Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant.

Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%-30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19-year-old proband with muscular dystrophy and negative clinical ES. Deep phenotypic analysis identified two critical data points: (1) the absence of emerin protein in muscle biopsy and (2) clinical features consistent with Emery-Dreifuss muscular dystrophy. Sequencing data analysis uncovered an ultra-rare, intronic variant in EMD, the gene encoding emerin. The variant, NM_000117.3: c.188-6A > G, is predicted to impact splicing by in silico tools. This case thus illustrates how better integration of clinicopathologic data into ES analysis can enhance diagnostic yield with implications for clinical practice.

[A case of Emery-Dreifuss muscular dystrophy with slight joint contracture].

A 42-year-old man with a history of two previous coronary embolisms was referred to our hospital. He had been experiencing muscle weakness since he was around 40 years old. He had muscle atrophy of the scapula, upper arm, and lower extremities, and electromyography revealed myogenic changes in the limb muscles. Histopathological analysis of the muscle biopsy specimen revealed a complete deficiency of emerin protein, and genetic examination revealed a mutation in the emerin (EMD) gene, resulting in a diagnosis of Emery-Dreifuss muscular dystrophy (EDMD). EDMD is a muscular disorder with three symptoms: joint contracture at early onset, muscle weakness and atrophy, and cardiac dysfunction. Although this patient showed no obvious joint contracture, the course and clinical symptoms vary among patients. Therefore, in patients in whom clinical diagnosis is difficult, muscle biopsy and genetic testing should be performed for EDMD in order to prevent sudden death due to this disease.

Dropped head related lamin A/C associated congenital muscular dystrophy case; previously defined as emerydreifuss muscular dystrophy.

Dropped head syndrome can be seen in many neuromuscular diseases. However, there are very few diseases in which neck extensors are weak among neuromuscular diseases. A 7 years old boy who had weakness of the neck extensor muscles, creatinine kinase elevation and dystrophy findings in biopsy followed up with the preliminary diagnosis of muscular dystrophy is presented. We detected p.N456K (c.1368C > A) heterozygote mutation by the gene sequencing in the Lamin A/C associated (LMNA) gene. This mutation was previously reported as Emery-Dreifuss muscular dystrophy.

X-Linked Emery-Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers.

X-linked Emery-Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers-25 familial and 5 sporadic cases-seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

Occurrence of Emery-Dreifuss muscular dystrophy in a rural setting of Cameroon: a case report and review of the literature.

BACKGROUND: Emery-Dreifuss muscular dystrophy is a rare genetic muscular disease, presenting mainly with contractures, weakness and cardiac conduction abnormalities. Its clinical and laboratory similarities to other muscular dystrophies, and rarity poses diagnostic challenges, requiring a high index of suspicion in resource limited settings. CASE PRESENTATION: An 8 year old sub-Saharan male presented with rigidity and deformity of both elbows and ankles, and weakness of the upper limbs and lower limbs for duration of 4 months. This progressed to inability to stand and walk. There was no mental impairment. Physical examination was remarkable for contractures of the elbows and ankles, and wasting of muscles of the limbs and trunk, with a scapulohumeroperoneal pattern, and tachycardia. After laboratory investigations, a diagnosis of Emery-Dreifuss muscular dystrophy was suspected. Physiotherapy was started, wheel chair was prescribed, and referral to a specialist center was done for appropriate management. CONCLUSIONS: Emery-Dreifuss muscular dystrophy is a rare disabling muscular disease which poses a diagnostic challenge. High index of suspicion is paramount for its early diagnoses to prevent orthopedic and cardiac complications. Prompt diagnosis and management is essential to improve on the prognosis of this disease.

Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

Partial deficiency of emerin caused by a splice site mutation in EMD.

Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the EMD gene on the X chromosome, which codes for emerin, an inner nuclear membrane protein. Monoclonal antibodies against the N-terminus of emerin protein are used to screen for emerin deficiency in clinical practice. However, these tests may not accurately reflect the disease in some cases. We herein describe the identification of a splice site mutation in the EMD gene in a Japanese patient who suffered from complete atrioventricular conduction block, mild muscle weakness and joint contracture, and a persistently elevated serum creatine kinase level. We used multiple antibodies to confirm the presence of a novel truncating mutation in emerin without the transmembrane region and C-terminus in the skeletal muscle.

Emery-Dreifuss muscular dystrophy, laminopathies, and other nuclear envelopathies.

The nuclear envelopathies, more frequently known as laminopathies are a rapidly expanding group of human hereditary diseases caused by mutations of genes that encode proteins of the nuclear envelope. The most frequent and best known form is Emery-Dreifuss muscular dystrophy (EDMD), a skeletal myopathy characterized by progressive muscular weakness, joint contractures, and cardiac disease. EMD gene, encoding emerin, causes the X-linked form of EDMD, while LMNA gene encoding lamins A and C, is responsible for autosomal forms, usually with a dominant transmission. In the last years, the spectrum of conditions has been extraordinarily enlarged, from a congenital muscular dystrophy with severe paralytic or rapidly progressive picture due to de novo mutations in LMNA (L-CMD) to a limb-girdle muscular dystrophy with adult onset and much milder weakness (LGMD1B). LMNA has also been involved in a form of isolated cardiomyopathy associated with cardiac conduction disease and in an axonal form of hereditary neuropathy. Identification of this gene has been reported also in a number of non-neuromuscular disorders including lipodystrophy syndromes and a wide spectrum of premature aging syndromes ranging from mandibuloacral dysplasia to restrictive dermopathy. Mutations in other genes implicated in the processing or maturation of nuclear lamins have also been found. The extraordinary complexity of the molecular and pathophysiological mechanisms of these diseases is still not well known and the occurrence of modifying factors or genes is highly suspected. Identification of new genes and investigation of new therapeutic approaches are in progress.

Regional and transmural dispersion of repolarisation in patients with Emery-Dreifuss muscular dystrophy.

BACKGROUND: The development of malignant ventricular arrhythmias is a possible feature in Emery-Dreifuss muscular dystrophy (EDMD) patients with normal left ventricular systolic function. This event may be the cause of sudden cardiac death in EDMD patients. QTc dispersion (QTc-D), JTc dispersion (JTc-D) and Tpeak-end dispersion (TDR) could reflect the physiological variability of regional and transmural ventricular repolarisation and could provide a substrate for life-threatening ventricular arrhythmias. AIM: The current study was designed to evaluate the heterogeneity of ventricular repolarisation in EDMD patients. METHODS: Echocardiograms and electrocardiograms from 40 EDMD patients (age 20 ± 13) were evaluated and compared to those of 40 healthy age-matched controls. RESULTS: The EDMD group, compared to the healthy control group, presented increased values of QTc-D (82.8 ± 44.1 vs. 53.3 ± 13.9, p = 0.003), JTc-D (73.6 ± 32.3 vs. 60.4 ± 11.1 ms, p = 0.001) and TDR (100.54 ± 19.06 vs. 92.15 ± 15.5 ms, p = 0.004). No correlation between QTc dispersion and ejection fraction (R = 0.2, p = 0.3) was found. CONCLUSIONS: EDMD is associated with significantly increased regional and transmural heterogeneity of ventricular repolarisation, in the absence of impaired systolic and diastolic cardiac function.

External and internal influences on muscle pathology.

Three cases of different types of neuromuscular diseases demonstrate different muscle responses to external stress or intrinsic muscle abnormalities. The first muscle biopsy shows stenosis of its vessels causing acute muscle ischemia, stress from an external vascular disease. The muscle response is similar to the cellular necrosis seen in primary muscle diseases (myopathies), but the histologic pattern is more focal than most myopathies. The second muscle biopsy demonstrates the effects of external motor nerve injury or disease causing groups of muscle fibers to atrophy. If a nerve reinnervates the muscle, it changes the fiber types in distinct patterns. The third muscle biopsy shows an intrinsic muscle abnormality causes chronic failure of the muscle fibers to thrive and repeated attempts by the fibers to regenerate, stimulating other tissue repair processes, like fibrosis, to change the muscle. Depending on the etiologic factor, muscle will respond to internal and external influences in different manners.

The empowerment of translational research: lessons from laminopathies.

The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.

Autosomal recessive Emery-Dreifuss muscular dystrophy caused by a novel mutation (R225Q) in the lamin A/C gene identified by exome sequencing.

INTRODUCTION: The aim of this study is to describe a new mutation in the LMNA gene diagnosed by whole exome sequencing. METHODS: A two-generation kindred with recessive limb-girdle muscular dystrophy was evaluated by exome sequencing of the proband's DNA. RESULTS: Exome sequencing disclosed 194,618 variants (170,196 SNPs, 8482 MNPs, 7466 insertions, 8307 deletions, and 167 mixed combinations); 71,328 were homozygotic and 123,290 were heterozygotic, with 11,753 non-synonymous, stop-gain, stop-loss, or frameshift mutations occurring in the coding region or nearby intronic region. The cross-referencing of these mutations in candidate genes for muscular dystrophy showed a homozygote mutation c.G674A in exon 4 of LMNA causing a protein change R225Q in an arginine conserved from human to Xenopus tropicalis and in lamin B1. CONCLUSIONS: This technique will be preferred for studying patients with muscular dystrophy in the coming years.

Successful surgical repair for Emery-Dreifuss muscular dystrophy valvular disease with long-term follow-up.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked muscular dystrophy in which cardiac involvement can be serious. The disease progresses rapidly and the prognosis is strongly associated with cardiac involvement. We present the case of a 49-year-old man who was admitted with shortness of breath. Echocardiography revealed a huge right atrium and severe tricuspid regurgitation caused by annular dilatation and destruction of leaflets and chordae by pacemaker leads. Tricuspid valve replacement, right atrial plication and implantation of epicardial pacemaker leads were performed. The patient is in a good condition seven years after surgery. Cardiac transplantation is the desired therapy for valvular disease in EDMD cardiomyopathy, but this case indicates that valve replacement is also acceptable if performed with the appropriate timing.

A novel LMNA gene mutation Leu162Pro and the associated clinical characteristics in a family with autosomal-dominant emery-dreifuss muscular dystrophy.

We report the clinical characteristics, genetic analysis, and muscle biopsy findings of a family with Emery-Dreifuss muscular dystrophy and a novel mutation (Leu162Pro) in the LMNA gene. Within this single family, the age of onset and disease severity varied among the family members. In addition, focal defects of nuclear membranes with chromatin blebs in endothelial cells was shown via electron microscopy.

Emery dreifuss muscular dystrophy: a clinico-pathological study.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare and genetically heterogeneous disorder. We report two patients with emerin deficient X-linked EDMD and two probable patients with EDMD with typical early contractures, progressive muscle weakness and cardiac involvement. Family history was noted in one case. Muscle biopsy revealed features of dystrophy in all.

[Emery-Dreifuss muscular dystrophy: case report]. / Distrofia muscular de Emery-Dreifuss: relato de caso.

The Emery-Dreifuss muscular dystrophy is a form of muscular dystrophy that frequently presents early contractures and cardiac conduction defects, caused by emerin deficiency in the inner nuclear membrane of the muscular fibers. A 19-years-old man it presented muscle weakness and hypotrophy in the proximal upper and lower limbs, dysphagia and early contractures in elbows and ankles, with familiar history compatible with X-linked inheritance form. The investigation showed increased serum creatinekinase levels electrocardiogram had a first degree atrioventricular block and right bundle branch block normal electromyography and nerve conduction study muscle biopsy disclosed myopathic characteristics and nuclear protein immunohystochemical analysis showed deficiency of emerin. The clinical and genetics manifestations, laboratorial and electromyography changes, as well as, the study of the pattern of inheritance for genetic counseling are discussed.

Distrofia muscular de Emery-Dreifuss: relato de caso / Emery-Dreifuss muscular dystrophy: case report

A distrofia muscular de Emery-Dreifuss é uma forma de distrofia muscular freqüentemente associada a contraturas articulares e defeitos de condução cardíaca, que pode ser causada pela deficiência da proteína emerina na membrana nuclear interna das fibras musculares. Descrevemos o caso de um homem de 19 anos com diminuição de força muscular, hipotrofia nas cinturas escapular e pélvica, disfagia, contraturas articulares em cotovelos e tornozelos, apresentando história familiar compatível com herança ligada ao cromossomo X. A investigação mostrou creatinaquinase sérica elevada, eletrocardiograma com bloqueio atrioventricular de primeiro grau e bloqueio de ramo direito, eletroneuromiografia normal, biópsia muscular com alterações miopáticas e a análise por imuno-histoquímica mostrou deficiência de emerina. São discutidas as manifestações clínicas e genéticas, alterações laboratoriais e eletroneuromiográficas, bem como, a importância do estudo do padrão de herança no aconselhamento genético destas famílias.

Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy.

The coexistence of neurogenic and myogenic features in scapuloperoneal syndrome is rarely ascribed to a single gene. Defects in the nuclear envelope protein lamin A/C, encoded by the LMNA gene, have been shown to be associated with a variety of disorders affecting mainly the muscular and adipose tissues and, more recently, with autosomal recessive Charcot-Marie-Tooth type 2 neuropathy. This report is about a patient presenting features of myopathy and neuropathy due to a dominant LMNA mutation, suggesting that the peripheral nerve might be affected in primary LMNA myopathy. Our observations further support the marked intrafamilial and interfamilial phenotypic heterogeneity associated with lamin A/C defects.

[Hauptmann-Thannhauser muscular dystrophy and differential diagnosis of myopathies associated with contractures]. / Die Hauptmann-Thannhauser-Muskeldystrophie und Differenzialdiagnosen von Myopathien mit Kontrakturen.

Hauptmann-Thannhauser muscular dystrophy is characterized by the clinical triad of early-onset contractures of elbow, Achilles tendons, and cervical spine, slowly progressive humeroperoneal muscle wasting and weakness, and life-threatening cardiac involvement with conduction blocks manifesting in the third decade. Hauptmann-Thannhauser muscular dystrophy is due to mutations in the LMNA gene affecting the nuclear envelope proteins lamin A and C. We present a 16-year-old German boy with typical muscular involvement and contractures and typical course of Hauptmann-Thannhauser muscular dystrophy due to the novel missense mutation R401C. The data of this family suggest a lower penetrance of muscular and especially cardiac symptoms than expected. Autosomal-dominant Hauptmann-Thannhauser muscular dystrophy and X-chromosomal Emery-Dreifuss muscular dystrophy are not clearly distinguishable by phenotypic criteria. Other muscular diseases associated with contractures and congenital or childhood onset are reviewed.

Anaesthetic management of a patient with Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy is a rare form of muscular dystrophy associated with cardiac implications such as cardiomyopathy and arrhythmias leading to sudden death. We describe the anesthetic management of a patient with Emery-Dreifuss muscular dystrophy who presented for orthopaedic surgery and discuss the disorder and its potential anaesthetic implications.