Clinical and Genetic Heterogeneity of Nuclear Envelopathy Related Muscular Dystrophies in an Indian Cohort.

Introduction: Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India. Methods: In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected. Results: Sixteen patients were included with median age at onset of 3 years (range: 1 month - 17 years). Three genes were involved: LMNA (11, 68.75%), EMD (4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654_658dup (EMD) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures. Conclusion: The salient features included ophthalmoparesis and facial weakness in LMNA, prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1.

Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction.

This review presents a comprehensive exploration of the pivotal role played by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, with a particular focus on Nesprin proteins, in cellular mechanics and the pathogenesis of muscular diseases. Distinguishing itself from prior works, the analysis delves deeply into the intricate interplay of the LINC complex, emphasizing its indispensable contribution to maintaining cellular structural integrity, especially in mechanically sensitive tissues such as cardiac and striated muscles. Additionally, the significant association between mutations in Nesprin proteins and the onset of Dilated Cardiomyopathy (DCM) and Emery-Dreifuss Muscular Dystrophy (EDMD) is highlighted, underscoring their pivotal role in disease pathogenesis. Through a comprehensive examination of DCM and EDMD cases, the review elucidates the disruptions in the LINC complex, nuclear morphology alterations, and muscular developmental disorders, thus emphasizing the essential function of an intact LINC complex in preserving muscle physiological functions. Moreover, the review provides novel insights into the implications of Nesprin mutations for cellular dynamics in the pathogenesis of muscular diseases, particularly in maintaining cardiac structural and functional integrity. Furthermore, advanced therapeutic strategies, including rectifying Nesprin gene mutations, controlling Nesprin protein expression, enhancing LINC complex functionality, and augmenting cardiac muscle cell function are proposed. By shedding light on the intricate molecular mechanisms underlying nuclear-cytoskeletal interactions, the review lays the groundwork for future research and therapeutic interventions aimed at addressing genetic muscle disorders.

Desmin and Plectin Recruitment to the Nucleus and Nuclei Orientation Are Lost in Emery-Dreifuss Muscular Dystrophy Myoblasts Subjected to Mechanical Stimulation.

In muscle cells subjected to mechanical stimulation, LINC complex and cytoskeletal proteins are basic to preserve cellular architecture and maintain nuclei orientation and positioning. In this context, the role of lamin A/C remains mostly elusive. This study demonstrates that in human myoblasts subjected to mechanical stretching, lamin A/C recruits desmin and plectin to the nuclear periphery, allowing a proper spatial orientation of the nuclei. Interestingly, 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. While describing a new mechanism of action headed by lamin A/C, these findings show a structural alteration that could be involved in the onset of the muscle defects observed in muscular laminopathies.

COMPREHENSIVE CARDIOVASCULAR THERAPY IN EMERY-DREIFUSS MUSCULAR DYSTROPHY: A CASE REPORT.

A 25-year-old male with known EDMD was referred for the cardiology consultation due to symptoms of heart failure. Echocardiography showed decrease left ventricular ejection fraction (LVEF) and therapy with ramipril, torsemide and rivaroxaban was initiated. Despite initial improvement, the patient later developed presyncope, bradycardia, irregular heartbeat and worsening of dyspnea. Therefore, implantation of resynchronization pacemaker with the function of implantable cardioverter-defibrillator (CRT-D/P) was performed. Ramipril was substituted by sacubitril/valsartan, and mineralocorticoid receptor antagonist and beta-blocker were initiated. Genetic testing found AD mutation in lamin A/C gene LMNA c.746G>A, p.(Arg249Gln). Upon follow-up, the patient demonstrated resolution of dyspnea and reverse remodeling of the left ventricle with complete restoration of the LVEF.

Emerin deficiency does not exacerbate cardiomyopathy in a murine model of Emery-Dreifuss muscular dystrophy caused by an LMNA gene mutation.

Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in genes encoding nuclear envelope proteins, is clinically characterized by muscular dystrophy, early joint contracture, and life-threatening cardiac abnormalities. To elucidate the pathophysiological mechanisms underlying striated muscle involvement in EDMD, we previously established a murine model with mutations in Emd and Lmna (Emd-/-/LmnaH222P/H222P; EH), and reported exacerbated skeletal muscle phenotypes and no notable cardiac phenotypes at 12 weeks of age. We predicted that lack of emerin in LmnaH222P/H222P mice causes an earlier onset and more pronounced cardiac dysfunction at later stages. In this study, cardiac abnormalities of EDMD mice were compared at 18 and 30 weeks of age. Contrary to our expectations, physiological and histological analyses indicated that emerin deficiency causes no prominent differences of cardiac involvement in LmnaH222P/H222P mice. These results suggest that emerin does not contribute to cardiomyopathy progression in LmnaH222P/H222P mice.

Heart transplant anesthetic approach in a patient with Emery Dreyfuss muscular dystrophy: A case report.

Emery-Dreifuss muscular dystrophy is associated with cardiac abnormalities and rarely heart transplantation may be the treatment of choice. In this case, a male patient with Emery- Dreifuss muscular dystrophy developed NYHA class IV heart failure at 33 years of age and was submitted to heart transplantation. Anesthesia was adapted to prevent the development of malignant hyperthermia and rhabdomyolysis. The surgery was a success and the patient's progress was extremely positive with symptomatic improvement. In these patients, is critical to adjust not only his positioning but also the therapy administered in order to reduce iatrogeny and promote a faster recovery.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). 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). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. 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. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Cardiac Rehabilitation in a Transplanted Person with Emery-Dreifuss Muscular Dystrophy. / Reabilitação Cardíaca na Pessoa Transplantada com Distrofia Muscular de Emery-Dreifuss.

Emery-Dreifuss muscular dystrophy is a rare hereditary neuromuscular disease. Its manifestations begin primarily in childhood. The most frequent manifestations are progressive muscle weakness, atrophy that usually begins in the scapula-vertebral region, extending later to the pelvic girdle, and spinal stiffness. Patients can also manifest cardiac involvement as palpitations, syncope, exercise intolerance, congestive heart failure, and variable heart rhythm disturbances. 1 - 3 The presence and severity of these manifestations can vary according to the individual and the disease's subtypes. 2 Cardiac involvement is the most worrisome feature of this disease, and there are some reports of the need for heart transplantation in this dystrophy. 4.

A distrofia muscular de Emery-Dreifuss é uma doença neuromuscular hereditária rara. Suas manifestações começam principalmente na infância. As manifestações mais frequentes são fraqueza muscular progressiva, atrofia que geralmente se inicia na região escápulo-vertebral, estendendo-se posteriormente para a cintura pélvica e rigidez da coluna vertebral. Os pacientes também podem manifestar envolvimento cardíaco como palpitações, síncope, intolerância ao exercício, insuficiência cardíaca congestiva e distúrbios variáveis do ritmo cardíaco. 1 - 3 A presença e a gravidade dessas manifestações podem variar de acordo com o indivíduo e os subtipos da doença. 2 O envolvimento cardíaco é a característica mais preocupante desta doença, havendo alguns relatos da necessidade de transplante cardíaco nesta distrofia. 4.

Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy.

Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear envelope protein NET39 in mice leads to neonatal lethality due to skeletal muscle dysfunction. To study the potential role of the Net39 gene in adulthood, we generated a muscle-specific conditional knockout (cKO) of Net39 in mice. 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. Net39 was downregulated in a mouse model of congenital myopathy, and restoration of Net39 expression through AAV gene delivery extended life span and ameliorated muscle abnormalities. These findings establish NET39 as a direct contributor to the pathogenesis of EDMD that acts by protecting against mechanical stress and DNA damage.

Early Muscle MRI Findings in a Pediatric Case of Emery-Dreifuss Muscular Dystrophy Type 1.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare disease characterized by early contractures, progressive muscle weakness, and cardiac abnormalities. Different subtypes of EDMD have been described, with the two most common forms represented by the X-linked EDMD1, caused by mutations in the EMD gene encoding emerin, and the autosomal EDMD2, due to mutations in the LMNA gene encoding lamin A/C. A clear definition of the magnetic resonance imaging (MRI) pattern in the two forms, and especially in the rarer EDMD1, is still lacking, although a preferential involvement of the medial head of the gastrocnemius has been suggested in EDMD2. We report a 13-year-old boy with mild limb girdle muscle weakness, elbow and ankle contractures, with absence of emerin at muscle biopsy, carrying a hemizygous frameshift mutation on the EMD gene (c.153dupC/p.Ser52Glufs*9) of maternal inheritance. Minor cardiac rhythm abnormalities were detected at 24-hour Holter electrocardiogram and required ß-blocker therapy. MRI scan of the thighs showed a mild diffuse involvement, while tibialis anterior, extensor digitorum longus, peroneus longus, and medial gastrocnemius were the most affected muscles in the leg. We also provide a review of the muscular MRI data in EDMD patients and highlight the relative heterogeneity of the MRI patterns found in EDMDs, suggesting that muscle MRI should be studied in larger EDMD cohorts to better define disease patterns and to cover the wide disease spectrum.

Several challenges associated with the anesthetic management of Emery-Dreifuss muscular dystrophy patients: case report

Abstract Emery-Dreifuss Muscular Dystrophy is a very rare type of muscular dystrophy, associated with contractures, atrophy, and muscle weakness, besides cardiomyopathy with severe arrhythmias. Published studies focusing on this disorder are scarce. We describe the anesthetic management of a male patient with Emery-Dreifuss Muscular Dystrophy, to be submitted to umbilical and inguinal hernioplasty and hydrocele repair under epidural anesthesia. The anesthesia approach enabled us to circumvent the patient's susceptibility to malignant hyperthermia and his potentially difficult airway, in addition to maintaining hemodynamic stability. The day after surgery the patient resumed walking, and two days later he was discharged from the hospital.

Detection of gonosomal mosaicism by ultra-deep sequencing and droplet digital PCR in patients with Emery-Dreifuss muscular dystrophy.

BACKGROUND: Emery-Dreifuss muscular dystrophy (EDMD2) is a rare form of muscular dystrophy that is inherited as an autosomal dominant trait. In some patients, it is inherited from parental mosaicism, and this increases the recurrence risk significantly. The presence of mosaicism is underestimated due to the limitations of genetic testing and the difficulty in obtaining samples. METHODS: A peripheral blood sample from a 9-year-old girl with EDMD2 was analyzed by enhanced whole exome sequencing (WES). Sanger sequencing in her unaffected parents and younger sister was performed for validation. In the mother, ultra-deep sequencing and droplet digital PCR (ddPCR) in multiple samples (blood, urine, saliva, oral epithelium, and nail clippings) were performed in order to identify the suspected mosaicism of the variant. RESULTS: WES revealed a heterozygous mutation (LMNA, c.1622G>A) in the proband. Sanger sequencing of the mother suggested the presence of mosaicism. The ratio of mosaic mutation was confirmed in different samples by ultra-deep sequencing and ddPCR (19.98%-28.61% and 17.94%-28.33%, respectively). This inferred that the mosaic mutation may have occurred early during embryonic development and that the mother had gonosomal mosaicism. CONCLUSION: We described a case of EDMD2 caused by maternal gonosomal mosaicism which was confirmed by using ultra-deep sequencing and ddPCR. This study illustrates the importance of a systematic and comprehensive screening of parental mosaicism with more sensitive approaches and the use of multiple tissue samples.

Several challenges associated with the anesthetic management of Emery-Dreifuss muscular dystrophy patients: case report.

Emery-Dreifuss Muscular Dystrophy is a very rare type of muscular dystrophy, associated with contractures, atrophy, and muscle weakness, besides cardiomyopathy with severe arrhythmias. Published studies focusing on this disorder are scarce. We describe the anesthetic management of a male patient with Emery-Dreifuss Muscular Dystrophy, to be submitted to umbilical and inguinal hernioplasty and hydrocele repair under epidural anesthesia. The anesthesia approach enabled us to circumvent the patient...s susceptibility to malignant hyperthermia and his potentially difficult airway, in addition to maintaining hemodynamic stability. The day after surgery the patient resumed walking, and two days later he was discharged from the hospital.

Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees.

Emery-Dreifuss muscular dystrophy (EDMD) is a genetically and clinically variable disorder. Previous attempts to use gene expression changes to find its pathomechanism were unavailing, so we engaged a functional pathway analysis. RNA-Seq was performed on cells from 10 patients diagnosed with an EDMD spectrum disease with different mutations in seven genes. Upon comparing to controls, the pathway analysis revealed that multiple genes involved in fibrosis, metabolism, myogenic signaling and splicing were affected in all patients. Splice variant analysis revealed alterations of muscle-specific variants for several important muscle genes. Deeper analysis of metabolic pathways revealed a reduction in glycolytic and oxidative metabolism and reduced numbers of mitochondria across a larger set of 14 EDMD spectrum patients and 7 controls. Intriguingly, the gene expression signatures segregated the patients into three subgroups whose distinctions could potentially relate to differences in clinical presentation. Finally, differential expression analysis of miRNAs changing in the patients similarly highlighted fibrosis, metabolism and myogenic signaling pathways. This pathway approach revealed a transcriptome profile that can both be used as a template for establishing a biomarker panel for EDMD and direct further investigation into its pathomechanism. Furthermore, the segregation of specific gene changes into distinct groups that appear to correlate with clinical presentation may template development of prognostic biomarkers, though this will first require their testing in a wider set of patients with more clinical information.

An autopsy case of sudden unexpected death of a young adult with progressive intraventricular conduction delay.

Herein, we describe an autopsy case of the sudden unexpected death of a 23-year-old man. Retrospective analysis of electrocardiograms revealed progressive widening of the QRS interval. Autopsy showed mild mitral valve prolapse and hypertrabeculation of the left ventricle. Microscopic examination revealed very scarce but considerable minimal myocardial necrotic foci in the left ventricle, and a marked reduction in conduction fibers in the left branch. These findings may be associated with intraventricular conduction delay. Genetic investigation revealed four rare possibly pathogenic variants, including the Emery-Dreifuss muscular dystrophy-associated genetic variant SYNE2_p.A6155 V that is evaluated as pathogenic by most in silico predictive tools. The other possibly pathogenic variants detected were PLEC_p.P973L, TTN_p.I22171T, and p.A12216T. Although these variants are reported to have uncertain significance in the guidelines of the American College of Medical Genetics and Genomics, progressive conduction delay may have been associated with vulnerability of myocytes due to Emery-Dreifuss muscular dystrophy-associated genetic variants in the present case. Younger individuals with progressive conduction delay may require medical work-up and genetic investigation, even if they have no other clinical signs and no or mild structural heart disease.

Surgical Treatment for Severe Cervical Hyperlordosis and Thoracolumar Kyphoscoliosis with Emery-Dreifuss Muscular Dystrophy: A Case Report and Literature Review.

BACKGROUND: Emery-Dreifuss muscular dystrophy (EDMD) is an uncommon, gradually progressive X-linked myopathy, and it could result in rigid spinal deformity. Only a few case reports have described surgical treatment of cervical hyperlordosis and thoracolumbar kyphoscoliosis secondary to EDMD. We report a rare case of EDMD to present the surgical strategies of severe cervical hyperlordosis and thoracolumbar kyphoscoliosis. CASE PRESENTATION: The patient was a 22-year-old man with EDMD who had severe cervical hyperlordosis and thoracolumbar kyphoscoliosis. A posterior spinal fusion from T9-S2 was performed to correct the thoracolumbar kyphoscoliosis at the age of 21 years. Six months later, with an anterior C7-T1 closing wedge bone-disc-bone osteotomy and a posterior-anterior-posterior cervicothoracic fusion from C4-T4, the cervical deformity was corrected, thus achieving a horizontal gaze. During 1.5-year follow-up, no loss of correction was observed. CONCLUSION: Cervical posterior-anterior-posterior closing-wedge osteotomy combined with long fusion at thoracolumbar spine can be a reliable surgical technique to correct severe spine deformity in EDMD. This two-stage revision surgical strategy can help restore a horizontal gaze on the basis of a balanced trunk. Cervical deformity in such patients should be corrected in the first stage considering its role as a "driver" of the global spine deformity.

Autosomal dominant Emery-Dreifuss muscular dystrophy caused by a mutation in the lamin A/C gene identified by exome sequencing: a case report.

BACKGROUND: Emery-Dreifuss Muscular Dystrophy (EDMD) is an uncommon genetic disease among the group of muscular dystrophies. EDMD is clinically heterogeneous and resembles other muscular dystrophies. Mutation of the lamin A/C (LMNA) gene, which causes EDMD, also causes many other diseases. There is inter and intrafamilial variability in clinical presentations. Precise diagnosis can help in patient surveillance, especially before they present with cardiac problems. Hence, this paper shows how a molecular work-out by next-generation sequencing can help this group of disorders. CASE PRESENTATION: A 2-year-10-month-old Javanese boy presented to our clinic with weakness in lower limbs and difficulty climbing stairs. The clinical features of the boy were Gower's sign, waddling gait and high CK level. His father presented with elbow contractures and heels, toe walking and weakness of limbs, pelvic, and peroneus muscles. Exome sequencing on this patient detected a pathogenic variant in the LMNA gene (NM_170707: c.C1357T: NP_733821: p.Arg453Trp) that has been reported to cause Autosomal Dominant Emery-Dreifuss muscular dystrophy. Further examination showed total atrioventricular block and atrial fibrillation in the father. CONCLUSION: EDMD is a rare disabling muscular disease that poses a diagnostic challenge. Family history work-up and thorough neuromuscular physical examinations are needed. Early diagnosis is essential to recognize orthopaedic and cardiac complications, improving the clinical management and prognosis of the disease. Exome sequencing could successfully determine pathogenic variants to provide a conclusive diagnosis.