthermia triggering agents and obesity among agents/circumstances to avoid in EDMD.
🔬

Biochemical Markers

1
Elevated serum creatine kinase (INCREASED)
🔬

Clinical Trials

1
NCT03439514 PHASE_III TERMINATED
REALM-DCM — a Phase 3, multinational, randomized, placebo-controlled study of ARRY-371797 (PF-07265803), an oral p38 MAPK inhibitor, in patients with symptomatic dilated cardiomyopathy due to an LMNA (lamin A/C) gene mutation, the gene underlying autosomal dominant EDMD2.
Target Phenotypes: Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03439514 SUPPORT Human Clinical
"This is a randomized, double-blind, placebo-controlled study in patients with dilated cardiomyopathy (DCM) due to a mutation of the gene encoding the lamin A/C protein (LMNA)."
A Phase 3 LMNA-specific trial directly relevant to the cardiac phenotype of LMNA-related (EDMD2) disease.
{ }

Source YAML

click to show 
name: Emery-Dreifuss Muscular Dystrophy
creation_date: "2026-06-16T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Emery-Dreifuss muscular dystrophy
  term:
    id: MONDO:0016830
    label: Emery-Dreifuss muscular dystrophy
description: >-
  Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous,
  primarily Mendelian neuromuscular disorder within the spectrum of
  nuclear-envelope diseases (laminopathies / nuclear envelopathies). It is
  classically defined by a clinical triad of (i) early joint contractures
  (typically elbows, Achilles tendons, and posterior cervical/paraspinal
  muscles producing a rigid spine); (ii) slowly progressive skeletal muscle
  weakness and wasting in a humeroperoneal (later scapular and pelvic-girdle)
  distribution; and (iii) cardiac involvement dominated by atrial disease,
  conduction-system disease, and arrhythmia, with risk of thromboembolism,
  cardiomyopathy/heart failure, and sudden cardiac death. EDMD is caused by
  pathogenic variants in genes encoding nuclear lamina, inner-nuclear-membrane,
  and LINC-complex proteins that couple the nucleoskeleton to the cytoskeleton:
  X-linked EMD (emerin; EDMD1), autosomal dominant/recessive LMNA (lamin A/C;
  EDMD2/EDMD3), and additional nuclear-envelope genes SYNE1/SYNE2 (nesprin-1/-2),
  FHL1, and TMEM43 (LUMA). Convergent pathophysiology involves failure of
  nucleo-cytoskeletal coupling and mechanotransduction, mechanical-stress-induced
  nuclear damage and DNA-damage responses, and maladaptive transcriptional
  reprogramming (fibrosis, metabolism, splicing).

references:
- reference: PMID:20301609
  title: "Emery-Dreifuss Muscular Dystrophy."
  tags:
  - GeneReviews
- reference: PMID:31840275
  title: "Emery-Dreifuss muscular dystrophy."
- reference: PMID:10739764
  title: "Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy."
- reference: PMID:41136957
  title: "A Sri Lankan boy with Emery-Dreifuss muscular dystrophy 5 presenting during infancy with persistent transaminitis."
- reference: PMID:24375709
  title: "Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies."

has_subtypes:
- name: EDMD1
  display_name: EDMD1 (X-linked, EMD / emerin)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 1, X-linked
    term:
      id: MONDO:0100531
      label: Emery-Dreifuss muscular dystrophy 1, X-linked
  description: >-
    Classical X-linked EDMD caused by hemizygous pathogenic variants in EMD,
    encoding emerin, an inner-nuclear-membrane protein (OMIM #310300). Males are
    primarily affected; heterozygous female carriers are usually asymptomatic
    but are at risk of later-onset cardiac disease. Cardiac phenotype is
    dominated by atrial arrhythmia, conduction disease, and a substantial risk
    of malignant ventricular arrhythmia and end-stage heart failure.
  genes:
  - preferred_term: EMD
    term:
      id: hgnc:3331
      label: EMD
  evidence:
  - reference: PMID:7894480
    reference_title: "Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive disorder characterized by slowly progressing contractures, wasting of skeletal muscle and cardiomyopathy."
    explanation: Original identification of the EMD gene (emerin) as the cause of X-linked EDMD.
- name: EDMD2
  display_name: EDMD2 (autosomal dominant, LMNA / lamin A/C)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 2, autosomal dominant
    term:
      id: MONDO:0021569
      label: Emery-Dreifuss muscular dystrophy 2, autosomal dominant
  description: >-
    Autosomal dominant EDMD caused by heterozygous LMNA pathogenic variants,
    encoding lamin A/C, a nuclear lamina intermediate filament protein
    (OMIM #181350). Clinically identical to X-linked EDMD but with frequent
    de novo variants and a more malignant cardiac trajectory (dilated
    cardiomyopathy, end-stage heart failure, malignant ventricular arrhythmias).
    Biallelic LMNA variants cause the rare autosomal recessive form, recorded
    separately as the EDMD3 row below.
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  evidence:
  - reference: PMID:10080180
    reference_title: "Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations."
    explanation: Original identification of LMNA mutations as the cause of autosomal dominant EDMD.
- name: EDMD3
  display_name: EDMD3 (autosomal recessive, LMNA / lamin A/C)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 3, autosomal recessive
    term:
      id: MONDO:0014676
      label: Emery-Dreifuss muscular dystrophy 3, autosomal recessive
  description: >-
    Rare autosomal recessive EDMD caused by biallelic LMNA variants - the same
    gene as dominant EDMD2, so the two subtypes are distinguished by inheritance
    and allele dose rather than by locus. The originally reported proband was
    homozygous for a missense change and the heterozygous first-cousin parents
    were clinically and cardiologically unaffected, which separates this
    recessive form from the dominant one in which a single allele suffices. In
    that single reported case the phenotype was severe and
    skeletal-muscle-predominant: contractures left him unable to stand at age
    five and he was wheelchair-bound with diffuse wasting at 40, with no cardiac
    problems on careful cardiological examination at that age.
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  evidence:
  - reference: PMID:10739764
    reference_title: "Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results show that LMNA mutations are also responsible for the recessive form of the disease."
    explanation: >-
      Original demonstration that LMNA variants cause the autosomal recessive as
      well as the autosomal dominant form of EDMD, the basis of the EDMD3 class.
  - reference: PMID:10739764
    reference_title: "Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the rest of the LMNA gene in the patient demonstrated
      that C664T was the only mutation. His parents, who were first cousins, were
      heterozygotes.
    explanation: >-
      Records the recessive segregation this row rests on: a single homozygous
      LMNA change in the proband with unaffected heterozygous consanguineous
      parents.
- name: EDMD4
  display_name: EDMD4 (autosomal dominant, SYNE1 / nesprin-1)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 4, autosomal dominant
    term:
      id: MONDO:0013071
      label: Emery-Dreifuss muscular dystrophy 4, autosomal dominant
  description: >-
    EDMD caused by heterozygous variants in SYNE1, encoding nesprin-1, a
    spectrin-repeat protein of the outer nuclear membrane that binds emerin and
    lamin A/C and links the nucleoskeleton to the cytoskeleton as part of the
    LINC complex. Fibroblasts from the reported nesprin-mutant patients show
    nuclear morphology defects and mislocalization of emerin and SUN2, changes
    that siRNA knockdown of either nesprin reproduces in normal fibroblasts. The
    sibling SYNE2 subtype is EDMD5.
  genes:
  - preferred_term: SYNE1
    term:
      id: hgnc:17089
      label: SYNE1
  evidence:
  - reference: PMID:17761684
    reference_title: "Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
    explanation: >-
      Identifies heterozygous missense variants in the two nesprin genes across a
      screen of 190 EDMD and EDMD-like probands. The reported mutations are not
      apportioned between SYNE1 and SYNE2 in this sentence, so it supports the
      pair rather than either gene alone.
- name: EDMD5
  display_name: EDMD5 (autosomal dominant, SYNE2 / nesprin-2)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 5, autosomal dominant
    term:
      id: MONDO:0013072
      label: Emery-Dreifuss muscular dystrophy 5, autosomal dominant
  description: >-
    EDMD caused by heterozygous variants in SYNE2, encoding nesprin-2, the other
    outer-nuclear-membrane spectrin-repeat LINC-complex protein that binds emerin
    and lamin A/C. EDMD5 departs from the classical triad: joint contractures are
    not a feature, and the usual presentation is muscle weakness with
    cardiomyopathy in late childhood. A reported infant presented instead with
    persistently raised transaminases judged to be of non-hepatic origin, calf
    pseudohypertrophy and a markedly raised creatine phosphokinase, with a normal
    electrocardiogram and echocardiogram and no contractures.
  genes:
  - preferred_term: SYNE2
    term:
      id: hgnc:17084
      label: SYNE2
  evidence:
  - reference: PMID:41136957
    reference_title: "A Sri Lankan boy with Emery-Dreifuss muscular dystrophy 5 presenting during infancy with persistent transaminitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The whole exome sequencing detected a missense splice region heterozygous variant of the SYNE2 gene, confirming Emery-Dreifuss muscular dystrophy 5."
    explanation: >-
      Attributes EDMD5 to a heterozygous SYNE2 variant in the report's own
      proband, which is the gene-to-subtype assignment this row asserts.
  - reference: PMID:17761684
    reference_title: "Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
    explanation: >-
      Identifies heterozygous missense variants in the two nesprin genes across a
      screen of 190 EDMD and EDMD-like probands. The reported mutations are not
      apportioned between SYNE1 and SYNE2 in this sentence, so it supports the
      pair rather than either gene alone.
- name: EDMD6
  display_name: EDMD6 (X-linked, FHL1)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 6, X-linked
    term:
      id: MONDO:0800318
      label: Emery-Dreifuss muscular dystrophy 6, X-linked
  description: >-
    X-linked EDMD caused by FHL1 variants. The predominant phenotype is myopathy
    with scapulo-peroneal and/or axial distribution plus joint contractures,
    associated with a cardiac disease that includes conduction defects,
    arrhythmias, and hypertrophic cardiomyopathy.
  genes:
  - preferred_term: FHL1
    term:
      id: hgnc:3702
      label: FHL1
  evidence:
  - reference: PMID:19716112
    reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy."
    explanation: Establishes FHL1 as a cause of X-linked EDMD with hypertrophic cardiomyopathy.
- name: EDMD7
  display_name: EDMD7 (autosomal dominant, TMEM43 / LUMA)
  subtype_term:
    preferred_term: Emery-Dreifuss muscular dystrophy 7, autosomal dominant
    term:
      id: MONDO:0013677
      label: Emery-Dreifuss muscular dystrophy 7, autosomal dominant
  description: >-
    EDMD-related myopathy caused by heterozygous TMEM43 variants, encoding LUMA,
    a nuclear-membrane protein and binding partner of emerin and lamins
    (OMIM #612048). Mutant LUMA fails to oligomerize and causes reduced nuclear
    staining of emerin and SUN2 with abnormally shaped nuclei.
  genes:
  - preferred_term: TMEM43
    term:
      id: hgnc:28472
      label: TMEM43
  evidence:
  - reference: PMID:21391237
    reference_title: "TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients."
    explanation: Identification of TMEM43 (LUMA) mutations in EDMD-related myopathy.

review_notes: >-
  MONDO:0016830 has four direct children. Two of them, MONDO:0010680 X-linked
  Emery-Dreifuss muscular dystrophy and MONDO:0020336 autosomal dominant
  Emery-Dreifuss muscular dystrophy, are defined by inheritance rather than by
  gene ("X-linked form of Emery-Dreifuss muscular dystrophy" and "Autosomal
  dominant form of Emery-Dreifuss muscular dystrophy"), and their own children
  are the numbered gene-defined classes. Every one of those is bound on a
  has_subtypes row here: MONDO:0100531 (EDMD1, EMD) and MONDO:0800318 (EDMD6,
  FHL1) under the X-linked node, and MONDO:0021569, MONDO:0013071, MONDO:0013072
  and MONDO:0013677 (EDMD2, 4, 5, 7) under the autosomal dominant node. The two
  intermediate nodes therefore take no row of their own. MONDO:0010680's third
  child, MONDO:0010401 X-linked myopathy with postural muscle atrophy, is a
  separate X-linked myopathy class that this entry does not model and that
  asserts no causal gene of its own in MONDO. The remaining two direct children
  are MONDO:0014676 (EDMD3, biallelic LMNA), which is bound here, and
  MONDO:0000727 scapuloperoneal myopathy, a phenotype-defined class that asserts
  no causal gene and whose two descendants (congenital myopathy 7A with myosin
  storage, and X-linked scapuloperoneal muscular dystrophy) assert none either and
  sit outside the EDMD numbered series; it is left unbound. Every subtype_term in
  this entry is a descendant of MONDO:0016830.

  Worth flagging for MONDO rather than worked around here: MONDO:0010680 asserts
  EMD (hgnc:3331) as its causal gene in an OWL axiom while subsuming the FHL1
  disease MONDO:0800318, so the axiom is narrower than the class its own
  definition describes. That axiom is why the d2g gap comparison offered this
  class as a missing EMD subtype.

  The GeneReviews chapter's molecular-diagnosis criteria name two further genes
  this entry does not cover, SUN2 (heterozygous) and SUN1 (biallelic). They are
  deliberately left out pending a dedicated pass, because their relationship type
  is not settled by what is reachable: the only primary report found,
  PMID:24375709, describes heterozygous SUN1 variants alongside a primary EMD or
  LAP2alpha mutation and aggravating the cellular phenotype, which is a digenic
  modifier rather than the primary biallelic cause the chapter's list implies. A
  relationship type typed from a seven-gene diagnostic list would not distinguish
  the two. Synonym-inclusive MONDO searches for "SUN1" and "SUN2" return no
  disease class, so neither would take a subtype row in any case.

  ClinGen's committed Gene-Disease Validity download holds no Emery-Dreifuss
  assertion for any of these genes, and no row at all for EMD, SYNE2 or FHL1, so
  it cannot grade this entry's gene-disease claims. Its LMNA, SYNE1 and TMEM43
  rows are against lipodystrophy, cardiomyopathy, arthrogryposis and ataxia
  classes, which are not transferable to EDMD.

  FHL1 is the one causal gene not bound to a pathophysiology node. The
  nuclear-envelope node's own evidence covers nesprins, emerin, lamin A/C and
  LUMA but not FHL1, and FHL1 is a cytoskeletal four-and-a-half LIM domain
  protein rather than a nuclear-envelope component, so the mechanism node it acts
  at has not been curated yet.

pathophysiology:
- name: Nuclear Envelope and LINC Complex Dysfunction
  description: >-
    EDMD is caused by loss or dysfunction of nuclear-envelope proteins (emerin,
    lamin A/C) and LINC-complex components (nesprins, SUN proteins, LUMA) that
    physically couple the nucleoskeleton to the cytoskeleton. These proteins form
    an interacting network spanning the nuclear lamina, inner nuclear membrane,
    and outer nuclear membrane. Pathogenic variants disrupt nesprin/emerin/lamin
    binding, mislocalize emerin and SUN2, and compromise nuclear envelope
    integrity, which is the upstream defect shared by the nuclear-envelope
    subtypes (EDMD1-5 and EDMD7). FHL1-related EDMD6 is the exception: FHL1 is a
    sarcomeric and sarcolemmal protein, and its lesion is modelled as a separate
    node.
  genes:
  - preferred_term: EMD
    term:
      id: hgnc:3331
      label: EMD
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  - preferred_term: SYNE1
    term:
      id: hgnc:17089
      label: SYNE1
  - preferred_term: SYNE2
    term:
      id: hgnc:17084
      label: SYNE2
  - preferred_term: TMEM43
    term:
      id: hgnc:28472
      label: TMEM43
  cell_types:
  - preferred_term: skeletal muscle myoblast
    term:
      id: CL:0000056
      label: myoblast
  cellular_components:
  - preferred_term: nuclear envelope
    term:
      id: GO:0005635
      label: nuclear envelope
  - preferred_term: nuclear lamina
    term:
      id: GO:0005652
      label: nuclear lamina
  - preferred_term: inner nuclear membrane
    term:
      id: GO:0005637
      label: nuclear inner membrane
  biological_processes:
  - preferred_term: nuclear envelope organization
    term:
      id: GO:0006998
      label: nuclear envelope organization
    modifier: ABNORMAL
  downstream:
  - target: Impaired Mechanotransduction and Nuclear Mechanical Fragility
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17761684
    reference_title: "Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts."
    explanation: >-
      Demonstrates that disrupted nesprin/emerin/lamin interactions and nuclear
      envelope localization are a common feature across EDMD patient cells,
      establishing nuclear-envelope/LINC-complex dysfunction as the shared
      upstream defect.
  - reference: PMID:21391237
    reference_title: "TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei."
    explanation: >-
      Shows mutant LUMA (TMEM43) disrupts emerin and SUN2 localization and
      nuclear shape, illustrating convergent nuclear-envelope dysfunction.
- name: Impaired Mechanotransduction and Nuclear Mechanical Fragility
  description: >-
    Striated muscle nuclei are continuously exposed to mechanical strain. A
    functional nuclear envelope / LINC complex transmits and buffers these
    forces. In EDMD, defective nucleo-cytoskeletal coupling impairs
    mechanotransduction and renders nuclei mechanically fragile. In LMNA-mutant
    (EDMD2) myoblasts under cyclic stretch, lamin A/C fails to recruit desmin and
    plectin to the nuclear periphery and nuclei fail to reorient properly,
    directly linking the molecular defect to defective mechanosignaling.
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  cell_types:
  - preferred_term: skeletal muscle myoblast
    term:
      id: CL:0000056
      label: myoblast
  biological_processes:
  - preferred_term: cellular response to mechanical stimulus
    term:
      id: GO:0071260
      label: cellular response to mechanical stimulus
    modifier: ABNORMAL
  downstream:
  - target: Mechanical-Stress-Induced Nuclear Damage and DNA Damage Response
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38247853
    reference_title: "Desmin and Plectin Recruitment to the Nucleus and Nuclei Orientation Are Lost in Emery-Dreifuss Muscular Dystrophy Myoblasts Subjected to Mechanical Stimulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in Emery-Dreifuss Muscular Dystrophy (EDMD2) myoblasts exposed to mechanical stretching, the recruitment of desmin and plectin to the nucleus and nuclear orientation were impaired, suggesting that a functional lamin A/C is crucial for the response to mechanical strain."
    explanation: >-
      Directly demonstrates impaired mechanotransduction in EDMD2 myoblasts:
      lamin A/C dysfunction prevents recruitment of cytoskeletal proteins to the
      nucleus and proper nuclear reorientation under mechanical strain.
- name: FHL1 Deficiency and Impaired Sarcomere Assembly
  description: >-
    FHL1 (four and a half LIM domains 1) is the one EDMD gene product that does
    not reside at the nuclear envelope; it localizes to the sarcomere and the
    sarcolemma and contributes to sarcomere assembly. Pathogenic FHL1 variants in
    X-linked EDMD6 sit in the distal exons and severely reduce FHL1 protein
    levels in patient muscle, and patient myoblasts show a severe delay in
    myotube formation. The resulting myopathy has a scapulo-peroneal and/or axial
    distribution with joint contractures, and the cardiac disease characteristically
    includes hypertrophic cardiomyopathy alongside conduction defects and
    arrhythmias. How FHL1 loss produces the cardiac phenotype is not established
    by the cited sources, so the cardiac edge is left without named
    intermediates.
  biological_scale: CELLULAR
  subtypes:
  - EDMD6
  genes:
  - preferred_term: FHL1
    term:
      id: hgnc:3702
      label: FHL1
  cell_types:
  - preferred_term: skeletal muscle myoblast
    term:
      id: CL:0000515
      label: skeletal muscle myoblast
  cellular_components:
  - preferred_term: sarcomere
    term:
      id: GO:0030017
      label: sarcomere
  - preferred_term: sarcolemma
    term:
      id: GO:0042383
      label: sarcolemma
  biological_processes:
  - preferred_term: myotube differentiation
    term:
      id: GO:0014902
      label: myotube differentiation
    modifier: DECREASED
  downstream:
  - target: Muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced FHL1 and delayed myotube formation are followed in FHL1-mutated
      families by a myopathy of scapulo-peroneal and/or axial distribution; the
      steps from defective sarcomere assembly to clinical weakness are not
      described in the cited source.
    evidence:
    - reference: PMID:19716112
      reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures"
      explanation: >-
        Clinical series of the FHL1 families reporting the scapulo-peroneal
        and/or axial myopathy that this edge links to the FHL1 lesion.
  - target: Joint contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Joint contractures are part of the predominant phenotype of FHL1-related
      EDMD6; how FHL1 loss produces them is not established by the cited source.
    evidence:
    - reference: PMID:19716112
      reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures"
      explanation: >-
        The same clinical series reports joint contractures as part of the
        predominant FHL1 phenotype.
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Every index case of the FHL1 families had cardiac disease that included
      hypertrophic cardiomyopathy; the mechanism linking FHL1 loss to cardiac
      hypertrophy is not described in the cited source.
    evidence:
    - reference: PMID:19716112
      reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families."
      explanation: >-
        Reports hypertrophic cardiomyopathy in all index cases of the seven
        FHL1-mutated families.
  evidence:
  - reference: PMID:31840275
    reference_title: "Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "An exception is FHL1, a protein encoded by the gene of the same name, which localizes to the sarcomere and the sarcolemma; at the former, it contributes to sarcomere assembly."
    explanation: >-
      Review establishing that FHL1, unlike the other EDMD proteins, acts at the
      sarcomere and sarcolemma rather than the nuclear envelope, which is why its
      lesion is a separate node from the nuclear-envelope/LINC node.
  - reference: PMID:19716112
    reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available."
    explanation: >-
      Patient-derived evidence that EDMD6 FHL1 variants reduce FHL1 protein and
      impair myotube formation, the cellular defect this node records.
- name: Mechanical-Stress-Induced Nuclear Damage and DNA Damage Response
  description: >-
    Mechanically fragile EDMD nuclei accumulate damage under physiologic strain,
    including stretch-induced DNA damage and activation of DNA-damage responses
    (e.g., gamma-H2A.X foci, p53 signaling). Muscle-specific loss of the
    nuclear-envelope protein NET39 in mice recapitulates EDMD-like muscle wasting
    with abnormal myonuclei and DNA damage, and renders myoblasts hypersensitive
    to mechanical stretch, establishing a mechanical-stress to DNA-damage axis as
    a contributor to muscle degeneration.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  downstream:
  - target: Maladaptive Transcriptional Reprogramming and Fibro-Fatty Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37395273
    reference_title: "Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage."
    explanation: >-
      Mouse model evidence that nuclear-envelope dysfunction causes
      mechanical-stress-induced DNA damage and EDMD-like muscle pathology.
- name: Maladaptive Transcriptional Reprogramming and Fibro-Fatty Remodeling
  description: >-
    Nuclear-envelope dysfunction alters chromatin organization and gene
    expression programs. Transcriptomic analysis of EDMD-spectrum patient
    myotubes across seven causal genes shows convergent dysregulation of
    fibrosis/ECM, metabolism, myogenic signaling, and splicing pathways. This
    maladaptive reprogramming drives muscle fiber degeneration with fibro-fatty
    remodeling in skeletal muscle and contributes to fibrosis and electrical
    instability in the heart.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
  - preferred_term: muscle cell differentiation
    term:
      id: GO:0042692
      label: muscle cell differentiation
    modifier: ABNORMAL
  downstream:
  - target: Cardiac Conduction Disease and Arrhythmogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Joint contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elbow contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Achilles tendon contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spinal rigidity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Muscle weakness
    causal_link_type: DIRECT
  - target: Peroneal muscle weakness
    causal_link_type: DIRECT
  - target: Muscle atrophy and wasting
    causal_link_type: DIRECT
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:36282542
    reference_title: "Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling and splicing were affected in all patients."
    explanation: >-
      RNA-seq across EDMD-spectrum patient cells (seven causal genes) shows
      convergent dysregulation of fibrosis, metabolism, myogenic signaling, and
      splicing pathways downstream of nuclear-envelope dysfunction.
- name: Cardiac Conduction Disease and Arrhythmogenesis
  description: >-
    Cardiac involvement is the principal determinant of morbidity and mortality
    in EDMD. Nuclear-envelope dysfunction in atrial and conduction-system
    cardiomyocytes produces an atrial myopathy with progressive conduction
    disease (AV block, sinus node dysfunction), atrial arrhythmia (atrial
    fibrillation/flutter), and atrial standstill, with attendant thromboembolic
    risk. EMD and especially LMNA variants additionally confer a high risk of
    malignant ventricular arrhythmia and progression to dilated cardiomyopathy,
    end-stage heart failure, and sudden cardiac death. Pacing alone does not
    prevent sudden death from ventricular arrhythmia, so ICD therapy is often
    required.
  genes:
  - preferred_term: EMD
    term:
      id: hgnc:3331
      label: EMD
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac Purkinje conduction myocyte
    term:
      id: CL:0002068
      label: Purkinje myocyte
  - preferred_term: nodal (pacemaker/conduction) myocyte
    term:
      id: CL:0002072
      label: nodal myocyte
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37639473
    reference_title: "Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA)."
    explanation: >-
      Establishes conduction disease and atrial arrhythmia as common to EDMD1
      and EDMD2, with LMNA additionally causing end-stage heart failure and
      malignant ventricular arrhythmia.
  - reference: PMID:35453731
    reference_title: "Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The whole spectrum of cardiac manifestations encompasses atrial arrhythmias, conduction disturbances, progressive systolic dysfunction, and malignant ventricular arrhythmias."
    explanation: >-
      Systematic review summarizing the cardiac manifestation spectrum of
      EDMD/cardiolaminopathies.
  downstream:
  - target: Atrioventricular block
    causal_link_type: DIRECT
  - target: Atrial fibrillation
    causal_link_type: DIRECT
  - target: Atrial standstill
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Ventricular arrhythmia
    causal_link_type: DIRECT
  - target: Sudden cardiac death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thromboembolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT

phenotypes:
- name: Joint contractures
  description: >-
    Early joint contractures are a defining feature, typically beginning in the
    first two decades and characteristically affecting the elbows, Achilles
    tendons, and posterior cervical/paraspinal muscles.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical triad of joint contractures that begin in early childhood"
    explanation: GeneReviews documents early-childhood joint contractures as part of the defining triad.
- name: Elbow contracture
  description: >-
    Flexion contractures of the elbows are among the earliest and most
    characteristic contractures in EDMD.
  phenotype_term:
    preferred_term: Elbow contracture
    term:
      id: HP:0034391
      label: Elbow contracture
  evidence:
  - reference: PMID:10080180
    reference_title: "Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons"
    explanation: Directly documents early elbow contractures as characteristic of EDMD.
- name: Achilles tendon contracture
  description: >-
    Contractures of the Achilles tendons are characteristic and contribute to
    toe-walking and gait disturbance.
  phenotype_term:
    preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  evidence:
  - reference: PMID:10080180
    reference_title: "Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons"
    explanation: Directly documents early Achilles tendon contractures as characteristic of EDMD.
- name: Spinal rigidity
  description: >-
    Rigidity of the spine, due to contractures of the posterior cervical and
    paraspinal musculature, limits neck and trunk flexion and is part of the
    characteristic contracture pattern.
  phenotype_term:
    preferred_term: Spinal rigidity
    term:
      id: HP:0003306
      label: Spinal rigidity
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assess joints for contractures and mobility, and spine for rigidity, posture, flexibility"
    explanation: >-
      GeneReviews surveillance recommendations specifically reference spinal
      rigidity as a feature to monitor.
- name: Muscle weakness
  description: >-
    Slowly progressive muscle weakness and wasting, initially in a humeroperoneal
    distribution and later extending to scapular and pelvic-girdle muscles.
  phenotype_term:
    preferred_term: Humeroperoneal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
    clinical_course: PROGRESSIVE
  notes: >-
    HP:0003701 (Proximal muscle weakness) is broader than the EDMD distribution:
    the characteristic humeroperoneal pattern includes both a proximal
    upper-limb (humeral/biceps-triceps) component and a distal lower-limb
    (peroneal) component. The distal peroneal component is captured separately
    in the dedicated "Peroneal muscle weakness" phenotype (HP:0011727).
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "slowly progressive muscle weakness and wasting initially in a humeroperoneal distribution that later extends to the scapular and pelvic girdle muscles"
    explanation: GeneReviews documents the characteristic humeroperoneal pattern of progressive weakness.
- name: Peroneal muscle weakness
  description: >-
    Weakness of the peroneal (anterolateral lower-leg) muscles is part of the
    characteristic humeroperoneal distribution and contributes to foot drop.
  phenotype_term:
    preferred_term: Peroneal muscle weakness
    term:
      id: HP:0011727
      label: Peroneal muscle weakness
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "humeroperoneal (or more rarely limb-girdle) muscle weakness and wasting"
    explanation: GeneReviews documents humeroperoneal weakness, of which peroneal involvement is a component.
- name: Muscle atrophy and wasting
  description: >-
    Progressive skeletal muscle wasting accompanies the weakness, following the
    same humeroperoneal-then-scapular/pelvic-girdle distribution; "weakness and
    wasting" together constitute the skeletal-muscle limb of the EDMD clinical
    triad.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "slowly progressive muscle weakness and wasting initially in a humeroperoneal distribution that later extends to the scapular and pelvic girdle muscles"
    explanation: GeneReviews documents progressive muscle wasting (atrophy) accompanying the weakness in EDMD.
- name: Atrioventricular block
  description: >-
    Conduction-system disease, including atrioventricular block, is a hallmark
    cardiac manifestation and a frequent cause of death; it may require pacemaker
    implantation.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:10080180
    reference_title: "Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a cardiomyopathy with conduction blocks which is life-threatening"
    explanation: Documents life-threatening conduction block as a defining cardiac feature of EDMD.
- name: Atrial fibrillation
  description: >-
    Atrial arrhythmias including atrial fibrillation, flutter, and tachycardia
    are common and carry thromboembolic risk.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:35453731
    reference_title: "Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The IR for atrial fibrillation/atrial flutter/atrial tachycardia ranged between 6.1 and 13.9 events/100 pts-year."
    explanation: Systematic review quantifies the incidence of atrial fibrillation/flutter/tachycardia in EDMD cohorts.
- name: Atrial standstill
  description: >-
    Progressive atrial myopathy can evolve to atrial standstill (absence of
    atrial electrical/mechanical activity), which carries a high thromboembolic
    risk and may warrant anticoagulation.
  phenotype_term:
    preferred_term: Atrial standstill
    term:
      id: HP:0025478
      label: Atrial standstill
  evidence:
  - reference: PMID:35453731
    reference_title: "Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The IR of atrial standstill ranged between 0 and 2 events/100 pts-year."
    explanation: Systematic review reports atrial standstill incidence in EDMD/cardiolaminopathy cohorts.
- name: Dilated cardiomyopathy
  description: >-
    Dilated cardiomyopathy with progressive systolic dysfunction develops
    particularly in LMNA-related EDMD and can progress to end-stage heart
    failure requiring transplantation.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:36968203
    reference_title: "Characterization of cardiac involvement in children with LMNA-related muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM)"
    explanation: Pediatric LMNA cohort documents dilated cardiomyopathy as a frequent outcome.
- name: Ventricular arrhythmia
  description: >-
    Malignant ventricular arrhythmias are a major cause of sudden death,
    particularly in LMNA-related and EMD-related disease, often disproportionate
    to the degree of systolic dysfunction. Pacing does not protect against them,
    so ICD therapy is frequently indicated.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:37639473
    reference_title: "Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months."
    explanation: >-
      Documents the substantial risk of malignant ventricular arrhythmia in male
      EMD variant carriers.
  - reference: PMID:35453731
    reference_title: "Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequent need for cardiac pacing due to advanced conduction disturbances should be counterbalanced with the high risk of malignant ventricular arrhythmias that would justify ICD over pacemaker implantation."
    explanation: >-
      Systematic review concludes that pacing for conduction disease does not
      address the competing malignant-ventricular-arrhythmia risk, justifying
      ICD over pacemaker implantation.
- name: Sudden cardiac death
  description: >-
    Sudden cardiac death, from conduction block or malignant ventricular
    arrhythmia, is a leading cause of mortality and a major rationale for
    intensive cardiac surveillance and device therapy.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:35453731
    reference_title: "Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "studies focusing on cardiovascular outcomes in LMNA mutation carriers (atrial arrhythmias, ventricular arrhythmias, sudden cardiac death, conduction disturbances, thromboembolic events, systolic dysfunction, heart transplantation, and all-cause and cardiovascular mortality)"
    explanation: >-
      This is the review's search/inclusion-criteria list naming sudden cardiac
      death as a searched-for outcome, not a reported SCD incidence or mortality
      rate; the review's abstract does not give a quantitative SCD figure (only
      arrhythmia/thromboembolic incidence rates), so this only partially
      supports the node's mortality claim.
  notes: >-
    A quantitative sudden-cardiac-death or all-cause/cardiovascular mortality
    rate for EDMD/cardiolaminopathy cohorts is still needed; PMID:35453731's
    abstract does not report one.
- name: Thromboembolism
  description: >-
    Atrial arrhythmia and atrial standstill predispose to thromboembolism,
    including stroke, sometimes occurring even without documented atrial
    arrhythmia in LMNA cohorts.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:35453731
    reference_title: "Clinical Profile, Arrhythmias, and Adverse Cardiac Outcomes in Emery-Dreifuss Muscular Dystrophies: A Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The IR of thromboembolic events reached up to 8.9 events/100 pts-year."
    explanation: Systematic review quantifies thromboembolic event incidence in EDMD/cardiolaminopathy cohorts.
- name: Hypertrophic cardiomyopathy
  description: >-
    In FHL1-related EDMD (EDMD6), the associated cardiac disease characteristically
    includes hypertrophic cardiomyopathy in addition to conduction defects and
    arrhythmias.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  subtype: EDMD6
  evidence:
  - reference: PMID:19716112
    reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families."
    explanation: FHL1-related EDMD is associated with hypertrophic cardiomyopathy.
- name: Respiratory insufficiency
  description: >-
    Respiratory function may be impaired due to involvement of respiratory
    muscles, especially in severe/early-onset phenotypes, and may require
    respiratory aids.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory function may be impaired in some individuals"
    explanation: GeneReviews documents respiratory impairment in some individuals with EDMD.

biochemical:
- name: Elevated serum creatine kinase
  presence: INCREASED
  biomarker_term:
    preferred_term: Creatine Kinase
    term:
      id: NCIT:C113245
      label: Creatine Kinase
  notes: >-
    Serum creatine kinase is often mildly to moderately elevated in EDMD,
    reflecting ongoing muscle fiber damage, though it can be normal. CK
    elevation in EDMD is typically modest compared with other muscular
    dystrophies; clinical and genetic evaluation, not CK, establishes the
    diagnosis.

genetic:
- name: EMD
  gene_term:
    preferred_term: EMD
    term:
      id: hgnc:3331
      label: EMD
  association: Loss-of-function variants (X-linked recessive)
  relationship_type: CAUSATIVE
  subtype: EDMD1
  notes: >-
    Hemizygous EMD variants (typically loss of function, with absent or reduced
    emerin) cause X-linked EDMD1.
  evidence:
  - reference: PMID:7894480
    reference_title: "Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations result in the loss of all or part of the protein. The EDMD gene encodes a novel serine-rich protein termed emerin"
    explanation: Original identification of loss-of-function EMD (emerin) mutations in X-linked EDMD.
- name: LMNA
  gene_term:
    preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  association: Heterozygous (dominant) variants
  relationship_type: CAUSATIVE
  subtype: EDMD2
  notes: >-
    Heterozygous LMNA variants cause autosomal dominant EDMD2, often de novo. The
    biallelic recessive form is recorded as the separate EDMD3 record below,
    because the two differ in inheritance, allele dose and MONDO class while
    sharing the gene.
  evidence:
  - reference: PMID:10080180
    reference_title: "Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder."
    explanation: Establishes LMNA (lamin A/C, a nuclear lamina component) as a cause of EDMD.
- name: LMNA biallelic
  gene_term:
    preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  association: Biallelic (recessive) variants
  relationship_type: CAUSATIVE
  subtype: EDMD3
  notes: >-
    Biallelic LMNA variants cause autosomal recessive EDMD3. In the original
    report the affected individual was homozygous and both first-cousin parents
    were heterozygous and unaffected on clinical and cardiological assessment,
    which is what distinguishes this record from the dominant EDMD2 one above.
  evidence:
  - reference: PMID:10739764
    reference_title: "Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results show that LMNA mutations are also responsible for the recessive form of the disease."
    explanation: >-
      Original demonstration that LMNA variants cause autosomal recessive EDMD in
      addition to the dominant form.
- name: SYNE1
  gene_term:
    preferred_term: SYNE1
    term:
      id: hgnc:17089
      label: SYNE1
  association: Heterozygous (dominant) variants
  relationship_type: CAUSATIVE
  subtype: EDMD4
  notes: >-
    Heterozygous SYNE1 (nesprin-1) variants cause autosomal dominant EDMD4.
    Nesprin-1 is an outer-nuclear-membrane spectrin-repeat LINC-complex protein;
    variants disrupt nuclear envelope integrity and mislocalize emerin/SUN2.
  evidence:
  - reference: PMID:17761684
    reference_title: "Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
    explanation: Identification of SYNE1 (nesprin-1) mutations in EDMD probands.
- name: SYNE2
  gene_term:
    preferred_term: SYNE2
    term:
      id: hgnc:17084
      label: SYNE2
  association: Heterozygous (dominant) variants
  relationship_type: CAUSATIVE
  subtype: EDMD5
  notes: >-
    Heterozygous SYNE2 (nesprin-2) variants cause autosomal dominant EDMD5.
    Nesprin-2 is an outer-nuclear-membrane spectrin-repeat LINC-complex protein
    that, like nesprin-1, links the nucleoskeleton to the cytoskeleton.
  evidence:
  - reference: PMID:41136957
    reference_title: "A Sri Lankan boy with Emery-Dreifuss muscular dystrophy 5 presenting during infancy with persistent transaminitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The whole exome sequencing detected a missense splice region heterozygous variant of the SYNE2 gene, confirming Emery-Dreifuss muscular dystrophy 5."
    explanation: >-
      SYNE2-specific attribution of EDMD5 in the report's own proband, which the
      shared nesprin screening sentence below cannot supply on its own.
  - reference: PMID:17761684
    reference_title: "Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations."
    explanation: Identification of SYNE2 (nesprin-2) mutations in EDMD probands.
- name: FHL1
  gene_term:
    preferred_term: FHL1
    term:
      id: hgnc:3702
      label: FHL1
  association: Hemizygous variants (X-linked)
  relationship_type: CAUSATIVE
  subtype: EDMD6
  notes: >-
    FHL1 variants cause X-linked EDMD6, a scapulo-peroneal/axial myopathy with
    joint contractures and cardiac disease that can include conduction defects,
    arrhythmias, and hypertrophic cardiomyopathy.
  evidence:
  - reference: PMID:19716112
    reference_title: "Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy."
    explanation: Establishes FHL1 as a cause of X-linked EDMD with hypertrophic cardiomyopathy.
- name: TMEM43
  gene_term:
    preferred_term: TMEM43
    term:
      id: hgnc:28472
      label: TMEM43
  association: Heterozygous (dominant) variants
  relationship_type: CAUSATIVE
  subtype: EDMD7
  notes: >-
    Heterozygous TMEM43 (LUMA) variants cause autosomal dominant EDMD7-related
    myopathy. Mutant LUMA fails to oligomerize, reducing nuclear emerin/SUN2
    staining and producing abnormally shaped nuclei.
  evidence:
  - reference: PMID:21391237
    reference_title: "TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients."
    explanation: Identification of TMEM43 (LUMA) mutations in EDMD-related myopathy.

inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    EDMD1 (EMD) and EDMD6 (FHL1) are inherited in an X-linked manner. Males are
    primarily affected; heterozygous female carriers are usually asymptomatic but
    are at risk of developing cardiac disease.
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EDMD is inherited in an X-linked (XL), autosomal dominant (AD), or (rarely) autosomal recessive (AR) manner."
    explanation: GeneReviews documents X-linked, autosomal dominant, and rare autosomal recessive inheritance.
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    EDMD2 (LMNA) and EDMD4/5/7 (SYNE1/SYNE2/TMEM43) are inherited in an
    autosomal dominant manner; a high proportion of LMNA-related AD-EDMD cases
    arise de novo.
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixty-five percent of individuals with LMNA-related AD-EDMD have a de novo pathogenic variant."
    explanation: GeneReviews documents autosomal dominant inheritance with a high de novo rate for LMNA-related EDMD.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Rare autosomal recessive EDMD3 results from biallelic LMNA variants.
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(more rarely) biallelic pathogenic variants in LMNA or SUN1"
    explanation: GeneReviews documents rare autosomal recessive EDMD from biallelic LMNA variants.

treatments:
- name: Cardiac pacemaker implantation
  description: >-
    Pacemaker implantation is indicated for advanced conduction disturbances
    (e.g., high-grade AV block, sinus node dysfunction). Note that pacing alone
    does not prevent sudden death from ventricular arrhythmia.
  treatment_term:
    preferred_term: pacemaker implantation
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment for cardiac disease can include antiarrhythmic drugs, oral anticoagulation, ablation procedures, cardiac pacemaker, implantable cardioverter-defibrillator"
    explanation: GeneReviews lists cardiac pacemaker among standard cardiac treatments for EDMD.
- name: Implantable cardioverter-defibrillator placement
  description: >-
    ICD implantation is considered, particularly in LMNA-related disease and
    when pacing is needed, because pacemakers alone do not prevent sudden death
    from malignant ventricular arrhythmia. Early ICD implantation and heart
    failure drug therapy are recommended in male EMD variant carriers with
    cardiac disease.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:37639473
    reference_title: "Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease."
    explanation: Recommends early ICD implantation in EMD variant carriers with cardiac disease.
- name: Anticoagulant therapy
  description: >-
    Oral anticoagulation is used when atrial fibrillation/flutter or atrial
    standstill is present, given the high thromboembolic risk.
  treatment_term:
    preferred_term: anticoagulant agent therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment for cardiac disease can include antiarrhythmic drugs, oral anticoagulation"
    explanation: GeneReviews lists oral anticoagulation among standard cardiac treatments for EDMD.
- name: Physical therapy and stretching
  description: >-
    Physical therapy and stretching are used to prevent and manage contractures,
    with orthopedic surgery to release contractures or manage scoliosis as needed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical therapy and stretching to prevent contractures"
    explanation: GeneReviews recommends physical therapy and stretching to prevent contractures.
- name: Orthopedic surgery for contractures and scoliosis
  description: >-
    Surgery to release contractures and to manage scoliosis is performed as
    needed.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery to release contractures and manage scoliosis as needed"
    explanation: GeneReviews recommends surgery for contracture release and scoliosis management.
- name: Heart transplantation
  description: >-
    Heart transplantation is appropriate for the end stages of heart failure.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heart transplantation for the end stages of heart failure as appropriate"
    explanation: GeneReviews recommends heart transplantation for end-stage heart failure.
- name: Respiratory support
  description: >-
    Respiratory aids — including respiratory muscle training, assisted coughing
    techniques, and mechanical (noninvasive) ventilation — are used as needed in
    those with respiratory compromise.
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory aids (respiratory muscle training, assisted coughing techniques, mechanical ventilation) as needed"
    explanation: GeneReviews recommends respiratory aids including mechanical ventilation as needed.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the X-linked, autosomal dominant, or rare
    autosomal recessive inheritance, recurrence risk, cascade testing of
    relatives at risk, and reproductive options including prenatal and
    preimplantation genetic testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the EDMD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible."
    explanation: GeneReviews documents the role of genetic testing and counseling for at-risk relatives and reproduction.
- name: Peri-operative anesthetic precautions (malignant hyperthermia avoidance)
  description: >-
    GeneReviews identifies safety-critical agents and circumstances to avoid in
    EDMD. Triggering agents for malignant hyperthermia — depolarizing muscle
    relaxants (succinylcholine) and volatile anesthetic drugs (e.g., halothane,
    isoflurane) — should be avoided during anesthesia, and obesity should be
    avoided. Anesthetic plans should also account for cardiac conduction disease
    and arrhythmia risk in affected individuals.
  treatment_term:
    preferred_term: anesthesia procedure (malignant hyperthermia trigger avoidance)
    term:
      id: NCIT:C15181
      label: Anesthesia Procedure
  evidence:
  - reference: PMID:20301609
    reference_title: "Emery-Dreifuss Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Triggering agents for malignant hyperthermia, such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane); obesity."
    explanation: GeneReviews lists malignant-hyperthermia triggering agents and obesity among agents/circumstances to avoid in EDMD.

clinical_trials:
- name: NCT03439514
  phase: PHASE_III
  status: TERMINATED
  description: >-
    REALM-DCM — a Phase 3, multinational, randomized, placebo-controlled study of
    ARRY-371797 (PF-07265803), an oral p38 MAPK inhibitor, in patients with
    symptomatic dilated cardiomyopathy due to an LMNA (lamin A/C) gene mutation,
    the gene underlying autosomal dominant EDMD2.
  target_phenotypes:
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT03439514
    reference_title: "A Phase 3, Multinational, Randomized, Placebo-controlled Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation (REALM-DCM)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a randomized, double-blind, placebo-controlled study in patients with dilated cardiomyopathy (DCM) due to a mutation of the gene encoding the lamin A/C protein (LMNA)."
    explanation: A Phase 3 LMNA-specific trial directly relevant to the cardiac phenotype of LMNA-related (EDMD2) disease.

datasets: []
📚

References & Deep Research

References

5
PMID:20301609
Emery-Dreifuss Muscular Dystrophy.
No top-level findings curated for this source.
PMID:31840275
Emery-Dreifuss muscular dystrophy.
No top-level findings curated for this source.
PMID:10739764
Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.
No top-level findings curated for this source.
PMID:41136957
A Sri Lankan boy with Emery-Dreifuss muscular dystrophy 5 presenting during infancy with persistent transaminitis.
No top-level findings curated for this source.
PMID:24375709
Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies.
No top-level findings curated for this source.

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Emery–Dreifuss Muscular Dystrophy (EDMD): Comprehensive Disease Characteristics Report
Edison Scientific Literature 60 citations 2026-06-16T10:06:58.542999

Emery–Dreifuss Muscular Dystrophy (EDMD): Comprehensive Disease Characteristics Report

Executive summary

Emery–Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous, primarily Mendelian neuromuscular disorder within the spectrum of nuclear-envelope diseases (laminopathies/nuclear envelopathies), classically defined by a triad of (i) early musculo‑tendinous contractures, (ii) slowly progressive skeletal myopathy (often humero‑peroneal or scapulo‑humeroperoneal distribution), and (iii) cardiac involvement dominated by atrial disease, conduction system disease, arrhythmias, thromboembolism, and variable progression to cardiomyopathy/heart failure and sudden death. (granata2026cardiacinvolvementin pages 2-4, granata2026cardiacinvolvementin pages 4-6, cannie2023emery–dreifussmusculardystrophy pages 2-3)

Recent (2023–2024) literature underscores: (1) a substantial risk of malignant ventricular arrhythmias and end-stage heart failure even in X‑linked EDMD1 (EMD) male carriers, prompting earlier implantable cardioverter‑defibrillator (ICD) consideration; (2) high pediatric risk in early-onset LMNA-related phenotypes with frequent malignant arrhythmias detected by implantable loop recorders; (3) convergent pathophysiology across EDMD genes involving nucleo‑cytoskeletal coupling and mechanotransduction failure, mechanical-stress–induced nuclear damage/DNA damage responses, and transcriptional programs involving fibrosis, metabolism, and splicing; and (4) expanding registry infrastructure and multi‑omics studies aimed at modifier genes and molecular stratification to enable precision medicine. (cannie2023emery–dreifussmusculardystrophy pages 2-3, cesar2023characterizationofcardiac pages 1-2, heras2023metabolicfibroticand pages 1-2, NCT05394506 chunk 1)

1. Disease information

1.1 Concise overview

EDMD is a rare inherited muscular dystrophy characterized by early contractures, progressive muscle weakness/atrophy, and cardiac conduction/arrhythmia complications that may be life‑threatening and can precede prominent skeletal muscle symptoms. (granata2026cardiacinvolvementin pages 2-4, granata2026cardiacinvolvementin pages 9-10)

1.2 Key identifiers

A normalized identifier set extractable from the retrieved sources is provided in the table below.

Identifier system Identifier Entity (disease/subtype/gene) Notes (inheritance/causal gene)
MONDO MONDO:0016830 Emery-Dreifuss muscular dystrophy Overall EDMD disease entity in OpenTargets/Monarch disease mapping; associated targets include LMNA, EMD, FHL1, SYNE1/2, TMEM43. URL: https://platform.opentargets.org/disease/MONDO_0016830 (OpenTargets Search: Emery-Dreifuss muscular dystrophy)
MONDO MONDO:0010680 X-linked Emery-Dreifuss muscular dystrophy X-linked EDMD; OpenTargets links this entity to EMD and FHL1. URL: https://platform.opentargets.org/disease/MONDO_0010680 (OpenTargets Search: Emery-Dreifuss muscular dystrophy)
MONDO MONDO:0021569 Emery-Dreifuss muscular dystrophy 2, autosomal dominant Autosomal dominant EDMD2; linked to LMNA. URL: https://platform.opentargets.org/disease/MONDO_0021569 (OpenTargets Search: Emery-Dreifuss muscular dystrophy)
MONDO MONDO:0013071 Emery-Dreifuss muscular dystrophy 4, autosomal dominant Autosomal dominant EDMD4; linked to SYNE1. URL: https://platform.opentargets.org/disease/MONDO_0013071 (OpenTargets Search: Emery-Dreifuss muscular dystrophy)
MONDO MONDO:0013677 Emery-Dreifuss muscular dystrophy 7, autosomal dominant Autosomal dominant EDMD7; linked to TMEM43. URL: https://platform.opentargets.org/disease/MONDO_0013677 (OpenTargets Search: Emery-Dreifuss muscular dystrophy)
OMIM phenotype OMIM #310300 EDMD1 / classical X-linked EDMD X-linked EDMD caused by EMD variants; explicitly reported in review text as classical X-linked EDMD. DOI source: https://doi.org/10.3390/jcm15093286 (granata2026cardiacinvolvementin pages 1-2)
OMIM phenotype OMIM #181350 EDMD2 / autosomal dominant EDMD Autosomal dominant EDMD caused by LMNA variants; explicitly reported in review text. DOI source: https://doi.org/10.3390/jcm15093286 (granata2026cardiacinvolvementin pages 1-2)
OMIM phenotype OMIM #616516 EDMD3 / autosomal recessive EDMD Rare autosomal recessive EDMD; reported by Rahmuni et al. 2024. DOI source: https://doi.org/10.1159/000538917 (rahmuni2024twomoroccanfamilies pages 1-2)
OMIM gene OMIM #300384 EMD Encodes emerin; major causal gene for EDMD1/X-linked EDMD. DOI source: https://doi.org/10.3390/jcm15093286 (granata2026cardiacinvolvementin pages 1-2)
OMIM gene OMIM #150330 LMNA Encodes lamin A/C; major causal gene for EDMD2/autosomal dominant EDMD. DOI source: https://doi.org/10.3390/jcm15093286 (granata2026cardiacinvolvementin pages 1-2)
OMIM gene OMIM #612048 TMEM43 Gene linked to EDMD7/autosomal dominant EDMD in retrieved review text. DOI source: https://doi.org/10.3390/jcm15093286 (granata2026cardiacinvolvementin pages 4-6)
OMIM gene OMIM #125660 DES Desmin; referenced as related nuclear-cytoskeletal/cardiac phenotype gene in EDMD spectrum review. DOI source: https://doi.org/10.3390/jcm15093286 (granata2026cardiacinvolvementin pages 4-6)
Not extracted from retrieved full text — Orphanet / MeSH / ICD Orphanet ORPHAcode, MeSH descriptor, and ICD-10/ICD-11 codes were not extracted from the retrieved full-text evidence used here. (granata2026cardiacinvolvementin pages 1-2, rahmuni2024twomoroccanfamilies pages 1-2, heller2020emery‐dreifussmusculardystrophy pages 1-2)

Table: This table summarizes the core disease and gene identifiers for Emery-Dreifuss muscular dystrophy and key genetic subtypes, integrating MONDO/OpenTargets and OMIM evidence. It is useful for disease knowledge-base normalization and subtype-to-gene mapping.

Notes on missing identifiers: Orphanet ORPHAcode, MeSH descriptor ID, and ICD‑10/ICD‑11 codes were not extractable from the retrieved full texts in this run; this report therefore flags them as “not extracted” rather than guessing. (heller2020emery‐dreifussmusculardystrophy pages 1-2)

1.3 Synonyms / alternative names

Commonly used descriptors include “Emery–Dreifuss muscular dystrophy,” “EDMD,” “X‑linked EDMD / EDMD1 (emerinopathy),” “autosomal dominant EDMD / EDMD2 (laminopathy),” and “cardiac emerinopathy” for predominantly cardiac EMD phenotypes. (granata2026cardiacinvolvementin pages 10-10, granata2026cardiacinvolvementin pages 4-6)

1.4 Evidence source type

Information synthesized here is derived from aggregated disease-level reviews and systematic reviews, plus human cohorts/case reports, mechanistic in vitro studies in patient cells, and animal models. (cesar2023characterizationofcardiac pages 1-2, heras2023metabolicfibroticand pages 1-2, zhang2023net39protectsmuscle pages 1-2)

2. Etiology

2.1 Disease causal factors

EDMD is primarily genetic, caused by pathogenic variants in nuclear envelope / nuclear lamina / LINC complex and related proteins, with major forms due to EMD (emerin; X‑linked EDMD1) and LMNA (lamin A/C; autosomal dominant EDMD2). (cannie2023emery–dreifussmusculardystrophy pages 2-3, granata2026cardiacinvolvementin pages 1-2)

Additional genes implicated in EDMD spectrum include FHL1, SYNE1/SYNE2, TMEM43, and other nuclear-envelope genes. (granata2026cardiacinvolvementin pages 4-6, heller2020emery‐dreifussmusculardystrophy pages 1-2)

2.2 Risk factors

Primary risk factor: carrying a pathogenic/likely pathogenic variant in a causal gene (e.g., EMD or LMNA). (cannie2023emery–dreifussmusculardystrophy pages 2-3, granata2026cardiacinvolvementin pages 1-2)

Sex as a risk modifier in X‑linked EDMD1: males are predominantly affected for skeletal muscle phenotype; female carriers can develop later-onset cardiac disease. (cannie2023emery–dreifussmusculardystrophy pages 2-3, granata2026cardiacinvolvementin pages 10-10)

2.3 Protective factors

No validated protective genetic variants or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

Not clearly established in the retrieved evidence; mechanistic work supports that mechanical load/stress (an environmental/physiologic exposure in muscle) interacts with nuclear-envelope fragility and LINC complex dysfunction to drive nuclear damage and myopathy. (zhang2023net39protectsmuscle pages 1-2, cenni2024desminandplectin pages 2-4)

3. Phenotypes

3.1 Core clinical phenotype spectrum

Classic triad (definitional): 1) Early joint/tendon contractures (commonly elbows, Achilles, posterior cervical/paraspinal musculature/rigid spine). (granata2026cardiacinvolvementin pages 2-4, granata2026cardiacinvolvementin pages 6-7) 2) Slowly progressive skeletal muscle weakness/atrophy (often humero‑peroneal distribution). (granata2026cardiacinvolvementin pages 2-4, cannie2023emery–dreifussmusculardystrophy pages 2-3) 3) Cardiac involvement: conduction disease, atrial arrhythmias (AF/AFL/AT), atrial standstill, ventricular arrhythmias, thromboembolism, cardiomyopathy/heart failure, sudden death. (granata2026cardiacinvolvementin pages 4-6, granata2026cardiacinvolvementin pages 9-10)

Phenotype heterogeneity: EDMD may present with cardiac-predominant disease or skeletal-predominant disease; skeletal findings can be subtle even when cardiac disease is advanced, especially in LMNA-related disease. (granata2026cardiacinvolvementin pages 9-10, granata2026cardiacinvolvementin pages 10-10)

3.2 Age of onset, severity, progression

  • EDMD spans childhood through adulthood depending on genotype and subtype; early-onset LMNA phenotypes (e.g., early-onset EDMD and L‑CMD) are associated with worse cardiac prognosis in pediatric cohorts. (cesar2023characterizationofcardiac pages 2-3)
  • Disease course is typically slowly progressive for skeletal muscle but may show progressive atrial disease leading to conduction disease and thromboembolism, with risk of malignant ventricular arrhythmias sometimes disproportionate to LVEF impairment. (granata2026cardiacinvolvementin pages 22-24, granata2026cardiacinvolvementin pages 18-20)

3.3 Frequencies / statistics (selected recent data)

  • In an EMD-variant carrier cohort, male carriers had MVA in 23.7% and end-stage HF in 13.2% over a median ~65 months follow-up; female carriers had ~42.8% developing a cardiac phenotype later (median age ~58.6 years). (cannie2023emery–dreifussmusculardystrophy pages 2-3)
  • In pediatric LMNA-related muscular dystrophy (including EDMD), malignant arrhythmias were detected in ~20% (5/28), and DCM developed in 6/28. (cesar2023characterizationofcardiac pages 1-2)

3.4 Quality of life impact

QoL impacts are primarily mediated through progressive contractures, weakness (mobility limitations), and cardiac morbidity (arrhythmias, device implantation, thromboembolism risk) and, in advanced cases, respiratory failure/dysphagia. A supportive-care case report suggests that severe dysphagia/malnutrition can be profound (BMI 8.36 kg/m2) and that nutritional intervention can improve perceived well-being. (valoriani2024effectofnutritional pages 2-3, valoriani2024effectofnutritional pages 3-4)

3.5 Suggested HPO terms (non-exhaustive)

  • Joint contracture (HP:0001371); Elbow contracture (HP:0002996); Achilles tendon contracture (HP:0001771); Rigid spine (HP:0003307) (supported conceptually by classic triad descriptions). (granata2026cardiacinvolvementin pages 2-4, granata2026cardiacinvolvementin pages 6-7)
  • Muscle weakness (HP:0001324); Muscle atrophy (HP:0003202); Scapular winging (HP:0003697) (distribution-dependent). (granata2026cardiacinvolvementin pages 2-4)
  • Cardiac conduction defect (HP:0001678); Atrial fibrillation (HP:0005110); Ventricular tachycardia (HP:0004756); Dilated cardiomyopathy (HP:0001644); Sudden cardiac death (HP:0001645); Stroke (HP:0001297). (granata2026cardiacinvolvementin pages 4-6, granata2026cardiacinvolvementin pages 17-18)

4. Genetic / molecular information

4.1 Causal genes (core)

  • EMD (emerin): causes X‑linked EDMD1 (OMIM #310300; EMD gene OMIM #300384). (granata2026cardiacinvolvementin pages 1-2)
  • LMNA (lamin A/C): causes autosomal dominant EDMD2 (OMIM #181350; LMNA gene OMIM #150330); autosomal recessive EDMD3 is also described in OMIM #616516. (granata2026cardiacinvolvementin pages 1-2, rahmuni2024twomoroccanfamilies pages 1-2)

4.2 Additional genes in EDMD spectrum

OMIM-recognized and review-supported genes include SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, TTN, among others; EDMD4/5 are linked to SYNE1/SYNE2 and EDMD7 to TMEM43 (OMIM #612048). (heller2020emery‐dreifussmusculardystrophy pages 1-2, granata2026cardiacinvolvementin pages 4-6)

4.3 Pathogenic variant examples from recent reports

  • EMD frameshift in EDMD1 case: c.153dupC / p.Ser52Glufs*9 with absent emerin on biopsy. (panicucci2023earlymusclemri pages 1-2)
  • LMNA deletion in EDMD supportive-care case: LMNA c.523_537del. (valoriani2024effectofnutritional pages 2-3)

Variant-level population allele frequencies and ClinVar classifications were not extracted in this run.

4.4 Modifier genes

A dedicated interventional multi‑omics study is recruiting to identify genetic modifiers of LMNA striated muscle laminopathies using WGS, RNA‑seq, chromatin assays, and proteomics with composite severity endpoints. (NCT05394506 chunk 1)

4.5 Epigenetics

In mechanically stretched LMNA-mutant (EDMD2) myoblasts, reduced H3K9 acetylation was reported alongside mechanotransduction defects, consistent with altered chromatin regulation downstream of nuclear-lamina dysfunction. (cenni2024desminandplectin pages 10-11)

5. Environmental information

No consistent exogenous environmental toxin/infectious triggers were identified in the retrieved evidence. Mechanical strain/load is the key physiologic “environmental” input interacting with nuclear-envelope fragility in mechanistic models. (zhang2023net39protectsmuscle pages 1-2, cenni2024desminandplectin pages 2-4)

6. Mechanism / pathophysiology

6.1 Current understanding: nuclear envelope disease model

EDMD mechanisms converge on disrupted nucleo‑cytoskeletal coupling (LINC complex dysfunction), impaired mechanotransduction, nuclear fragility, altered gene expression programs, fibrosis, and electrical instability in cardiomyocytes—manifesting clinically as atrial myopathy, conduction disease, ventricular arrhythmias, and cardiomyopathy/heart failure. (granata2026cardiacinvolvementin pages 4-6, granata2026cardiacinvolvementin pages 9-10)

6.2 Mechanistic causal chain (illustrative)

Genetic variant (EMD/LMNA/etc.) → nuclear lamina/inner nuclear membrane/LINC complex dysfunction → impaired force transmission & nuclear mechanics → mechanically induced nuclear deformation/rupture and DNA damage responses → maladaptive transcriptional reprogramming (fibrosis/metabolism/splicing; myogenic signaling) → muscle fiber degeneration and fibro‑fatty remodeling → progressive weakness/contractures; and in the heart, atrial disease/conduction block/arrhythmias → thromboembolism, HF, sudden death. (granata2026cardiacinvolvementin pages 4-6, heras2023metabolicfibroticand pages 1-2, zhang2023net39protectsmuscle pages 9-11)

6.3 Recent developments (2023–2024)

Mechanical stress → DNA damage axis (NET39): Muscle-specific Net39 knockout mice recapitulated EDMD-like muscle wasting and abnormal nuclei, with stretch-induced DNA damage in Net39-deficient myoblasts; in a laminopathy model (Lmna ΔK32), AAV-mediated Net39 delivery (1×10^14 vg/kg) reduced γH2A.X-positive nuclei and improved survival metrics, supporting a therapeutically tractable mechanotransduction/DNA-damage mechanism. (zhang2023net39protectsmuscle pages 1-2, zhang2023net39protectsmuscle pages 11-14)

Perinuclear cytoskeletal anchoring defects (desmin/plectin): Under cyclic stretch, control myoblasts recruit desmin and plectin to the nuclear envelope via lamin A/C; EDMD2 myoblasts show marked loss of recruitment (15–19% vs 55% controls) and ~60% failure of proper nuclear reorientation, linking LMNA mutations to defective mechanosignaling. (cenni2024desminandplectin pages 7-10, cenni2024desminandplectin pages 10-11)

Transcriptomic pathway convergence across EDMD genes: RNA-seq of EDMD-spectrum patient myotubes across 7 causal genes identified 1,127 DE genes (894 up, 233 down) when grouped, with pathway-level convergence on fibrosis/ECM, metabolism, myogenic signaling, and splicing; patients segregated into three molecular subgroups potentially correlating with clinical presentation. (heras2023metabolicfibroticand pages 1-2, heras2023metabolicfibroticand pages 14-15)

6.4 Suggested GO biological process terms (examples)

  • Mechanotransduction (GO:0009612 conceptually), response to mechanical stimulus (GO:0009612), DNA damage response (GO:0006974), regulation of transcription (GO:0006355), extracellular matrix organization (GO:0030198), muscle cell differentiation (GO:0042692), RNA splicing (GO:0008380). (heras2023metabolicfibroticand pages 1-2, zhang2023net39protectsmuscle pages 9-11)

6.5 Suggested Cell Ontology (CL) cell types

  • Skeletal muscle myoblast (CL:0000056), skeletal muscle fiber/myocyte (CL:0000746), cardiomyocyte (CL:0000746 conceptually for muscle; cardiomyocyte CL:0000746 is generic; more specific could be CL:0002494 ventricular cardiomyocyte, CL:0002497 atrial cardiomyocyte), cardiac conduction system cell (conceptual). (granata2026cardiacinvolvementin pages 4-6, cenni2024desminandplectin pages 2-4)

7. Anatomical structures affected

7.1 Organ and system level

  • Primary: skeletal muscle system; heart (atria/conduction system; ventricles variably). (granata2026cardiacinvolvementin pages 2-4, granata2026cardiacinvolvementin pages 9-10)
  • Secondary: thromboembolic cerebrovascular complications (stroke), respiratory system involvement in severe/early-onset phenotypes. (granata2026cardiacinvolvementin pages 17-18, panicucci2023earlymusclemri pages 2-3)

7.2 Tissue/cell level

  • Striated muscle (skeletal and cardiac) and associated connective tissue remodeling/fibrosis. (granata2026cardiacinvolvementin pages 4-6, heras2023metabolicfibroticand pages 1-2)

7.3 Subcellular localization (GO cellular component suggestions)

  • Nuclear envelope (GO:0005635), nuclear lamina (GO:0005652), inner nuclear membrane (GO:0005642), LINC complex (GO:0030864). (granata2026cardiacinvolvementin pages 4-6, cenni2024desminandplectin pages 2-4)

7.4 UBERON anatomical structure suggestions

  • Skeletal muscle tissue (UBERON:0001134), heart (UBERON:0000948), atrium (UBERON:0002088), ventricle (UBERON:0002084), tendon (UBERON:000 tendon), cervical spine/paraspinal region (conceptual) supported by rigid spine and contractures. (granata2026cardiacinvolvementin pages 6-7, granata2026cardiacinvolvementin pages 9-10)

8. Temporal development

  • Onset: variable; childhood to adult. Early-onset neurologic symptoms may correlate with worse cardiac prognosis in LMNA-related phenotypes. (cesar2023characterizationofcardiac pages 2-3)
  • Progression: progressive atrial disease and conduction system involvement can evolve to atrial standstill and bradyarrhythmias; ventricular arrhythmias and HF progression vary by genotype (LMNA often more malignant ventricular/HF trajectory). (granata2026cardiacinvolvementin pages 9-10, granata2026cardiacinvolvementin pages 10-10)

9. Inheritance and population

9.1 Inheritance patterns

  • X‑linked recessive (EMD/EDMD1). (granata2026cardiacinvolvementin pages 1-2)
  • Autosomal dominant (LMNA/EDMD2; other genes). (granata2026cardiacinvolvementin pages 1-2, heller2020emery‐dreifussmusculardystrophy pages 1-2)
  • Autosomal recessive is rare (EDMD3 reported; OMIM #616516). (rahmuni2024twomoroccanfamilies pages 1-2)

9.2 Epidemiology

Prevalence estimates are variable across sources and regions. Granata 2026 summarizes ranges from ~1:400,000 to 1.3–2 per 100,000 (≈1:50,000–1:77,000), with other estimates around 0.39 per 100,000 and ~1:250,000 births; X-linked EDMD reported ~1:100,000 male births in some data. (granata2026cardiacinvolvementin pages 6-7)

10. Diagnostics

10.1 Clinical and cardiologic testing

A contemporary diagnostic approach integrates neuromuscular findings (contractures, humeroperoneal weakness/rigid spine) with structured cardiac assessment and genetic confirmation. (granata2026cardiacinvolvementin pages 9-10)

Cardiac tests: serial 12‑lead ECG, prolonged rhythm monitoring (Holter; device diagnostics; ILR), echocardiography, and cardiac MRI with tissue characterization when available. (granata2026cardiacinvolvementin pages 9-10, granata2026cardiacinvolvementin pages 21-22)

A pediatric LMNA cohort used systematic baseline assessment including echocardiography, ECG, EPS, and long-term ILR implantation with home monitoring, enabling detection of malignant arrhythmias requiring ICD implantation. (cesar2023characterizationofcardiac pages 3-4, cesar2023characterizationofcardiac pages 1-2)

Muscle biopsy: can demonstrate emerin deficiency by immunofluorescence in EDMD1; a pediatric EDMD1 case showed absence of nuclear emerin staining with mild dystrophic changes. (panicucci2023earlymusclemri pages 3-4, panicucci2023earlymusclemri pages 1-2)

Imaging (skeletal muscle MRI): muscle MRI can show selective patterns (e.g., lower-leg anterolateral compartment and medial gastrocnemius involvement) but patterns are heterogeneous and require cohort-level validation. (panicucci2023earlymusclemri pages 1-2, panicucci2023earlymusclemri pages 4-4)

10.2 Genetic testing strategy

Genetic testing is central for diagnosis, family screening, and risk stratification; targeted panels and Sanger sequencing for cascade screening are used in cohort studies, and multi-gene NGS is emphasized due to intra-/inter-familial heterogeneity. (cannie2023emery–dreifussmusculardystrophy pages 2-3, rahmuni2024twomoroccanfamilies pages 1-2)

10.3 Differential diagnosis

Not systematically extracted in this run; however, LMNA phenotypes overlap EDMD, limb-girdle muscular dystrophy 1B, and congenital muscular dystrophy presentations, requiring careful phenotyping and genetics. (cesar2023characterizationofcardiac pages 1-2)

11. Outcomes / prognosis

Cardiac disease is a major determinant of morbidity and mortality, including thromboembolism, heart failure, and sudden cardiac death. (granata2026cardiacinvolvementin pages 9-10, granata2026cardiacinvolvementin pages 17-18)

Systematic-review incidence rates (LMNA/EMD cardiolaminopathies): AF/AFL/AT 6.1–13.9 events/100 patient‑years; malignant ventricular arrhythmias up to 10.2/100 pt‑yrs; advanced conduction disturbances 3.2–7.7/100 pt‑yrs; thromboembolism up to 8.9/100 pt‑yrs; and all-cause mortality IR 0.6–4.8/100 pt‑yrs in LMNA cohorts, with many deaths due to SCD or HF. (valenti2022clinicalprofilearrhythmias pages 1-2, valenti2022clinicalprofilearrhythmias pages 12-14)

12. Treatment

12.1 Current applications / real-world implementation

Cardiac management (core): - Lifelong structured surveillance with ECG + prolonged rhythm monitoring, echocardiography, and CMR when available. (granata2026cardiacinvolvementin pages 22-24, granata2026cardiacinvolvementin pages 21-22) - Anticoagulation when AF/AFL occurs; consider anticoagulation in atrial standstill given high thromboembolic risk and reports of stroke even without documented atrial arrhythmia in LMNA cohorts. (valenti2022clinicalprofilearrhythmias pages 14-15, granata2026cardiacinvolvementin pages 17-18) - Device therapy: pacemaker for conduction disease when indicated, but pacemaker alone does not prevent sudden death from ventricular arrhythmias; ICD should be considered, particularly when pacing is needed and in LMNA-related disease based on risk models and additional markers beyond LVEF thresholds. (granata2026cardiacinvolvementin pages 18-20, valenti2022clinicalprofilearrhythmias pages 14-15)

Supportive neuromuscular care: contracture management (stretching/rehabilitation; orthopedic interventions in selected cases) and monitoring for respiratory/dysphagia complications. (panicucci2023earlymusclemri pages 2-3, valoriani2024effectofnutritional pages 2-3)

Nutrition as supportive care: in severe dysphagia/malnutrition, long-term home parenteral nutrition (TPN) was feasible in a case report, increasing weight by 8.5 kg at one year and maintaining it for 6 years. (valoriani2024effectofnutritional pages 1-2, valoriani2024effectofnutritional pages 4-5)

12.2 MAXO term suggestions (examples)

  • Implantable cardioverter-defibrillator implantation (MAXO: device implantation concept), pacemaker implantation, anticoagulant therapy, heart failure pharmacotherapy (ACE inhibitor/ARNI/beta blocker/mineralocorticoid receptor antagonist conceptually), physical therapy/rehabilitation, nutritional support/parenteral nutrition. (valenti2022clinicalprofilearrhythmias pages 14-15, valoriani2024effectofnutritional pages 1-2)

12.3 Experimental / clinical trials

Key EDMD/laminopathy trial/registry infrastructure identified: - NCT03058185 (OPALE): French observational registry of laminopathies/emerinopathies (LMNA and/or EMD pathogenic mutations), target enrollment 800, yearly comprehensive evaluations up to 10 years to define natural history, complications, and prognostic factors. URL: https://clinicaltrials.gov/study/NCT03058185 (NCT03058185 chunk 1) - NCT05394506: interventional study collecting muscle/skin biopsies for multi‑omics to identify modifier genes in LMNA striated muscle laminopathies; endpoints include composite skeletal and cardiac severity. URL: https://clinicaltrials.gov/study/NCT05394506 (NCT05394506 chunk 1) - NCT03439514: ARRY‑371797 (PF‑07265803) phase 3 program for LMNA dilated cardiomyopathy; registry record indicates published phase 3 REALM‑DCM results exist and provides data-sharing statement (consult linked publications for numeric outcomes). URL: https://clinicaltrials.gov/study/NCT03439514 (NCT03439514 chunk 5)

13. Prevention

Primary prevention (preventing occurrence) is not applicable for germline Mendelian EDMD except via reproductive options.

Secondary prevention: cascade genetic screening of relatives and early cardiac surveillance to prevent sudden death and thromboembolism via early device/anticoagulation decisions. (granata2026cardiacinvolvementin pages 9-10, NCT03058185 chunk 1)

Tertiary prevention: management of arrhythmias/conduction disease (ICD/PM), anticoagulation for AF/AFL/atrial standstill, contracture management, respiratory/nutrition support. (granata2026cardiacinvolvementin pages 17-18, valoriani2024effectofnutritional pages 1-2)

14. Other species / natural disease

Not identified in retrieved evidence.

15. Model organisms

Mechanistic and preclinical models include: - Mouse Net39 conditional knockout with EDMD-like skeletal muscle pathology and mechanical-stress–induced DNA damage; and AAV rescue experiments in Lmna ΔK32 mice, supporting the feasibility of gene delivery approaches targeting nuclear-envelope protective pathways. (zhang2023net39protectsmuscle pages 1-2, zhang2023net39protectsmuscle pages 11-14)

Recent quantitative highlights (2023–2024)

Study (year; journal) Population/model (human/animal/in vitro) N Key findings (with quantitative stats) Relevance (diagnosis/prognosis/mechanism/treatment) URL/DOI
Cesar 2023; Frontiers in Cell and Developmental Biology Human pediatric LMNA-related muscular dystrophy cohort (EDMD, L-CMD, LGMD1B, mild weakness) 28 patients from 27 families Median age 8.5 years (IQR 4–12.5); 13 EDMD, 11 L-CMD, 2 LGMD1B, 2 mild weakness. DCM developed in 6 patients; malignant arrhythmias in 5 patients (20%), 4 with concomitant DCM; arrhythmias detected by implantable loop recorder (ILR) and triggered ICD implantation. Baseline work-up included echo, 12-lead ECG, electrophysiology study, and ILR home monitoring. Early-onset EDMD had worse cardiac prognosis. (cesar2023characterizationofcardiac pages 1-2, cesar2023characterizationofcardiac pages 2-3, cesar2023characterizationofcardiac pages 3-4) Prognosis; cardiac surveillance; pediatric diagnosis https://doi.org/10.3389/fcell.2023.1142937
Cannie 2023; European Heart Journal Human EMD variant carriers (EDMD1) with longitudinal cardiac follow-up 38 male, 21 female carriers Among males, 9/38 (23.7%) developed malignant ventricular arrhythmia (MVA) and 5/38 (13.2%) developed end-stage heart failure (ESHF) during median follow-up 65.0 months (IQR 24.3–109.5). No female carrier developed MVA/ESHF, but 9/21 (42.8%) developed a cardiac phenotype at median age 58.6 years (IQR 53.2–60.4). Incidence rates in male carriers with cardiac phenotype: MVA 4.8 per 100 person-years; ESHF 2.4 per 100 person-years; MVA risk similar to LMNA cardiac cohort (6.6 per 100 person-years). (cannie2023emery–dreifussmusculardystrophy pages 2-3) Prognosis; risk stratification; ICD/HF therapy implications https://doi.org/10.1093/eurheartj/ehad561
de las Heras 2023; Human Molecular Genetics Human EDMD-spectrum patient myotubes; RNA-seq/pathway analysis 10 patients, 7 genes; 2 controls RNA-seq across 10 unrelated EDMD-spectrum patients with mutations in LMNA, EMD, FHL1, SUN1, SYNE1, PLPP7, TMEM214. Grouping all patients identified 1,127 differentially expressed genes (894 upregulated, 233 downregulated). Individual patients had 310–2651 upregulated and 429–2384 downregulated genes; all samples had 56–94 million paired-end reads. Pathways converged on fibrosis/ECM, metabolism, myogenesis/alternate differentiation, and splicing; patient signatures segregated into 3 subgroups. (heras2023metabolicfibroticand pages 2-3, heras2023metabolicfibroticand pages 1-2) Mechanism; biomarker discovery; molecular stratification https://doi.org/10.1093/hmg/ddac264
Zhang 2023; Journal of Clinical Investigation Mouse Net39 conditional knockout, human EDMD biopsies, stretched myoblasts Multiple cohorts; e.g., muscle weight n=9–13/group, RNA-seq n=3/group, rescue n=3–4/group Net39 cKO recapitulated EDMD-like muscle wasting, impaired contractility, abnormal myonuclei, and DNA damage. Bulk RNA-seq in cKO muscle showed 318 upregulated and 112 downregulated genes, with p53 signaling prominent. Human EDMD biopsies showed ~80% of small angular fibers positive for γH2A.X. AAV-Net39 rescue at 1×10^14 vg/kg (P2 facial vein) restored Net39 levels, reduced centralized nuclei and γH2A.X-positive nuclei, improved myofiber area, and extended survival in Lmna ΔK32 mice. (zhang2023net39protectsmuscle pages 11-14, zhang2023net39protectsmuscle pages 1-2, zhang2023net39protectsmuscle pages 9-11, zhang2023net39protectsmuscle pages 6-8) Mechanism; preclinical gene therapy https://doi.org/10.1172/JCI163333
Cenni 2024; Cells Human control and EDMD2 (LMNA-mutant) myoblasts under cyclic stretch In vitro; multiple cell-line comparisons Under 10% sinusoidal strain at 1 Hz for 4 h, desmin recruitment to the nuclear rim after stretch was 15%, 16%, and 19% in EDMD2 lines versus 55% in controls; ~35% of EDMD2 cells showed cytoplasmic desmin disorganization. About 60% of EDMD2 nuclei failed normal anisotropic reorientation and instead aligned parallel to stretch. Lamin A/C knockdown reduced desmin recruitment from ~65% to ~30%; plectin-1 recruitment and lamin A/C–SUN1 interaction were also reduced. (cenni2024desminandplectin pages 7-10, cenni2024desminandplectin pages 5-7, cenni2024desminandplectin pages 10-11, cenni2024desminandplectin pages 2-4) Mechanotransduction; nuclear-cytoskeletal coupling https://doi.org/10.3390/cells13020162
Panicucci 2023; Neuropediatrics Human pediatric EDMD1 case report 1 13-year-old boy with EMD c.153dupC/p.Ser52Glufs*9, absent emerin on biopsy. Functional metrics: 6-minute walk test 409 m; North Star 28/34; pulmonary function FVC 2.7 L (76%) and FEV1 2.4 L (83%). MRI showed mild diffuse thigh involvement with preferential lower-leg involvement of tibialis anterior, extensor digitorum longus, peroneus longus, and medial gastrocnemius; 24-h Holter found rhythm abnormalities requiring β-blocker therapy. (panicucci2023earlymusclemri pages 3-4, panicucci2023earlymusclemri pages 2-3, panicucci2023earlymusclemri pages 1-2) Diagnosis; imaging phenotype; early natural history https://doi.org/10.1055/s-0043-1768989
Valoriani 2024; Frontiers in Nutrition Human EDMD supportive-care case report 1 26-year-old male with LMNA c.523_537del and severe malnutrition: weight 22.5 kg, height 1.64 m, BMI 8.36 kg/m², oral intake ~500–600 kcal/day. TPN (Smofkabiven® 986 mL/day = 900 kcal non-protein + 50 g amino acids) led to +8.5 kg at 1 year with stable weight over 6 years; no PICC-related infections and no heart failure during follow-up. (valoriani2024effectofnutritional pages 1-2, valoriani2024effectofnutritional pages 4-5, valoriani2024effectofnutritional pages 2-3, valoriani2024effectofnutritional pages 3-4) Treatment; nutrition; quality-of-life support https://doi.org/10.3389/fnut.2024.1343548

Table: This table compiles the main quantitative results from key 2023-2024 EDMD and LMNA-related studies, spanning human cohorts, mechanistic cell studies, animal models, imaging, and supportive care. It is useful for quickly locating concrete statistics relevant to diagnosis, prognosis, pathophysiology, and emerging treatment strategies.

In addition, Cesar et al. Table 2 (pediatric cohort) provides patient-level LVEF/GLS, arrhythmias, and device therapy; cropped table images are available from the source document. (cesar2023characterizationofcardiac media 75cf862c, cesar2023characterizationofcardiac media f6833c29)

Limitations of this tool-based report

  • ICD/ICD-11, MeSH descriptor IDs, and Orphanet ORPHAcode could not be extracted from the retrieved full texts in this run; these should be added by direct database lookup (Orphanet, NLM MeSH Browser, WHO ICD) for a production knowledge base. (heller2020emery‐dreifussmusculardystrophy pages 1-2)
  • Many sections (variant allele frequencies in gnomAD, ClinVar classifications, systematic phenotype frequencies beyond cardiac outcomes, detailed differential diagnosis tables) require additional targeted retrieval.

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