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Emery-Dreifuss muscular dystrophy: a test case for precision medicine.

ABSTRACT: Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of scapulohumeroperoneal muscle weakness, joint contractures, and cardiac defects that include arrhythmias and dilated cardiomyopathy. Although there is a defining group of clinical findings, the proteins responsible and their underlying gene defects leading to EDMD are varied. A common aspect of the gene defects is their involvement in, or with, the nuclear envelope. Treatment approaches are largely based on clinical symptoms. The genetic diversity of EDMD predicts that a cure will ultimately depend upon the individual's defect at the gene level, making this an ideal candidate for a precision medicine approach.

SUBMITTER: Pillers DA

PROVIDER: S-EPMC4771400 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Emery-Dreifuss muscular dystrophy: a test case for precision medicine.

Pillers De-Ann M DA Von Bergen Nicholas H NH

The application of clinical genetics 20160224

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of scapulohumeroperoneal muscle weakness, joint contractures, and cardiac defects that include arrhythmias and dilated cardiomyopathy. Although there is a defining group of clinical findings, the proteins responsible and their underlying gene defects leading to EDMD are varied. A common aspect of the gene defects is their involvement in, or with, the nuclear envelope. Treatment approaches are largely based on clinica ...[more]

PMID: 26966385

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Emery-Dreifuss muscular dystrophy.

Project description:Emery-Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life-threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.

| S-EPMC7154529 | biostudies-literature

Clinical aspects of Emery-Dreifuss muscular dystrophy.

Project description:Emery-Dreifuss muscular dystrophy (EDMD), clinically characterized by scapulo-humero-peroneal muscle atrophy and weakness, multi-joint contractures with spine rigidity and cardiomyopathy with conduction defects, is associated with structural/functional defect of genes that encode the proteins of nuclear envelope, including lamin A and several lamin-interacting proteins. This paper presents clinical aspects of EDMD in context to causative genes, genotype-phenotype correlation and its emplacement within phenotypic spectrum of skeletal muscle diseases associated with envelopathies.

| S-EPMC5973255 | biostudies-literature

Emery-Dreifuss muscular dystrophy: focal point nuclear envelope.

Project description:Purpose of reviewEmery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in EMD encoding emerin and LMNA encoding A-type lamins, proteins of the nuclear envelope. In the past decade, there has been an extraordinary burst of research on the nuclear envelope. Discoveries resulting from this basic research have implications for better understanding the pathogenesis and developing treatments for EDMD.Recent findingsRecent clinical research has confirmed that EDMD is one of several overlapping skeletal muscle phenotypes that can result from mutations in EMD and LMNA with dilated cardiomyopathy as a common feature. Basic research on the nuclear envelope has provided new insights into how A-type lamins and emerin function in force transmission throughout the cell, which may be particularly important in striated muscle. Much of the recent research has focused on the heart and LMNA mutations. Prevalence and outcome studies have confirmed the relative severity of cardiac disease. Robust mouse models of EDMD caused by LMNA mutations has allowed for further insight into pathogenic mechanisms and potentially beneficial therapeutic approaches.SummaryRecent clinical and basic research on EDMD is gradually being translated to clinical practice and possibly novel therapies.

| S-EPMC7550203 | biostudies-literature

Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy.

Project description:Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, only 35% of EDMD cases are genetically elucidated and associated with EMD or LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the FHL1 gene in three informative families belonging to our EMD- and LMNA-negative cohort. Analysis of the FHL1 gene identified seven mutations, in the distal exons of FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. 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. In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy.

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Case Reports: Emery-Dreifuss Muscular Dystrophy Presenting as a Heart Rhythm Disorders in Children.

Project description:Emery-Dreifuss muscular dystrophy (EDMD) is inherited muscle dystrophy often accompanied by cardiac abnormalities in the form of supraventricular arrhythmias, conduction defects and sinus node dysfunction. Cardiac phenotype typically arises years after skeletal muscle presentation, though, could be severe and life-threatening. The defined clinical manifestation with joint contractures, progressive muscle weakness and atrophy, as well as cardiac symptoms are observed by the third decade of life. Still, clinical course and sequence of muscle and cardiac signs may be variable and depends on the genotype. Cardiac abnormalities in patients with EDMD in pediatric age are not commonly seen. Here we describe five patients with different forms of EDMD (X-linked and autosomal-dominant) caused by the mutations in EMD and LMNA genes, presented with early onset of cardiac abnormalities and no prominent skeletal muscle phenotype. The predominant forms of cardiac pathology were atrial arrhythmias and conduction disturbances that progress over time. The presented cases discussed in the light of therapeutic strategy, including radiofrequency ablation and antiarrhythmic devices implantation, and the importance of thorough neurological and genetic screening in pediatric patients presenting with complex heart rhythm disorders.

| S-EPMC8137911 | biostudies-literature

Role of Cdkn2a in the Emery-Dreifuss Muscular Dystrophy Cardiac Phenotype.

Project description:The Cdkn2a locus is one of the most studied tumor suppressor loci in the context of several cancer types. However, in the last years, its expression has also been linked to terminal differentiation and the activation of the senescence program in different cellular subtypes. Knock-out (KO) of the entire locus enhances the capability of stem cells to proliferate in some tissues and respond to severe physiological and non-physiological damages in different organs, including the heart. Emery-Dreifuss muscular dystrophy (EDMD) is characterized by severe contractures and muscle loss at the level of skeletal muscles of the elbows, ankles and neck, and by dilated cardiomyopathy. We have recently demonstrated, using the LMNA Δ8-11 murine model of Emery-Dreifuss muscular dystrophy (EDMD), that dystrophic muscle stem cells prematurely express non-lineage-specific genes early on during postnatal growth, leading to rapid exhaustion of the muscle stem cell pool. Knock-out of the Cdkn2a locus in EDMD dystrophic mice partially restores muscle stem cell properties. In the present study, we describe the cardiac phenotype of the LMNA Δ8-11 mouse model and functionally characterize the effects of KO of the Cdkn2a locus on heart functions and life expectancy.

| S-EPMC8103514 | biostudies-literature

Cardiac dysrhythmias,cardiomyopathy and muscular dystrophy in patients with Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B.

Project description:Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM 310300). A 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed atrial tachycardia with high grade AV block. She was diagnosed as autosomal dominant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. Cardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults.

| S-EPMC2808607 | biostudies-literature

Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy.

Project description:The LMNA gene encodes lamins A and C, two intermediate filament-type proteins that are important determinants of interphase nuclear architecture. Mutations in LMNA lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), which affects skeletal and cardiac muscle. The cellular mechanisms by which mutations in LMNA cause disease have been elusive. Here, we demonstrate that defects in neuromuscular junctions (NMJs) are part of the disease mechanism in AD-EDMD. Two AD-EDMD mouse models show innervation defects including misexpression of electrical activity-dependent genes and altered epigenetic chromatin modifications. Synaptic nuclei are not properly recruited to the NMJ because of mislocalization of nuclear envelope components. AD-EDMD patients with LMNA mutations show the same cellular defects as the AD-EDMD mouse models. These results suggest that lamin A/C-mediated NMJ defects contribute to the AD-EDMD disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD.

| S-EPMC2615092 | biostudies-literature

Perinatal Management of Pregnancy Complicated by Autosomal Dominant Emery-Dreifuss Muscular Dystrophy.

Project description:Introduction Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) is rare compared with other forms of muscular dystrophy and is characterized by cardiac conduction defects. Here, we present the case of a patient diagnosed with AD-EDMD during the first trimester of pregnancy who developed acute preeclampsia and subsequently, congestive heart failure (CHF) following cesarean section. Case A 36-year-old, gravida 0 para 0 woman was diagnosed with AD-EDMD by genetic testing during the first trimester of pregnancy, and she suddenly developed preeclampsia and partial HELLP (hemolytic anemia, elevated liver enzymes, and low platelets) syndrome at 33 weeks of gestation. The patient subsequently developed CHF following cesarean section. Conclusion CHF can occur as a direct result of the cardiac defects arising due to EDMD, and therefore, careful prenatal and postpartum management is recommended for such cases.

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Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice.

Project description:Mutations in the gene encoding the inner nuclear membrane proteins lamins A and C produce cardiac and skeletal muscle dysfunction referred to as Emery Dreifuss muscular dystrophy. Lamins A and C participate in the LINC complex that, along with the nesprin and SUN proteins, LInk the Nucleoskeleton with the Cytoskeleton. Nesprins 1 and 2 are giant spectrin-repeat containing proteins that have large and small forms. The nesprins contain a transmembrane anchor that tethers to the nuclear membrane followed by a short domain that resides within the lumen between the inner and outer nuclear membrane. Nesprin's luminal domain binds directly to SUN proteins. We generated mice where the C-terminus of nesprin-1 was deleted. This strategy produced a protein lacking the transmembrane and luminal domains that together are referred to as the KASH domain. Mice homozygous for this mutation exhibit lethality with approximately half dying at or near birth from respiratory failure. Surviving mice display hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology and cardiac conduction defects develop. The protein components of the LINC complex, including mutant nesprin-1alpha, lamin A/C and SUN2, are localized at the nuclear membrane in this model. However, the LINC components do not normally associate since coimmunoprecipitation experiments with SUN2 and nesprin reveal that mutant nesprin-1 protein no longer interacts with SUN2. These findings demonstrate the role of the LINC complex, and nesprin-1, in neuromuscular and cardiac disease.

| S-EPMC2722216 | biostudies-literature

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