Search

In the Eastern European Plain, the Desna valley has delivered few gravettian settlements. The group of Pushkari is characterized by final gravettian occupations relied to the Last Glacial Maximum, before the maximum peak. These are the sites of Pushkari I and Pushkari VIII (Pogon). New excavations were conducted for the last decades. In order to highlight the subsistence strategies adopted by humans we proceeded to the zooarchaeological and lithic analyses of these assemblages. In both sites, the faunal spectrum is restricted, mainly composed of Mammuthus primigenius, then Equus sp., R. tarandus, Canis lupus and Vulpes vulpes/Vulpes lagopus. The skeletal preservation and mortality profile of mammoth shows that they were slaughtered and butchered by human groups. Furthermore some bones were gathered, particularly tusks, which are associated to a new dwelling structure, fireplaces and small pits. These are two of the few final Gravettian sites showing a quite developed organization of the camps. Reindeer, horse and canids could also be hunted more punctually for the exploitation of fur, fat, meat and marrow. Moreover we have an important use of bones as fuel, whose mammoth bones. According to the lithic study, this is local flint exploited to produce blades and bladelets, tool-kit contains backed points and rectangles, points of large form and burins, relied to hunting and butchering activities. The Pushkari group shows among the last occupations of the Desna valley by late Gravettian peoples of a specific ethnic group, before that the end of the Last Glacial Maximum peak marks the disappearance of late Gravettian peoples and of human populations between 19 and 16,000 BP.

The first part of the Upper Pleniglacial (around 26000—20000 BP) is characterized by a deterioration in weather conditions, which reached its peak during the Last Glacial Maximum. In the East European Plain, most of its lands were dominated by a periglacial steppe-tundra with the maximum extension of ice sheet in the North and permafrost. The different animal species had to adapt to these environments, also as human groups.The recent works realized in Ukraine permit to better understand the lifestyles of the Palaeolithic human groups, particularly their subsistence activities, the modalities of settlements and the technocultural practices. We based our study on the main sites, Dorochivtsy III, Galich 1, Klussy, Korman, Molodova V, Obollonia, Oselivka, Pushkari 1 and Pogon (Pushkari 8). These sites are very important to better understand the human occupations for all the East European Plain. Here we particularly focus on the zooarchaeological remains, which permitted to better determine the taphonomic conditions, the human activities, the seasonality of occupations and the human and other animal relationships. The main species present in archaeological sites are Mammoth, Reindeer, Horse, Fox and Wolf, who have important implication on the territory modification and the food resource for humans. Moreover the animal eco-ethology involvement of their acquisition-exploitation by nomadic hunter-gatherers, permits to highlight the potential human behavioral strategies. They show the continuous occupation of the territories by humans, in any seasons, with the persistence of organized activities, innovations and varied behaviors. This period corresponds to the changes between middle Gravettian and late Gravettian, then first Epigravettian features. The end of the Last Glacial Maximum peak marks the disappearance of Late Gravettian and of human populations between 19—16000 BP, followed by a hiatus until 16000 BP.

The Palaeolithic site of Rascov 8, discovered in the 1950's, was recently subjected to new investigations. It yielded archaeological layers from the Upper Pleniglacial. We used zooarchaeological methods to deepen knowledge about this site. We focused on the taphonomy, the anatomical representation of the different species and the anthropogenic activities to better determine the use of natural resources by humans, in particular of animal origin, to understand which strategies were used, the technocultural practices and territory occupation. The taphonomic observations are quite typical of a dry and cold environment. They also suggest that the 3 and 3a layers result from the same or chronogically closely occupations, affected by soil movements. Concerning the anthropogenic features, repeated short-term occupations, on a seasonal basis, mainly hunting and butchering activities of one or several small human groups have been highlighted. Whereas in the older layer humans exploited the carcass of a mammoth, in the other layers they hunted reindeer and horses and butchered the carcasses on the site, probably transporting some parts elsewhere. Whereas the lithic industries are different between layers 4/3-3a (Epiaurignacian) and 2/1 (Epigravettian), the subsistence behavior is similar and quite typical of Molodovian.

Palaeolithic archaeological sites of the Western Ukraine are clustered along the Prut and Dniester Rivers. Different sites provided data enabling reconstruction of the paleoenvironment, chronology and cultures of human group during the Upper Paleolithic (notably Molodova V). During the second part of the Pleniglacial, between 23 000 and 20 000 years BP, palaeoclimatic variations took place. The intensification of cold and arid conditions is liable to force human groups to adapt to a changing environment. Little is known about this period, with only a few assemblages. Ongoing excavations continue to provide new data. The archaeological site of Dorochivtsy III has an important sequence stratigraphy with several archaeological layers. Among the seven Upper Palaeolithic layers, layers 6, 5, 4 and 3 testify to activities of a human group during the Upper Pleniglacial. We studied the faunal assemblages applying zooarchaeological methods, identifying mammoth (Mammuthus primigenius), reindeer (Rangifer tarandus), horse (Equus sp.) and fox (Alopex lagopus/Vulpes vulpes). The Gravettian layers 3, 4, 5 have anthropogenic clues in connection with subsistence activities oriented on reindeer, then horses, and finally fox. Concerning mammoths, we cannot define the modes of acquisition and use. These occupations have been interpreted as recurrent hunting occupations linked to procurement of local flint and lithic production for butchering activities. Layer 6 dated to 22 330 ± 100 BP is remarkable because of previously unseen practises. The lithic assemblage combined with bone industry and engraved tusk is a novel set of cultural elements in this area, called ancient Epigravettian. This layer testifies to the diversity of human activities during the Upper Pleniglacial and to the particular status of mammoth ivory as an artistic medium. Palynological data and taphonomic observations on bones indicate the persistence of relatively moist conditions during some periods, which could favour the movement of human groups. Although little is known about the Upper Pleniglacial period, Dorochivtsy III testifies to the continuity of a large exploitation of the territory of the Dniester valley.

Oculopharyngeal muscular dystrophy (OPMD) is mainly characterized by ptosis and dysphagia. The genetic cause is a short expansion of a (GCN)10 repeat encoding for polyalanine in the poly(A) binding protein nuclear 1 (PABPN1) gene to (GCN)12–17 repeats. The (GCN)11/Ala11 allele has so far been described to be either a polymorphism or a recessive allele with no effect on the phenotype in the heterozygous state. Here we report the clinical and histopathological phenotype of a patient carrying a single (GCN)11/Ala11 heterozygous allele and presenting an atypical form of OPMD with dysphagia and late and mild oculomotor symptoms. Intranuclear inclusions were observed in his muscle biopsy. This suggests a dominant mode of expression of the (GCN)11/Ala11 allele associated with a partial penetrance of OPMD.

The Pushkari archaeological complex is one of the few sites which shows human occupations related to the first part of the Upper Pleniglacial. Pushkari I furnished rich archaeological material. Study of the lithic industry identified a facies of Gravettian with epigravettian features, called Pushkarian. In order to figure out acquisition and treatment modalities of large mammals, and to test the hypothesis of the use of woolly mammoth as a source of food and building material, we conducted a zooarchaeological study of the faunal remains from excavation VII of Pushkari I. The faunal spectrum is made of Mammuthus primigenius , the predominant species, Equus sp., R. tarandus , Canis lupus and Vulpes vulpes/Alopex lagopus . Taphonomic study suggests that some bone remains of mammoth lay in open-air for a long time before they were buried while bones of carnivores and other bones of mammoth were quickly buried. All the assemblage was affected by acid sandy deposits. Phenomena of freeze-thaw action were observed, but the archaeological layer was little disturbed. Mammoths came regularly on the promontory. The skeletal preservation shows that they died there. The mortality profile with a majority of adults combined with a palethnographic interpretation suggests that they were slaughtered and butchered by human groups. Tusks were stored. The spatial distribution indicates a campsite, which corresponds to recurrent short-termed occupations on the promontory by human groups. This site is a strategic place to collect flint to make weapons, to find dry mammoth bones, and to hunt and butcher mammoths. This study provides new data to understand the particular status of the woolly mammoth for the Upper Pleniglacial human groups in the Russo-Ukrainian plain.

Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. Results: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a “dropped head” syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. Interpretation: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD). Ann Neurol 2008;64:177–186

Background: Heart-hand syndromes are a heterogeneous group of genetic disorders characterized by the association of congenital cardiac disease and limb deformities. Laminopathies are a group of diseases caused by mutations in the LMNA gene encoding A-type lamins. Results: We report a new LMNA mutation (c.1609-12T>G, IVS9-12 T>G) that creates a new cryptic splicing site with the retention of 11 intronic nucleotides in the mRNA. This LMNA mutation segregates with a new type of heart-hand syndrome in a previously reported family suffering from adult-onset progressive conduction system disease, atrial and ventricular tachyarrhythmias, sudden death, dilated cardiomyopathy, and brachydactyly with predominant foot involvement. Analysis of the fibroblasts of 2 affected family members identified for the first time a truncated lamin A/C protein resulting from the frame shift created by the new splicing site, together with nuclear envelope abnormalities confirming that this LMNA mutation is pathogenic. Conclusions: This new heart-hand syndrome should therefore be considered as a new kind of laminopathy. And as part of laminopathies with heart involvement, patients presenting with this phenotype and their relatives are at risk for developing sudden cardiac death and should beneficiate from appropriate LMNA genetic diagnosis.

The Upper Pleniglacial, between 23 000–20 000 BP, is characterized by the intensification of cold climate and is followed by the maximum extent of ice sheets. There is a little bit information about the human activities during this period. New archaeological excavations in Ukraine permit to evidence data about behavioural human adaptations. These open air sites are on the one hand Pushkari 1 (excavation VII), Pogon (excavation VII) and Obollonia in the Desna valley and on the other hand Dorochivtsy III in the Dniester valley. These sites are characterised by atypical lithic industries made on local flint relied to the Gravettian but containing Epigravettian or Aurignacoid elements. In order to better understand the subsistence strategy we carried out zooarchaeological and taphonomical studies, which allow us to reveal the strategy of fauna exploitation by the human groups. We highlighted that all these sites are characterized by a restricted faunal spectrum with the presence of mammoth, reindeer, horse and carnivores (mainly fox [Vulpes vulpes and Alopex lagopus] and wolf). In the Dniester valley the reindeer was the most exploited, whereas the mammoth is the most exploited in the Desna valley. Indeed, it was probably hunt in Pushkari 1, maybe in Pogon and Obollonia. It was exploited as combustible, food resources and bones as raw material. In Dorochivtsy III/6 ivory was used to make tools and as artistic support. Indeed this site and Obollonia present grooved ivory points, this is the oldest occurrence of this kind of artefacts in the both regions. Moreover two engraved tusks presenting more or less figurative pictures were found in Dorochivtsy III/l.6 and Obollonia. The other large herbivores were also consumed and carnivores were exploited for their pelts in all these sites. The settlements are recurrent camps with little development occupied during varied seasons oriented to hunting and butchering activities linked with exploitation of local flint. These sites demonstrate the continuity of human occupations within the Eastern European plain, with the persistence of hunting methods and the relative diversity of animal exploitation, during the Upper Pleniglacial. These sites are really important for the understanding of cultural processes in the Eastern European Upper Palaeolithic, and particularly for the understanding of Epigravettian origin.

Resume Introduction La dystrophie musculaire des ceintures de type 1B (LGMD1B), due a des mutations du gene LMNA , associe une faiblesse musculaire des ceintures a une atteinte cardiaque caracterisee par des troubles de la conduction auriculo-ventriculaire et une cardiomyopathie dilatee. Elle reste une forme peu connue de dystrophie des ceintures, et seulement 7 mutations du gene LMNA ont ete decrites comme etant responsables d’une LGMD1B. Le diagnostic clinique et genetique de cette myopathie est essentiel pour assurer la prise en charge de l’atteinte cardiaque et le conseil genetique. Patients et methodes Nous decrivons l’atteinte musculaire et cardiaque de 14 patients appartenant a 8 familles chez qui ont ete identifiees 6 mutations differentes, dont 4 nouvelles, du gene LMNA . Resultats Onze patients avaient une LGMD1B avec une atteinte scapulo-humerale et pelvi-femorale. Treize patients avaient une atteinte cardiaque. Des troubles de la conduction etaient presents chez 12 patients, et des troubles du rythme chez 9 patients. Sept patients ont beneficie de l’implantation d’un pacemaker ou d’un defibrillateur. Une transplantation cardiaque fut pratiquee dans 2 cas. Conclusion Cette etude permet de preciser les principales caracteristiques cliniques de cette affection musculaire ainsi que les premieres relations phenotype/genotype resultant de ces nouvelles observations.

Emery Dreifuss muscular dystrophy is a genetically heterogeneous disorder characterized by the clinical triad of early onset contractures, progressive muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects. Mutations in the Lamin A/C (LMNA) gene are responsible for the autosomal dominant and the autosomal recessive forms. Familiar and sporadic patients carrying mutations in the LMNA gene show high variability in the clinical symptomatology and age of onset. In this report, we describe four families harboring missense mutations in the LMNA gene and we show that the effect of mutations ranges from silent to fully penetrant. We suggest that incomplete penetrance of dominant mutations in the LMNA gene is a common feature and we emphasize the significance of mutational analysis in relatives of sporadic cases of laminopathies, as asymptomatic carriers face high risk of sudden cardiac death.

Background —The 2 genes KCNQ1 (LQT1) and HERG (LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients. Methods and Results —The T-wave morphology of carriers of mutations in KCNQ1 (n=133) or HERG (n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively, P P HERG . Conclusions —This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting HERG core domain missense mutations.

Life-threatening cardiac and respiratory complications are common in LMNA-related myopathies and early diagnosis is important for optimal patient care. Lamin A/C related congenital muscular dystrophy (L-CMD) is often caused by de novo mutation in LMNA, affecting a single child in a family. Germinal mosaicism is a rarer variant that can lead to two children inheriting the same new heterozygous mutation from a clinically unaffected parent. Both patterns mimic autosomal recessive (AR) inheritance and the possibility of de novo L-CMD may be forgotten since most causes of congenital muscular dystrophy follow AR inheritance. To illustrate the challenge of diagnosing L-CMD, we present a consanguineous family in which two children have early onset LMNA-related myopathy likely due to paternal germinal mosaicism. This emphasises that germinal mosaicism (and de novo mutations) for LMNA can arise in any family and direct gene sequencing is required to confirm or exclude the diagnosis.

Background —The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG . In this study, we investigated the 3′ part of HERG for mutations. Methods and Results —New specific primers allowed the amplification of the 3′ part of HERG , the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG , 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1 . The 2 more severely affected sisters bore both mutations. Conclusions —The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.

Introduction En garantissant une qualite irreprochable de l’ensemble des techniques de preparation du prelevement, le technicien en anatomie et cytologie pathologique (ACP) a un role central et indispensable pour permettre l’etablissement d’un diagnostic. Devant le developpement de la specialite, son role evolue. Pour accompagner ces changements, un groupe de techniciens s’est structure en Midi-Pyrenees sous l’egide du reseau regional de cancerologie ONCOMIP. Un groupe de travail, compose d’une vingtaine de techniciens volontaires issus de laboratoires ACP publics et prives de la region, a ete mis en place en 2013. Objectifs Elaborer des fiches techniques dans le cadre du processus qualite, renforcer les echanges et la communication entre pairs, ameliorer et reactualiser les pratiques professionnelles. Methodes La coordination operationnelle est effectuee par ONCOMIP et tous les travaux du groupe sont relus et valides par le reseau des pathologistes de Midi-Pyrenees. Resultats Entre 2013 et 2015, le groupe s’est reuni lors de 13 seances de travail en presence de 7 techniciens en moyenne. Les premieres reunions ont permis la mise en place du groupe avec notamment son mode de fonctionnement, le choix des themes techniques a aborder ainsi que les premiers objectifs. La conception des premieres fiches a necessite plus d’une annee de travail, plusieurs reunions et de nombreux echanges. La fiche technique coloration Hemalun-Eosine est la premiere fiche technique elaboree par le groupe. L’Hemalun-Eosine est une coloration histologique topographique qui donne une vue d’ensemble d’un tissu. C’est la 1re etape necessaire et essentielle pour etablir un diagnostic. La fiche technique Inclusion explique l’etape d’inclusion d’un tissu. Cette technique consiste a enrober le tissu prealablement deshydrate pour realiser le bloc. Cette etape conditionne la qualite de la coupe et la conservation du prelevement. Ces fiches ont ete elaborees en utilisant la methodologie standardisee des documents de reference et en appliquant la charte graphique d’ONCOMIP. Toutes les fiches porteront des elements communs comme l’identification du type de fiche, un cartouche qualite, et suivront un plan comprenant le principe, le protocole, les resultats et les points de vigilance propres a chaque technique. Les fiches sont accessibles et telechargeables librement sur le site Internet d’ONCOMIP ( http://www.oncomip.org/fr ). Leur telechargement sera suivi afin de connaitre leur utilisation dans la region. Les fiches elaborees pourront servir de base dans le cadre du processus qualite de chaque structure et de support pour les nouveaux techniciens. Conclusion Le groupe des techniciens permet d’accompagner et de renforcer la structuration de l’activite d’anatomo-cytopathologie a l’echelle regionale. De plus, il facilite les echanges entre les techniciens de la region, quelle que soit leur structure d’exercice. Il est ainsi un veritable support de partage d’experience et d’amelioration des pratiques.

International audience; Introduction: Post-synaptic congenital myasthenic syndromes (CMSs) (OMIM_ #608931) is a group of genetic disorders affecting neuromuscular transmission and due to acetylcholine receptor (AChR) deficiency in 80% of cases.[1] These autosomal recessive CMSs may be caused by mutations in genes encoding the AChR or one of the AChR-clustering or anchoring proteins, rapsyn, Dok-7 or MuSK.[1-4] Spectra of rapsyn mutations show allelic heterogeneity and suggest that the common substitution p.Asn88Lys (N88K) (variant_021217 in Q13702) results in less stable AChR clusters.[5] Until recently, all patients harbouring mutations in RAPSN are either homozygous for the p.Asn88Lys substitution or heteroallelic for p.Asn88Lys and a mutation which is in most of cases an amino acid substitution but can be also a null allele.[6] Analysis of disease severity in patients suggested that the second mutant allele may largely determine severity of the phenotype.[7] Recently, a patient with two non p.Asn88Lys in RAPSN has been described and the first chromosomal deletion event was described by Müller and colleagues.[8,9]

Desmin myopathy is a heterogeneous neuromuscular disorder characterized by skeletal myopathy and cardiomyopathy, inherited mostly in an autosomal dominant pattern. We report a five generation Uruguayan family with severe cardiomyopathy and skeletal myopathy. Its most striking features are: atrial dilation, arrhythmia, conduction block and sudden death due to conduction impairment. Affected skeletal muscle shows alteration of mitochondria with paracrystallin inclusions and granulofilamentous material scattered in the muscle fibres. This family carries an unusual deletion p.E114del within the 1A rod domain of desmin. Transfected cells expressing the mutated desmin show punctuated and speckled cytoplasmic aggregates. The mutation causes a local conformational change in heptads a/d residues and charge positions. These findings lead to the hypothesis that coiled-coil interactions may be impaired, resulting in severe alterations in the desmin network. This is the first time that a mutation affecting this domain in the desmin molecule is described in a desminopathy.

Laminopathies are now recognized as a group of disorders due to mutations of the LMNA gene, which encodes A-type lamins. Primarily, mutations in LMNA have been associated to the autosomal forms of Emery-Dreifuss muscular dystrophy, a rare slowly progressive humero-peroneal muscular dystrophy accompanied by early contractures and dilated cardiomyopathy with conduction defects. LMNA mutations have been reported to be responsible for up to 10 distinct phenotypes that affect specifically either the skeletal and/or cardiac muscle, the adipose tissue, the peripheral nervous tissue, the bone tissue or more recently premature ageing. So far more than 180 different LMNA mutations have been identified in 903 individuals. The first studies of phenotype/genotype relationships revealed no dear relation between the phenotype and the type and/or the localization of the mutation, except perhaps for the globular tail domain of lamins A/C. Studies of the consequences of LMNA mutations in the skin cultured fibroblasts from the patients reveal abnormal nuclei in variable proportions, with dysmorphic nuclei exhibiting abnormal patterns of expression of B-type lamins and emerin. Finally, the development of KO and KI LMNA mice, will certainly give further insight into the pathophysiological mechanisms associated with LMNA mutations. For example, Lmna(H222P/H222P) mice harbour phenotypes reminiscent of Emery-Dreifuss muscular dystrophy.

Background: Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery–Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes. Methods: Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin. Results: Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892C→T, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD -mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts. Conclusions: This highlights the crucial role of lamin A/C–emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery–Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.

Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B.We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation.This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.

Background Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, have been associated with 7 distinct pathologic conditions. Objective To report 5 cases with the same missense mutation in exon 6 of the LMNA gene, resulting in an E358K substitution in the central rod domain. Design Case report. Setting Three muscle centers in England. Patients Five patients with missense mutations of the LMNA gene. Results All 5 individuals had muscle involvement, but the onset, severity, distribution of muscle weakness, and presence of associated features were highly variable. Three patients had humeroperoneal distribution of weakness and typical features of Emery-Dreifuss muscular dystrophy. Two other patients showed additional novel features. One had congenital onset and predominant axial weakness, with poor neck control and inability to sit independently at the age of 21 months. Another patient presented in childhood with an unusual pattern of muscle weakness, short stature, and midface hypoplasia with striking fat accumulation around the face and neck, in contrast to wasting of adipose tissue and muscle in the limbs. She developed both respiratory failure and cardiac arrhythmias in her late 20s. Conclusion Our cases expand the clinical spectrum associated with mutations in the LMNA gene and further illustrate the overlapping phenotypes of the laminopathies.

Mutations in the lamin A/C gene are found in Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy with cardiac conduction disturbances, dilated cardiomyopathy with conduction system disease, and familial partial lipodystrophy. Cases with lamin A/C mutations presenting with lipodystrophy in combination with cardiac and/or skeletal muscle abnormalities are described.

Abstract —The voltage-gated K + channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K + homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the α subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1 , which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA) n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of the complete KCNQ1 gene. By use of these tools, five novel mutations were identified in LQTS patients by PCR–single-strand conformational polymorphism (SSCP) analysis in the C-terminal part of KCNQ1 : two missense mutations, a 20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the C-terminal domain of the gene may be more frequent than previously expected, because this region has not been analyzed so far. This could explain the low percentage of mutations found in large LQTS cohorts.

The LMNA gene encodes two nuclear envelope proteins, lamins A and C, derived from alternative splicing. First identified in autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD),1 mutations in this gene are implicated in up to seven diseases including autosomal recessive EDMD (AR-EDMD),2 limb-girdle muscular dystrophy type 1B (LGMD1B),3 dilated cardiomyopathy with conduction defects (DCM-CD),4,5 autosomal dominant partial lipodystrophy of Dunnigan type,6 autosomal recessive axonal Charcot-Marie-Tooth disease (AR-CMT2),7 mandibuloacral dysplasia,8 and Hutchinson-Gilford progeria syndrome.9,10 In addition, some patients appear to have a combination of these different phenotypes11,12 or a clinical variant including skin abnormalities.13 To extend the clinical spectrum of laminopathies, we report a previously undescribed dominant missense mutation, E33D, identified in LMNA and clinically characterised by the combination of axonal neuropathy with myopathic features, cardiac disease including dilated cardiomyopathy, conduction disturbances and arrhythmia, and leuconychia. The LMNA gene is therefore the first gene implicated in both autosomal dominant and recessive forms of CMT2. The pedigree of a white family originating from the south west of France is shown in fig 1. The index case (II-5) and his affected daughter (III-13) were neurologically and cardiologically assessed by one of our team; only partial information was available for other affected members through questioning of patient III-13. The clinical features of all the affected members are shown in table 1. The results of nerve electrophysiological examination of patients II-5 and III-13 are shown in table 2. A muscle CT scan performed for patient II-5 showed wasting and marked fatty infiltration predominating in paraspinal, vasti, hamstring, and gastrocnemius muscles (fig 2). Fig 3 shows the fingernails of patients II-5 and III-13, exhibiting leuconychia. View this table: Table 1 Clinical features of the affected family members View this table: Table 2 Electrophysiological study of patients II-5 and III-13 Figure 1 Pedigree of the family. Arrow …