Mutations In LMNA Gene Research Articles

0460: Right heart involvement in patients with laminopathies

Laminopathies are rare genetic diseases, with various clinical manifestations. Cardiac involvement may include conduction system disease, supraventricular and ventricular arrhythmias, and dilated cardiomyopathy. In other cardiac diseases, right ventricular dysfunction has been associated with an impaired prognosis. To study the prevalence of right ventricular involvement in laminopathies and its influence on patient outcome. We retrospectively included 138 patients (age=37 [25-49], female=58%) with LMNA gene mutations. At baseline, conduction system disease was present in 36% of patients, supraventricular arrhythmias in 25%, non-sustained and sustained ventricular tachyarrhythmias (VT) in 7 and 6%, left ventricular dysfunction in 42%. The association of right ventricular systolic dysfunction and clinical signs of right heart failure was observed in 18 patients (13%) including 9 who presented with isolated right ventricular without left ventricular systolic dysfunction. Over a 13.5 median follow-up duration, 47 patients (34%) developed major cardiac adverse events, including 23 with end-stage heart failure, 28 with sustained VT, and 26 with 2 nd degree Mobitz II or 3 rd degree AV blocks. Right ventricular involvement was significantly associated with truncating mutations (44% vs. 22%, p=0.04), higher global mortality (44% vs. 17%, p<0.001), end-stage heart failure (56% vs. 11%, p<0.001), sustained ventricular tachycardia (56% vs. 17%, p<0.001), supraventricular tachyarrhythmias (94% vs. 49%, p<0.001), and sinus node dysfunction (33% vs. 7%, p<0.001). Patients with laminopathies are at risk for right ventricular dysfunction, which may be present without any left ventricular systolic dys-function and frequently leads to end-stage heart failure.

Advances in muscle imaging for Emery-Dreifuss muscular dystrophy

Laminopathies are a heterogeneous group of disorders related to alterations on genes coding for proteins of the nuclear envelope. Among these clinical entities, there are several diseases affecting mainly the cardiac and skeletal muscles. These disorders include forms with a selective cardiac compromise and muscular dystrophies (autosomal and X-linked forms of Emery-Dreifuss muscular dystrophy, Limb girdle muscular dystrophy 1B, LMNA-related congenital muscular dystrophy and other rare clinical entities). We performed imaging studies on a large cohort of subjects bearing either LMNA or EMD gene mutations; each patient enrolled displayed variable compromise on posterior legs’ muscles, ranging from mild compromise on soleus and medial head of gastrocnemius to overt alterations on soleus, medial head of gastrocnemius [1,3]. Of note, we saw that even subjects presenting with clinically selective cardiac compromise displayed, on imaging studies, variable alterations on skeletal muscles. This findings showed a continuum in skeletal muscles compromise among different phenotypes related to LMNA or EMD gene mutations and lead to hypothesize a common mechanism in the process of damage of skeletal muscles fibers.

LMNA-associated myopathies: the Italian experience in a large cohort of patients

We conducted a retrospective study in a large cohort of myopathic patients carrying LMNA gene mutations to evaluate clinical and molecular features associated with different phenotypes. To this purpose we included 90 LMNA-mutated myopathic patients and 36 LMNA-mutated familial cases without muscle involvement. Among the myopathic patients LGMD1B was by far the most frequent phenotype, observed in 43 (48%) patients, followed by L-CMD in 21 (23%), EDMD2 in 20 (22%) and an atypical myopathy in 6 (7%). The different myopathic phenotypes shared a similar cardiac impairment. On the other hand comparing cardiac features between myopathic and familial cases without muscle involvement we observed that cardioverter defibrillator or pacemaker were implanted more frequently in myopathic patients (n=43) (p=0.006). In addition heart transplantation and death were observed only in myopathic subgroup, respectively in 8 (9%) and 10 (11%) patients. In conclusion LMNA-related myopathies represent a continuum clinical spectrum; their clinical course appears to be dominated by cardiac involvement, considering the relatively low frequency of other complications, including loss of ambulation, assisted ventilation, surgery for scoliosis or gastrostomy. Longitudinal studied are needed to better investigate their natural history and provide indications for early management of heart involvement, in particular in first decades of life, to prevent the risk of fatal events.

Clinical aspects of cardiolaminopathies and prospects for a cardiolaminopathy registry

Mutations in the LMNA gene, encoding nuclear proteins lamin A/C, have been associated with neurological and cardiac disease and a high risk of sudden death. The implant of a cardioverter defibrillator (ICD) is to date the only effective intervention, but no specific guidelines are available. We decided to create a common Italian database integrating clinical and genetic data of patients bearing LMNA gene mutations to improve knowledge of natural history of cardiopathy, define a risk stratification protocol for ICD implant and investigate genotype/phenotype correlations. To date, 113 patients (age 47±18) from 11 Italian centers have been included in our database and followed for 7±11 years. We evaluated age at onset of different phenotypes. 70% developed cardiac symptoms, including both rhythm (atrial fibrillation, atrio-ventricular block, ventricular tachycardias) and structural defects (dilated cardiomyopathy, mitral insufficiency), which may or may not be preceded by neurological signs. Cardiac magnetic resonance was pathologic in 2/3 of studied patients. We also evaluated the occurrence of ICD implantation, appropriate shocks, cardiac transplantation and heart failure. Open questions include the identification of predictors of arrhythmias to allow early diagnosis and improve risk stratification and management of asymptomatic patients.

Génétique des lipodystrophies congénitales

Congenital lipodystrophies are heterogeneous genetic diseases, leading to the loss of adipose tissue. This loss of adipose tissue can be generalized or partial, thus defining different phenotypes. These lipodystrophies have a major metabolic impact, secondary to lipotoxicity. This lipotoxicity is responsible for insulin resistance, dyslipidemia and hepatic steatosis. The severity of the metabolic impact correlates with the severity of the loss of adipose tissue. Mutations in 15 predisposition genes are currently described; BSCL2 and AGPT2 genes are the major genes in the generalized forms. On the contrary, LMNA and PPARG gene mutations are recovered in partial lipodystrophies forms. These different genes encode for proteins involved in adipocyte physiology, altering adipocyte differentiation, triglycerides synthesis and lysis or playing a major role in the lipid droplet formation. Congenital lipodystrophies treatment is based on the management of metabolic comorbidities but recombinant leptin therapy appears to have promising results.These different points have been recently discussed during the 2015 Endocrine Society Congress, notably by S. O'Rahilly and are highlighted in this review.

Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway.

Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand the pathogenesis caused by mutant lamins, we performed a structural and functional analysis on LMNA missense mutations identified in muscular dystrophy patients. These mutations perturb the tertiary structure of the conserved A-type lamin Ig-fold domain. To identify the effects of these structural perturbations on lamin function, we modeled these mutations in Drosophila Lamin C and expressed the mutant lamins in muscle. We found that the structural perturbations had minimal dominant effects on nuclear stiffness, suggesting that the muscle pathology was not accompanied by major structural disruption of the peripheral nuclear lamina. However, subtle alterations in the lamina network and subnuclear reorganization of lamins remain possible. Affected muscles had cytoplasmic aggregation of lamins and additional nuclear envelope proteins. Transcription profiling revealed upregulation of many Nrf2 target genes. Nrf2 is normally sequestered in the cytoplasm by Keap-1. Under oxidative stress Nrf2 dissociates from Keap-1, translocates into the nucleus, and activates gene expression. Unexpectedly, biochemical analyses revealed high levels of reducing agents, indicative of reductive stress. The accumulation of cytoplasmic lamin aggregates correlated with elevated levels of the autophagy adaptor p62/SQSTM1, which also binds Keap-1, abrogating Nrf2 cytoplasmic sequestration, allowing Nrf2 nuclear translocation and target gene activation. Elevated p62/SQSTM1 and nuclear enrichment of Nrf2 were identified in muscle biopsies from the corresponding muscular dystrophy patients, validating the disease relevance of our Drosophila model. Thus, novel connections were made between mutant lamins and the Nrf2 signaling pathway, suggesting new avenues of therapeutic intervention that include regulation of protein folding and metabolism, as well as maintenance of redox homoeostasis.

Various lamin A/C mutations alter expression profile of mesenchymal stem cells in mutation specific manner.

Various mutations in LMNA gene, encoding for nuclear lamin A/C protein, lead to laminopathies and contribute to over ten human disorders, mostly affecting tissues of mesenchymal origin such as fat tissue, muscle tissue, and bones. Recently it was demonstrated that lamins not only play a structural role providing communication between extra-nuclear structures and components of cell nucleus but also control cell fate and differentiation. In our study we assessed the effect of various LMNA mutations on the expression profile of mesenchymal multipotent stem cells (MMSC) during adipogenic and osteogenic differentiation. We used lentiviral approach to modify human MMSC with LMNA-constructs bearing mutations associated with different laminopathies--G465D, R482L, G232E, R527C, and R471C. The impact of various mutations on MMSC differentiation properties and expression profile was assessed by colony-forming unit analysis, histological staining, expression of the key differentiation markers promoting adipogenesis and osteogenesis followed by the analysis of the whole set of genes involved in lineage-specific differentiation using PCR expression arrays. We demonstrate that various LMNA mutations influence the differentiation efficacy of MMSC in mutation-specific manner. Each LMNA mutation promotes a unique expression pattern of genes involved in a lineage-specific differentiation and this pattern is shared by the phenotype-specific mutations.

Mutation in Genes FBN1, AKT1, and LMNA: Marfan Syndrome, Proteus Syndrome, and Progeria Share Common Systemic Involvement

Genetic mutations are becoming more deleterious day by day. Mutations of Genes named FBN1, AKT1, LMNA result specific protein malfunction that in turn commonly cause Marfan syndrome, Proteus syndrome, and Progeria, respectively. Articles about these conditions have been reviewed in PubMed and Google scholar with a view to finding relevant clinical features. Precise keywords have been used in search for systemic involvement of FBN1, AKT1, and LMNA gene mutations. It has been found that Marfan syndrome, Proteus syndrome, and Progeria commonly affected musculo-skeletal system, cardiovascular system, eye, and nervous system. Not only all of them shared identical systemic involvement, but also caused several very specific anomalies in various parts of the body. In spite of having some individual signs and symptoms, the mutual manifestations were worth mentioning. Moreover, all the features of the mutations of all three responsible genes had been co-related and systemically mentioned in this review. There can be some mutual properties of the genes FBN1, AKT1, and LMNA or in their corresponding proteins that result in the same presentations. This study may progress vision of knowledge regarding risk factors, patho-physiology, and management of these conditions, and relation to other mutations.

Analysis of clinical characteristics and causative genes of Hutchinson-Gilford progeria syndrome in a family

Objective To assess clinicopathological features of and genetic factors in Hutchinson-Gilford progeria syndrome（HGPS）in a family. Methods General information was collected from 3 patients with Hutchinson-Gilford progeria syndrome in a family, which included 5 members over 2 generations with all the 3 children affected by HGPS. All the 3 patients underwent clinical investigation, image analysis of hands, lungs and mandibles, as well as karyotype analysis of chromosomes. LMNA gene mutations were analyzed in these family members. Results All the 3 patients developed skin sclerosis with severe growth retardation and appearance of extreme aging at about 6 months of age. Image analysis showed osteoporosis and mandibular hypoplasia in the elder patient. Karyotype analysis showed no abnormality in the patients or their parents. Mutation analysis revealed a homozygous mutation 1579 C > T（R527C）in exon 9 of the LMNA gene in all the patients, but a heterozygous mutation R527C in the LMNA gene in their parents. Conclusions The patients in this family present characteristic manifestations of HGPS, which may be caused by the homozygous LMNA mutation R527C. Key words: Progeria; LMNA gene; DNA mutational analysis; Hutchinson-Gilford syndrome

Novel linkage of LMNA Single Nucleotide Polymorphism with Dilated Cardiomyopathy in an Indian case study

BackgroundDilated Cardiomyopathy (DCM) is one of the most commonly encountered heart diseases reported globally. It is characterized by enlarged ventricles with impaired systolic and diastolic functions. Mutations in LMNA gene are one of the causative factors to precipitate the disease. However, association of SNPs of LMNA with DCM in particular has not been well documented. MethodHere we present a limited and restricted case study of patients from south eastern part of India afflicted with idiopathic DCM and conduction defects. By using next generation sequencing we have sequenced the exons of LMNA gene from genomic DNA isolated from patients. ResultWe have identified the linkage of 8 different LMNA SNPs with idiopathic DCM viz. rs121117552, rs538089, rs505058, rs4641, rs646840, rs534807, rs80356803 and rs7339. These SNPs are scattered throughout the gene with prevalence for the region encoding the central rod domain of lamin A/C. ConclusionMost of these SNPs in LMNA were previously reported to be involved in various disorders other than DCM. We conclude that, variation in LMNA is one of the major underlying genetic causes for the pathogenesis of DCM, as observed in few Indian populations.

Tissue specific loss of A-type lamins in the gastrointestinal epithelium can enhance polyp size

The nuclear lamina, comprised of the A and B-type lamins, is important in maintaining nuclear shape and in regulating key nuclear functions such as chromatin organization and transcription. Deletion of the A-type lamins results in genome instability and many cancers show altered levels of A-type lamin expression. Loss of function mutations in the mouse Lmna gene result in early postnatal lethality, usually within 3–5 weeks of birth making an analysis of the role of lamins in carcinogenesis difficult. To circumvent early lethality, and determine the role of the A-type lamins in specific tissues in older mice we derived a conditional allele of LmnaFL/FL (floxed). LmnaFL/FL was specifically deleted in the gastrointestinal (GI) epithelium by crossing the LmnaFL/FL mice with Villin-Cre mice. Mice lacking Lmna in the GI are overtly normal with no effects on overall growth, longevity or GI morphology. On a GI specific sensitized (ApcMin/+) background, polyp numbers are unchanged, but polyp size is slightly increased, and only in the duodenum. Our findings reveal that although A-type lamins are dispensable in the postnatal GI epithelium, loss of Lmna under malignant conditions may, to a limited extent, enhance polyp size indicating that A-type lamins may regulate cell proliferation in the transformed GI epithelium.

First report of a novel LMNA mutation in a Chinese family with limb-girdle muscular dystrophy.

LMNA gene encodes the ubiquitous protein lamin A/C, which is a component of the fibrous meshwork of intermediate filaments located at the inner surface of the nuclear envelope (Worman 2012). Lamin A/C are splicing variants encoded by the LMNA gene and share the first 566 amino acids. Mutations in LMNA gene are recently known to be responsible for more than 10 different clinical syndromes, most of which show overlapping features. Worman and Bonne (2007) classified the disorders into four major types: diseases of skeletal and cardiac muscle, lipodystrophy syndromes, peripheral neuropathy and premature ageing. Of the skeletal and cardiac muscles types, limb–girdle muscular dystrophy type 1B (LGMD1B), autosomal dominant Emery–Dreifuss muscular dystrophy 2 (EDMD2) and dilated cardiomyopathy 1A (CMD1A) are common (Capell and Collins 2006). Among the muscle type disorders related to LMNA gene mutations, LGMD1B is slowly progressive, with age-related atrioventricular cardiac conduction disturbance, dilated cardiomyopathy, muscle weakness and the absence of early contractures. However, EDMD2 is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and cardiomyopathywith a variable degree of conduction system disease (Capell and Collins 2006). In this report, we characterized a large Chinese family with atrioventricular block (AVB) as the most prominent feature, with concomitant moderate pelvic limb skeletal muscle defects. Due to the medical history, clinical manifestations and neurological/cardiological examinations, this family was diagnosed with autosomal LGMD1B. Then, a mutation

LMNA-associated myopathies: the Italian experience in a large cohort of patients.

Our aim was to conduct a comparative study in a large cohort of myopathic patients carrying LMNA gene mutations to evaluate clinical and molecular features associated with different phenotypes. We performed a retrospective cohort study of 78 myopathic patients with LMNA mutation and 30 familial cases with LMNA mutation without muscle involvement. We analyzed features characterizing the various forms of LMNA-related myopathy through correlation statistics. Of the 78 patients, 37 (47%) had limb-girdle muscular dystrophy 1B (LGMD1B), 18 (23%) congenital muscular dystrophy (MDCL), 17 (22%) autosomal dominant Emery-Dreifuss muscular dystrophy 2 (EDMD2), and 6 (8%) an atypical myopathy. The myopathic phenotypes shared a similar cardiac impairment. Cardioverter defibrillator or pacemaker was implanted in 41 (53%) myopathic patients compared to 7 (23%) familial cases without muscle involvement (p = 0.005). Heart transplantation was performed in 8 (10.3%) myopathic patients and in none of the familial cases. Ten (12.8%) myopathic patients died; there were no deaths among the familial cases (p = 0.032). Missense mutations were found in 14 patients (82%) with EDMD2 and 14 patients (78%) with MDCL compared to 17 patients (45%) with LGMD1B and 4 (67%) atypical patients. Frameshift mutations were detected in 17 (45%) LGMD1B compared to 3 (18%) EDMD2, 1 (6%) MDCL, and 2 (33%) with atypical myopathy (p = 0.021). Furthermore, frameshift mutations were found in 30 of 73 patients (41%) with heart involvement compared to 4 of 35 (11%) without heart involvement (p = 0.004). Our data provided new insights in LMNA-related myopathies, whose natural history appears to be dominated by cardiac involvement and related complications.

Role of nuclear Lamin A/C in cardiomyocyte functions.

Lamin A/C is a structural protein of the nuclear envelope (NE) and cardiac involvement in Lamin A/C mutations was one of the first phenotypes to be reported in humans, suggesting a crucial role of this protein in the cardiomyocytes function. Mutations in LMNA gene cause a class of pathologies generically named 'Lamanopathies' mainly involving heart and skeletal muscles. Moreover, the well-known disease called Hutchinson-Gilford Progeria Syndrome due to extensive mutations in LMNA gene, in addition to the systemic phenotype of premature aging, is characterised by the death of patients at around 13 typically for a heart attack or stroke, suggesting again the heart as the main site sensitive to Lamin A/C disfunction. Indeed, the identification of the roles of the Lamin A/C in cardiomyocytes function is a key area of exploration. One of the primary biological roles recently conferred to Lamin A/C is to affect contractile cells lineage determination and senescence. Then, in differentiated adult cardiomyocytes both the 'structural' and 'gene expression hypothesis' could explain the role of Lamin A in the function of cardiomyocytes. In fact, recent advances in the field propose that the structural weakness/stiffness of the NE, regulated by Lamin A/C amount in NE, can 'consequently' alter gene expression.

Limb-girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic muscular dystrophies, involving 16 autosomal recessive subtypes and eight autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms. Method: Thirty seven patients were classified as LGMD and included in this analysis. The study period extended from 2009-2012. The female to male ratio was 3:1. The age of onset ranged from two to 13 years, mean 7,5 years. Onset in the first decade was seen in 90%. Results: The initial clinical signs included: frequent falls (22 cases), difficulty in climbing stairs (13 cases), walk on tip toes (2 cases), difficulty in rising from the floor (2 cases) and difficulty on walking (1 case). The serum CK levels were high in all cases. Among the 37 patients, 15 (40,5%) were classified as sarcoglycanopathies (LGMD2C-F), five (13,5%) as dysferlinopathy (LGMD2B), five (13,5%) as calpainopathy (LGMD2A). Mutations in LMNA gene (LGMD1B), FKRP gene (LGMDI) and caveolin gene (LGMD 1C) were identified in two (5,5%), two (5,5%) and one patient (2,5%), respectively. In seven of 37 cases (19%) it was impossible to determine specific diagnosis. Calf hypertrophy, scapular winging and scoliosis were the most characteristic signs in sarcoglycanopathies. In LGMD2I calf hypertrophy is also observed. Atrophy of posterior compartment of thighs is frequent in children with LGMD2B and could suggest the diagnosis. In LGMD2A winging of scapulae and contractures in Achilles tendons were important findings. Muscle biopsy showed a dystrophic pattern in all cases, more intense in sarcoglycanopathies and LGMD2I. Differently from adult’s patients, inflammation changes in dysferlinopaties were uncommon. Lobuled fibers were characteristic changes in calpainopathies in children. Conclusions: A definitive diagnosis among various subtypes of LGMD in children is challenging. Our series was a large study on LGMD in Brazilian children and showed high frequency of sarcoglycanopathies followed by LGMD2A, LGMD2B, LGMD2I, LGMD1B and LGMD1C.

Muscle Disease

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

LMNA gene mutation as a model of cardiometabolic dysfunction: From genetic analysis to treatment response

AimThis report highlights the metabolic, endocrine and cardiovascular comorbidities in a case of familial partial lipodystrophy (FPLD), and also evaluates the efficacy and safety of metformin therapy. MethodsMutational analysis was carried out of the LMNA gene in a teenage girl with an FPLD phenotype. Insulin resistance, sex hormones and metabolic parameters were also evaluated, and echocardiography, electrocardiography and 24-h blood pressure monitoring were also done. ResultsThe patient showed atypical fat distribution, insulin resistance and hypertrophic cardiomyopathy. Physical examination revealed muscle hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, yet excess fat deposits in the face, neck and dorsal cervical region. LMNA sequencing revealed a heterozygous missense mutation (c.1543A>G) in exon 9, leading to substitution of lysine by glutamic acid at position 515 (K515E). Moderate hypertension and secondary polycystic ovary syndrome were also assessed. Treatment with metformin resulted in progressive improvement of metabolic status, while blood pressure values normalized with atenolol therapy. ConclusionsVery rapid and good results with no side-effects were achieved with metformin therapy for FPLD. The association of an unusual mutation in the LMNA gene was also described.

A novel donor site mutation in LMNA gene leading to severe form of Dilated Cardiomyopathy in a proband of a family from Bihar, India

Methods The proband underwent Echocardiography and ECG to confirm the diagnosis. 5ml blood was collected and DNA was extracted using Phenol-chloroform method. The hot spot regions exon 23 of MYH7 gene, exon3 and exon 4 along with the intron3 of LMNA gene were sequenced using Sanger sequencing (ABI 3730xl). ACE 287bpI/D and TNNT25bpI/D polymorphisms were also genotyped. In silico analysis of this novel mutation by using softwares, Human splicing finder (HSF) and MaxENT to understand the effect of mutation on splicing. The study was ethically approved by Institutional committee and informed written consent was taken from all participants.

Phenotype/genotype analysis of 4 cases of LMNA related congenital muscular dystrophy with inflammatory changes

Objective To analyze the clinical characteristics, muscle pathological features and pathogenic gene mutation in 4 cases with LMNA-related congenital muscular dystrophy(L-CMD). Methods Clinical data of the probands and the parents were collected. Skeletal muscle specimens were biopsied from the probands for pathological analysis. Genomic DNA and RNA were extracted from peripheral blood leukocytes, and PCR, reverse transcription(RT)-PCR and DNA direct sequencing were employed to analyze the LMNA gene to determine the gene mutation and confirm the pathogenicity. Results Four patients had symptoms from fetal period to several months after birth. They presented with motor retardation, muscle weakness with prominent the proximal upper limbs, distal lower limbs and neck extensor, hypotonia, contractures, with mild to moderate elevation of CK level. The muscle biopsies showed muscular dystrophic and with inflammatory changes, and the abnormal nuclear morphology was observed with transmission electron microscopy. Genetic analysis of them detected 4 dominant de novo mutations. Three of them had unreported pathogenic mutations. The same sites of the LMNA gene were wild type in their parents. Conclusions Four cases of L-CMD are genetically identified. Genetic counseling of the family can be possible. The patients should be considered LMNA gene mutation of they present themselves with muscle weakness with the proximal upper limbs, distal lower limbs and neck extensor, hypotonia, contractures, mild to moderate elevation of CK level, and if the biopsies show muscular dystrophic changes but also with inflammatory changes should be considered LMNA gene mutation. Genetic analysis is the most reliable method for diagnosing L-CMD. Key words: LMNA related congenital muscular dystrophy; Inflammatory myopathy; LMNA gene; Mutation

Abnormal adipose tissue distribution with unfavorable metabolic profile in five children following hematopoietic stem cell transplantation: a new etiology for acquired partial lipodystrophy.

We report five consecutive patients who underwent hematopoietic stem cell transplantation (HSCT) to treat leukemia or neuroblastoma early in their lives and later manifested abnormal patterns of adipose tissue distribution. Lipoatrophy was remarkable in the gluteal regions and extremities, whereas subcutaneous fat was preserved in the cheeks, neck, and abdomen. In addition, visceral fat deposition, fatty changes in the liver, and metabolic derangements such as insulin resistance and hypertriglyceridemia were evident. These features resemble Dunnigan-type familial partial lipodystrophy, which is a rare condition caused by LMNA gene mutation. These patients shared a common medical history involving HSCT, including conditioning with total body irradiation (TBI). They also received intensive chemotherapy because of multiple metastases (n = 3), relapse (n = 3), and repetitive HSCT (n = 3). We propose HSCT as a new etiology for acquired partial lipodystrophy and recommend that patients who undergo HSCT with TBI and intensive chemotherapy early in their lives must receive careful observation for the possible development of lipodystrophy and metabolic complications.