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BACKGROUND: Emery-Dreifuss Muscular Dystrophy (EDMD) is an extremely rare muscular dystrophy due to either emerinopathy ( EMD ) or laminopathy ( LMNA ). The main risk for patients is that of cardiovascular complications. AIMS: The aim of this study was to identify predictors of adverse clinical events in patients with EDMD in long-term follow-up observation. METHODS: A total of 45 patients with confirmed EMD or LMNA mutation were included in the study. The relationships between clinical parameters, the overall survival rate, and risk factors for disease progression were assessed. The primary endpoint was defined as death, while the secondary endpoint comprised death, resuscitated cardiac arrest (RCA), heart transplant (HTX), stroke, end-stage heart failure (ESHF), and hospitalization due to heart failure (HF). RESULTS: During a median length of follow-up observation of ten years (interquartile range, 5–15), ten patients (22%) died, one suffered RCA, two had HTX, and six suffered ischemic strokes (13%). Seven patients developed ESHF and eight were hospitalized due to HF. The secondary endpoint occurred in 16 patients (36%). LMNA mutation (hazard ratio [HR], 6.01; 95% confidence interval [CI], 1.61–22.4; P = 0.008) and higher serum N-terminal fragment of B-type natriuretic peptide (NT-proBNP) concentration (HR, 1.29; 95% CI, 1.06–1.56 per 100 pg/ml; P = 0.01) increased the risk of death. Higher tricuspid annular plane systolic excursion (TAPSE) decreased the risk for the secondary endpoint (HR, 0.78; 95% CI, 0.68–0.90 mm; P 257 pg/ml and TAPSE

Introduction: Cardiac involvement in patients with muscular dystrophy associated with Lamin A/C mutations (LMNA) is characterized by atrioventricular conduction abnormalities and life-threatening cardiac arrhythmias. Little is known about cardiac involvement in patients with emerin mutation (EMD). The aim of our study was to describe and compare the prevalence and time distribution of cardiac arrhythmias at extended follow-up. Patients and methods: 45 consecutive patients affected by muscular dystrophy associated to laminopathy or emerinopathy were examined. All patients underwent clinical evaluation, 12-lead surface electrocardiogram (ECG), 24 h electrocardiographic monitoring, and cardiac implanted device interrogation. Results: At the end of 11 (5.0–16.6) years of follow-up, 89% of the patients showed cardiac arrhythmias. The most prevalent was atrial standstill (AS) (31%), followed by atrial fibrillation/flutter (AF/Afl) (29%) and ventricular tachycardia (22%). EMD patients presented more frequently AF/AFl compared to LMNA (50% vs. 20%, p = 0.06). Half of the EMD patients presented with AS, whilst there was no occurrence of such in the LMNA (p = 0.001). Ventricular arrhythmias were found in 60% of patients with laminopathy compared to 3% in patients with emerinopathy (p &lt, 0.001). The age of AVB occurrence was higher in the LMNA group (32.8 +/− 10.6 vs. 25.1 +/− 9.1, p = 0.03). Conclusions: Atrial arrhythmias are common findings in patients with muscular dystrophy associated with EMD/LMNA mutations, however, they occurred earlier in EMD patients. Ventricular arrhythmias were very common (60%) in LMNA and occurred definitely earlier compared to the EMD group.

LMNA-related congenital muscular dystrophy (L-CMD) is the most severe phenotypic form of skeletal muscle laminopathies. This paper reports clinical presentation of the disease in 15 Polish patients from 13 families with genetically confirmed skeletal muscle laminopathy. In all these patients floppy infant syndrome was the first manifestation of the disease. The genetic diagnosis was established by next generation sequencing (targeted panel or exome; 11 patients) or classic Sanger sequencing (4 patients). In addition to known pathogenic LMNA variants: c.116A > G (p.Asn39Ser), c.745C > T (p.Arg249Trp), c.746G > A (p.Arg249Gln), c.1072G > A (p.Glu358Lys), c.1147G > A (p.Glu383Lys), c.1163G > C (p.Arg388Pro), c.1357C > T (p.Arg453Trp), c.1583C > G (p.Thr528Arg), we have identified three novel ones: c.121C > G (p.Arg41Gly), c.1127A > G (p.Tyr376Cys) and c.1160T > C (p.Leu387Pro). Eleven patients had de novo mutations, 4 – familial. In one family we observed intrafamilial variability of clinical course: severe L-CMD in the male proband, intermediate form in his sister and asymptomatic in their mother. One asymptomatic father had somatic mosaicism. L-CMD should be suspected in children with hypotonia in infancy and delayed motor development, who have poor head control, severe hyperlordosis and unstable and awkward gait. Serum creatine kinase may be high (~1000IU/l). Progression of muscle weakness is fast, leading to early immobilization. In some patients with L-CMD joint contractures can develop with time. MRI shows that the most frequently affected muscles are the serratus anterior, lumbar paraspinal, gluteus, vastus, adductor magnus, hamstrings, medial head of gastrocnemius and soleus. Ultra-rare laminopathies can be a relatively common cause of generalized hypotonia in children. Introduction of wide genome sequencing methods was a breakthrough in diagnostics of diseases with great clinical and genetic variability and allowed approach “from genotype do phenotype”. However target sequencing of LMNA gene could be considered in selected patients with clinical picture suggestive for laminopathy.

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.

Mild skeletal muscle symptoms might be accompanied with severe cardiac disease, sometimes indicating a serious inherited disorder. Very often it is a cardiologist who refers a patient with cardiomyopathy and/or cardiac arrhythmia and discrete muscle disease for neurological consultation, which helps to establish a proper diagnosis. Here we present three families in which a diagnosis of skeletal muscle laminopathy was made after careful examination of the members, who presented with cardiac arrhythmia and/or heart failure and a mild skeletal muscle disease, which together with positive family history allowed to direct the molecular diagnostics and then provide appropriate treatment and counseling.

X-linked Emery&ndash, 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&mdash, 25 familial and 5 sporadic cases&mdash, 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 &ge, 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.

Laminopathies, a group of heterogeneous disorders associated with lamin A/C gene (LMNA) mutations, encompass a wide spectrum of clinical phenotypes, which may present as separate disease or as overlapping syndromes. We describe a 35-year-old female in whom a novel sporadic heterozygous mutation c.1001_1003delGCC (p.Ser334del) of the LMNA gene was found. The patient presented with overlapping syndrome of heart failure secondary to dilated cardiomyopathy, limb-girdle dystrophy and partial lipodystrophy. Endomyocardial biopsy revealed strong up-regulation of HLA classes I and II antigens on microvessels and induction of the class I antigens on cardiomyocytes. On muscle biopsy, a wide range of fiber sizes and small clusters of inflammatory infiltrations were found. In the rapid progression of heart failure with arrhythmias or conduction defect, accompanied with muscle atrophy and lipodystrophy, the genetic disease should be taken into consideration. In addition, undefined inflammatory response and fibrosis in the heart or skeletal muscle might further justify screening of the lamin A/C gene.

Wstep: Tkankowe inhibitory metaloproteinaz macierzy (TIMPs) są zaangazowane w patogeneze chorob ukladu sercowo-naczyniowego. Dotychczas nie badano stezenia TIMPs u pacjentow z kardiomiopatią rozstrzeniową w przebiegu dystrofii mieśniowej Emery’ego-Dreifussa (EDMD). Cel: Celem badania bylo określenie stezenia TIMPs w surowicy pacjentow z EDMD w celu rozstrzygniecia, czy moglyby stanowic biomarker dysfunkcji mieśnia sercowego na wczesnych etapach choroby i pomoc w wykrywaniu kardiomiopatii w okresie przedklinicznym. Metody: Zbadano 25 pacjentow z EDMD związaną z mutacją w genie laminy A/C (AD-EDMD) lub w genie emeryny (X-EDMD) oraz 20 zdrowych osob z grupy kontrolnej, dobranych pod wzgledem wieku. Stezenia TIMP-1, -2, -3 w surowicy określono za pomocą testu immunoenzymatycznego ELISA z odpowiednimi przeciwcialami. Wyniki: Stezenia TIMP-1 w surowicy byly prawidlowe u chorych z AD-EDMD, a zwiekszone u wiekszości pacjentow z X-EDMD. Stezenie TIMP-2 w surowicy bylo obnizone u 25% i /21% chorych, odpowiednio, z AD-EDMD i X-EDMD. Stezenie TIMP-3 bylo znamiennie obnizone u wszystkich badanych pacjentow. Krzywe ROC wskazywaly, ze spośrod wszystkich zbadanych TIMPs pod wzgledem czulości i specyficzności TIMP-3 (a w mniejszym stopniu TIMP-2) jest najlepszym biomarkerem uszkodzenia mieśnia sercowego u chorych z EDMD. Wnioski: Uzyskane wyniki wskazują, ze u chorych z EDMD stezenia TIMP-3 w surowicy, a w niektorych przypadkach takze TIMP-2, są obnizone. Obserwowany spadek moze sie wiązac z niekorzystnym wplywem na metaloproteinazy macierzy oraz remodelowaniem macierzy miokardium. Specyficzny spadek stezenia TIMP-3 w surowicy chorych wskazuje, ze biomarker ten moglby byc uzyteczny we wczesnej detekcji zajecia mieśnia sercowego w EDMD. Regulacja w gore TIMP-1 u wiekszości pacjentow z X-EDMD wskazuje na zwiekszony obrot macierzy zewnątrzkomorkowej, zaś obserwowane remodelowanie tkanki moze uczestniczyc w rozwoju zaburzen rytmu serca, czesto stwierdzanych w tej postaci choroby.

Introduction: During human myogenesis and synaptogenesis, the first contact between multiaxonal nerve terminals and the primary myotube occurs at an early stage of gestation, then monoaxonal nerve terminals form and postsynaptic clusters of acetylcholine-receptor are modified and redistributed to the site of muscle-nerve contact. The aim of this study is to present the ultrastructural features of muscle and motor-junction immaturity severe enough to lead to death in the first months of life. Material and methods: Ultrastructural-level analysis was carried out on the quadriceps femoris muscle of an infant born at full term with severe respiratory distress but with normal SMN1 and IGHMBP2 genes. Results: Arrested muscle maturation was manifested in the presence of primary and mature myotubes, prepatterned acetylcholine-receptor clusters devoid of terminal axons, lack of synapses and multiaxonal unmyelinated intramuscular nerves. Conclusion: The “naked” prepatterned clusters observed on the surface of myotubes normally never observed in neonates might be a sign of a new genetic defect in innervation.

As osteopontin (OPN) may be assumed to have diagnostic/prognostic value in heart diseases, it is worth assessing whether it is also involved in the pathogenesis and can be applied in the diagnosis of the dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD).Serum levels of osteopontin were quantified by means of sandwich immunoassay in 25 EDMD patients (10 laminopathies AD-EDMD and 15 emerinopathies--X-EDMD), eight carriers of X-EDMD, nine disease controls (patients with dystrophinopathy) and 20 age-matched healthy controls.The levels of circulating OPN were elevated in all AD-EDMD and X-linked EDMD patients, as well as in X-EDMD carriers and patients suffering progressive muscular dystrophy. There was no correlation between the osteopontin level and different cardiac parameters, including left-ventricular end-diastolic diameter, left atrial diameter, the left ventricular ejection fraction and the CK-MB level. There was a slight negative correlation with the ages of the patients.The presented results indicate that assessments of circulating OPN levels may help to identify EDMD patients at risk of dilated cardiomyopathy and might be therefore included among the set of biomarkers referred to with a view to appropriate early cardiologic diagnosis and therapy being commenced with in time.

The study demonstrates a 12-year-old patient with progressive proximal muscle weakness, joint contractures, rigidity of the neck, and absence of emerin and lamin A in the muscle nuclei, which is caused by intronic mutation IVS3-27del18 (c.266-27del18) in the emerin gene. The most surprising finding was the appearance of IBM-like inclusions in euchromatin, as well as aberrant nuclei. It may be speculated that altered expression of the emerin-lamin complex and modification of the nuclear matrix leads to formation of tubulofilamentous structures in the presented case.

In recent years numerous mutations in the LMNA gene encoding lamin A/C were shown to segregate with a wide spectrum of phenotypes. A recurrent p.R377H mutation in the LMNA gene was reported in patients with Emery-Dreifuss dystrophy (EDMD2) with various ethnic backgrounds. We present a patient with EDMD2 caused by a p.R377H mutation, associated with mild peripheral polyneuropathy. The analysis of peripheral myelin protein 22 (PMP22), ganglioside induced differentiation-associated protein 1 (GDAP1), gap junction β-1 protein (GJB1), and myelin protein zero (MPZ) genes did not reveal mutations; however, we identified a new sequence intronic variant in the mitofusin 2 (MFN2) gene of unknown pathogenic significance. A complex phenotype in the presented patient might depend either on single mutation in the LMNA gene or on bigenic defect; therefore, a wide genetic investigation is needed to elucidate the molecular background of EDMD2/polyneuropathy in this case.

Background: Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition associated with cardiac arrhythmias. The patients typically develop early, asymptomatic bradyarrhythmia, which may lead to sudden death, preventable with a cardiac implantable electronic device (CIED). EDMD may be characterised by atrial electrical silence. Intra-operative electrophysiological evaluation of the myocardium helps ultimately determine the true nature of the disorder and select an appropriate CIED. Aim: To analyse permanent electrotherapy procedures in EDMD patients: atrial pacing limitations that stem from the electrophysiological properties of the myocardium and long-term follow-up of implanted devices. Methods: A total of 21 EDMD patients (mean age 29 ± 9 years) with a CIED implanted (1976–2014) due to bradyarrhythmia were included in the study. The implantation procedures and factors determining the CIED type selection were analysed. Results: CIEDs were implanted in five women and in 16 men with EDMD types 1 and 2 (mean follow-up: 11 ± 8 years). Intra-operatively assessed atrial electrophysiology resulted in changing the planned CIED type during the procedure in three men with EDMD type 1. Eventually, we implanted: eight DDD, one VDD, 11 VVI, and one CD-DR device, with four of the patients’ devices switched later from DDD to VVI mode in response to electrophysiological changes in the atria. Conclusions: Intra-operative assessment of atrial electrophysiological properties resulted in changing the planned DDD mode for VVI in 19% of patients with EDMD type 1. Progression of the underlying disease over a 39-year follow-up resulted in a later change of the initially selected pacing mode from DDD to VVI in 40% of cases.

Congenital fiber type disproportion with delayed fiber type maturation and the appearance of cap structures were analyzed in a child with p.Arg168Gly mutation in TPM3 gene. Very narrow myotube-like Type 1 fibers with single nuclei decorated by cap structures seem to be a result of a failure in fusion process and mature fiber formation. Repeated mutations in exon 5 of TPM3 gene giving cap structures may be a different consequence of the loss of specific isoform normally operating in the fusion process and sarcomer formation.

Objectives: Emery-Dreifuss muscular dystrophy (EDMD) is a very rare genetic disorder affecting skeletal and heart muscles. The aim of this study was to identify factors which might influence the ability to work in EDMD patients in Poland. Material and Methods: The study included 24 patients suffering from either of the two EDMD forms: 17 with emerinopathy (EDMD1; EDMD caused by mutations in the emerin gene) and 7 with laminopathy (EDMD2; EDMD caused by the lamin A/C gene mutations). After clinical evaluation of EDMD course, study participants were questioned about their education, current and former employment, and disability certificates and pensions. Results: 54% of the study participants were employed, and 90% of them had job position corresponding to their education. Undertaking work did not correlate with the level of physical performance or disease complication, but it revealed statistically significant correlation with a higher level of education (p = 0.015). Only 23% of professionally active patients were employed in a sheltered workplace. Disability certificate was granted to all EDMD2 and to 90% of EDMD1 patients. All EDMD2 and 50% of EDMD1 patients received a disability pension, which reflects more severe course of EDMD2. Conclusions: Higher level of education increased the chance of employment, even if significant disability was present. Therefore, I hypothesize that advice on education and jobcounseling should be applied as early as possible after the diagnosis of EDMD.

The LMNA gene encodes lamin A and lamin C, structural components of the nuclear lamina. The nuclear lamina of nuclear envelope (NE) is a scaffold, which provides structural and mechanical stability for the NE; it consists primarily of type V intermediate filament proteins (A-type and B-type lamins) and many inner nuclear membrane proteins.1 ,2 Interaction of lamins with heterochromatin and with transcriptional regulators suggests their important role in the maintenance of chromatin organisation and ingene expression.3 At the NE periphery, lamin precursors undergo a series of post-translational modifications. B-type lamins are permanently isoprenylated, whereas prelamin A loses its modification after incorporation into the lamina by lamin A-specific processing steps involving Zmpste24 endoprotease.4 ,5 The LMNA gene is located on chromosome 1q21.2–q21.3.6 Its coding region spans approximately 24 kb and contains 12 exons; alternative splicing within exon 10 gives rise to two different mRNAs that code for prelamin A and lamin C.7 Different diseases have been ascribed to mutations in this gene including these affecting skin, cardiac and/or skeletal muscles, nerves, fat tissue and bones.8 One of the diseases associated with the LMNA mutations is Hutchinson–Gilford progeria syndrome (HGPS), usually arising due to the de novo heterozygous single base change (GGC>GGT) in exon 11 creating an abnormal splice donor site and resulting in the production of truncated protein, progerin.9–12 HGPS is a very rare, fatal disorder characterised by postnatal growth retardation, midface hypoplasia, premature atherosclerosis, absence of subcutaneous fat, alopecia and generalised osteodysplasia with osteolysis and pathological fractures.9 ,10 ,13 The skin of children with HGPS has atrophic epidermis, dermal fibrosis (scleroderma-like with thickening, disorganisation and hyalinisation of collagen bundles), thin or absent hypodermis and a complete loss of skin appendages or decrease in number of sebaceous glands and hair …

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.

Background Danon disease is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). Materials and Methods Our study describes a 19-year-old man with isolated hypertrophic cardiomyopathy, in whom we performed DNA analysis and compared results of microscopic analysis of skeletal and cardiac muscles. Results Sequencing of the LAMP-2 gene revealed a novel point mutation c.137G > A in exon 2, leading to premature stop codon. Ultrastructural analysis of cardiac and skeletal muscles revealed the presence of unusual autophagic vacuoles in both. Although some vacuoles in skeletal muscle reacted strongly with dystrophin, β-sarcoglycan, and laminin, those in cardiomyocytes showed no immunoreactivity. Conclusion Our immunohistochemical and ultrastructural findings reinforce the claim that in Danon disease the pathomechanism of chaperone-mediated autophagy in cardiomyocytes differs from that in skeletal muscle.

Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area.

Introduction: Levels of natriuretic peptides in blood are often tested for as screening for heart disease and their progress assessed. Dilated cardiomyopathy (DCM) with conduction disturbances is one of the leading serious manifestations in genetically transmitted Emery-Dreifuss muscular dystrophy (EDMD). However, the potential significance of and variability to brain-natriuretic peptides (BNP) and atrial-natriuretic peptides (ANP) in this disease has not been tested hitherto. It seemed worth considering whether estimation of natriuretic peptides might help in defining cardiac dysfunction in the early stages of the disease, prior to the appearance of echocardiographic changes. This is perceived especially important in cardiologically asymptomatic patients, who are still at risk of cardiac sudden death. Patients and Methods: Serum levels of BNP, NT-proBNP, ANP and NT-proANP were quantified by ELISA sandwich immunoassay in 25 EDMD patients (10 autosomal-dominant AD-EDMD, 15 X-linked EDMD), 8 X-EDMD carriers, 9 patients with dystrophinopathy as disease controls, and 20 age-matched healthy controls. Results: Serum levels of BNP, NT-pro-BNP, ANP, and NT-proANP were elevated in the blood of about 50% of patients with both the AD-EDMD and the X-EDMD form. Values were distributed from normal through to highly elevated. In the X-EDMD group there was a marked increase in the ANP and NT-proANP values. The X-EDMD group also manifested a correlation between level of atrial natriuretic peptides, echocardiographic parameters and severity of cardiac symptoms. Conclusions: The presented results indicate that assessment of circulating natriuretic peptides is of limited value in identifying cardiac involvement in EDMD. However, when included to the panel of other cardiologic biomarkers the estimation of natriuretic peptides may offer additional information in respect of proper diagnosis, prognosis, monitoring of appropriate treatment, prediction of outcome. and help to prevent cardiac decompensation and sudden death.

Background Tenascin-C (TN-C), an extracellular matrix glycoprotein, is of diagnostic and prognostic value in different heart diseases. One such dilated cardiomyopathy (DCM) with conduction disturbances is one of the most serious manifestations in Emery-Dreifuss muscular dystrophy (EDMD). Herein we therefore detail work to evaluate the potential significance of circulating TN-C in patients with EDMD, speculating that it may define the cardiac dysfunction, especially in patients who may be cardiac asymptomatic, but still be at risk of sudden death. Material and method Serum levels of TN-C were quantified by sandwich immunoassay ELISA in 25 EDMD patients (10 with laminopathy—AD-EDMD and 15 with emerinopathy—X-EDMD), 8 X-EDMD carriers, 9 disease controls (patients with dystrophinopathy), and 15 age-matched healthy controls. Fourteen of the EDMD patients had repeated TN-C examinations after 3 to 7 years. Results The levels of circulating TN-C were elevated in AD-EDMD and X-EDMD patients, as well as in some X-EDMD carriers, and patients with dystrophinopathy. The correlation between the TN-C level and left end-systolic ventricle diameter (LVDD) was significant in X-EDMD, while those with left atrium diameter (LAD) and the ejection fraction (EF) were not. In “follow-up” studies TN-C levels were not found to change over time in AD-EDMD, while rising in X-EDMD. Conclusions The presented results indicate that assessments of circulating TN-C levels may help to identify EDMD patients at risk of dilated cardiomyopathy. TN-C might therefore be considered a candidate for a new biomarker, useful in detecting of cardiomyopathy and in further monitoring of the DCM therapy in patients with EDMD.

Familial partial lipodystrophy (FPLD) belongs to the family of laminopathies - disorders associated with mutation in the lamin A/C gene (LMNA). FPLD is characterized by loss of subcutaneous adipose tissue from the limbs, trunk and buttocks, with its concomitant accumulation on the face, neck and intra-abdominal region, and by metabolic disorders. We present the first Polish family with FPLD confirmed genetically. A 34-year-old woman admitted with myalgia and cushingoid appearance was found to have a round face with double chin, neck bump, and loss of fat on extremities. Diagnostic tests revealed impaired glucose tolerance and increased levels of liver enzymes, and ultrasonography revealed hepatic steatosis. Her 9-year-old daughter presented a similar phenotype, but no fat loss. A genetic test revealed the presence of a heterozygous LMNA gene mutation: c.1445G>A, consistent with the "hot spot" for FPLD. Treatment with metformin to improve insulin resistance and address the diabetes proved successful.

The authors present the results of a 4-year follow-up of patients with Emery-Dreifuss dystrophy (EDMD) included in a project on laminopathies. The focus of the discussion is on the clinical and genetic characteristics, and the classification of the two forms of Emery-Dreifuss dystrophy [i.e. associated with either emerinopathy (EDMD1) or laminopathy (EDMD2)].The study includes 37 patients from 12 families with EDMD, 28 having emerinopathy and 9 with laminopathy. On the basis of findings from clinical examination and laboratory tests (24-hour ECG monitoring, echocardiography, histological and immunohistochemical studies of muscle), the authors describe phenotypes of the two forms of Emery-Dreifuss dystrophy, the natural course of the disease, and a possible severe cardiovascular involvement which may lead to severe cardiac complications and sudden death. The patients with EDMD were treated mainly by cardiologists. Besides symptomatic management, implantation of a cardiac pacemaker or cardioverter-defibrillator is often required.The intrafamilial and interfamilial variability of laminopathies is discussed in relation to interactions between nuclear proteins. Since the EDMD carrier state in females is associated with cardiac symptoms (without skeletal muscle involvement), systematic cardiological supervision is indicated. Likewise, there are certain patients presenting a typical EDMD phenotype in which no mutations in the EMD or LMNA genes can be confirmed. This may indicate that an Emery-Dreifuss-like dystrophy could also be associated with mutations in other genes.

Hutchinson–Gilford progeria is a rare genetic disorder resulting from mutations in the LMNA gene encoding lamin A/C. In addition to the classical phenotype usually caused by the 1824C>T mutation of LMNA, a number of atypical progeroid syndromes have been described. They have some distinct features, such as skeletal deformities or scleroderma-like skin changes. The underlying defect is usually a homozygous mutation of LMNA, or a combined defect of LMNA and another gene, for example, ZMPSTE-24. We present a 2-year-old girl born to consanguineous parents affected by progeroid syndrome with scleroderma-like skin changes. Genetic analysis revealed the homozygous LMNA mutation 1303C>T (R435C). The same heterozygous mutation was found in the patient's parents and 11 other family members. The progeroid syndrome in our patient shares the signs of two laminopathies: progeria and restrictive dermatopathy. Two other children in the family died at the age of 2 due to a disease similar to that in the proposita. On the basis of the family pedigree we presume that these children probably had the same homozygous LMNA mutation. Scleroderma-like skin changes in infants, associated with growth retardation and dysmorphic features, suggest premature aging syndrome, requiring genetic testing and counseling of asymptomatic carriers of LMNA mutations. © 2009 Wiley-Liss, Inc.

We present a 6-year-old girl with premature aging associated with mild myopathy, displaying muscle weakness, joint contractures and hyporeflexia. Genetic analysis revealed rare heterozygous point mutation in lamin A/C gene, g.428C>T. Cardiological evaluation showed atrial fibrillation, but we did not find signs of coronary heart disease, which is life-threatening cardiovascular complication in progeria. Electron microscopy of the muscle revealed abnormalities in nuclear architecture, i.e. blebbing, thick lamina and peripheral distribution of heterochromatin. As some diagnostic criteria characteristic for classic progeria are not fulfilled, this case could be regarded as atypical progeria associated with myopathy and atrial fibrillation. To our knowledge, this is the second case of such association described in the literature.

Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disorder caused by mutations of the SMN1 gene. Because of the autosomal recessive type of transmission, the genetic risk of the disease in the following generations is small and is estimated to be about 1%. Here we present a case report of a father and son suffering from SMA. The father is affected with a mild form of SMA, with onset at about 13 years of age. The son suffers from SMA type 2, with onset at about 13 months of age. In both father and son, genetic analysis showed biallelic deletion of exons 7 and 8 in the SMN1 gene. The boy's mother is a carrier of the deletion at the SMA locus. Quantitative analysis revealed one copy of the SMN1 gene.

Hutchinson-Gilford progeria causing premature aging of children is a genetic disease and according to most authors has an autosomal dominant inheritance. It has been regarded as a model of the process of aging. In 2003 mutations in the LMNA gene, localized f in chromosome 1, responsible for the disease, were identified. The most frequent mutation is located in exon 11, C1824T and does not change glycin in position 608 of protein chain, but activates cryptic splice site. This results in shortened lamin A synthesis which is named progerin. Point mutations in other exons of LMNA, found in progeria patients, are responsible for atypical phenotypes.

LMNA gene encodes for nuclear intermediate filament proteins lamin A/C. Mutations in this gene lead to a spectrum of genetic disorders, collectively referred to as laminopathies. Lamin A/C are widely expressed in most differentiated somatic cells but not in early embryos and some undifferentiated cells. To investigate the role of lamin A/C in cell phenotype maintenance and differentiation, which could be a determinant of the pathogenesis of laminopathies, we examined the role played by exogenous lamin A and its mutants in differentiated cell lines (HeLa, NHDF) and less-differentiated HEK 293 cells. We introduced exogenous wild-type and mutated (H222P, L263P, E358K D446V, and ∆50) lamin A into different cell types and analyzed proteins’ impact on proliferation, protein mobility, and endogenous nuclear envelope protein distribution. The mutants give rise to a broad spectrum of nuclear phenotypes and relocate lamin C. The mutations ∆50 and D446V enhance proliferation in comparison to wild-type lamin A and control cells, but no changes in exogenous protein mobility measured by FRAP were observed. Interestingly, although transcripts for lamins A and C are at similar level in HEK 293 cells, only lamin C protein is detected in western blots. Also, exogenous lamin A and its mutants, when expressed in HEK 293 cells underwent posttranscriptional processing. Overall, our results provide new insight into the maintenance of lamin A in less-differentiated cells. Embryonic cells are very sensitive to lamin A imbalance, and its upregulation disturbs lamin C, which may influence gene expression and many regulatory pathways. Electronic supplementary material The online version of this article (doi:10.1007/s00412-016-0610-9) contains supplementary material, which is available to authorized users.

In the pathogenesis of dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD) matrix metalloproteinases (MMPs) are supposed to be involved and may have diagnostic/prognostic value. Serum levels of MT1-MMP, MMP-2 and MMP-9 were quantified by ELISA and zymography in 22 EDMD patients and 15 age-matched controls. In the autosomal-dominant EDMD MMP-2 and MT1-MMP were increased in all cases, and MMP-9 was increased in two of the eight examined patients. In the X-linked EDMD MMP-2 expression was increased in all the cases, MMP-9 level was elevated in 3 of the 14 cases, and MT1-MMP was decreased in eight of these patients. There was no evident correlation between the MMPs level and the different cardiac parameters including left-ventricular end-diastolic diameter, left atrial diameter and left ventricular ejection fraction in either form of EDMD. The presented results indicate that a changed level of matrix metalloproteinases, especially that of MMP-2 in serum, may be of value for detection of cardiac involvement in EDMD patients, especially in those patients with no evident subjective cardiac symptoms. Further follow-up studies of MMPs are needed to check if their determination is of value for monitoring of the progression of atrial/ventricular dilatation. MMPs determinations may also be useful for monitoring DCM treatment by synthetic MMPs inhibitors.