Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin

Desminopathy is a genetically heterogeneous disorder with autosomal dominant pattern of inheritance in most affected families; the age of disease onset is on average 30 years. We studied a patient with a history of recurrent episodes of syncope from infancy who later developed second-degree AV block and restrictive cardiomyopathy; she subsequently suffered several episodes of ventricular tachyarrhythmia requiring implantation of bicameral defibrillator. Neurological examination revealed rapidly progressive bilateral facial weakness, winging of the scapulae, symmetric weakness and atrophy of the trunk muscles, shoulder girdle and distal muscles of both upper and lower extremities. Muscle biopsy demonstrated signs of myofibrillar myopathy with prominent subsarcolemmal desmin-reactive aggregates. Molecular analysis identified a homozygous deletion in DES resulting in a predicted in-frame obliteration of seven amino acids (p.R173_E179del) in the 1B domain of desmin. We describe the youngest known desminopathy patient with severe cardiomyopathy and aggressive course leading to the devastation of cardiac, skeletal and smooth musculature at an early age

Transcription-terminating mutation in telethonin causing autosomal recessive muscular dystrophy type 2G in a European patient

A 27-year-old woman of Moldavian origin presented at the age of 15 with progressive proximal limb weakness and painful cramps in her calf muscles. Clinical examination revealed prominent Muscle weakness in proximal muscles of the lower extremities and distal anterior compartment of legs, and mild weakness in shoulder girdle muscles. In addition, she had marked calf hypertrophy, Muscle atrophy involving the anterior and posterior compartments of the thighs, and the distal anterior compartment of legs, as well as mild scapular winging and hyperlordosis. A muscle biopsy taken from the biceps brachii showed mild dystrophic changes, absent vacuoles, and abundant lobulated fibers. Immunofluorescence and Western blot assays demonstrated complete telethonin deficiency. Molecular analysis revealed a homozygous Trp25X mutation in the telethonin (TCAP) gene resulting in termination of transcription at an early point. Four families from Brazil with telethonin deficiency have previously been reported and classified as LMD2G, but the actual frequency of this disease is unknown. With this current identification of a case outside the Brazilian Population, telethonin mutation-associated LGMD should be considered worldwide. (C) 2008 Elsevier B.V. All rights reserved

Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype?

Myotilinopathies are a group of muscle disorders caused by mutations in the MYOT gene. It was first described in two families suffering from limb girdle muscle dystrophy type 1 (LGMD 1A), and later identified in a subset of dominant or sporadic patients suffering from myofibrillar myopathy, as well as in a family with spheroid body myopathy. Disease phenotypes associated with MYOT mutations are clinically heterogeneous and include pure LGMD forms as well as late-onset distal myopathies. We report here on a 53-year-old male suffering from a unique clinical profile characterized by generalized symmetrical increase in muscle bulk leading to a Herculean appearance. Muscle weakness and stiffness in the lower extremities were the patient's main complaints. Muscle MRI showed extensive fatty infiltration in the thigh and leg muscles and a muscle biopsy showed a myofibrillar myopathy with prominent protein aggregates. Gene sequencing revealed a Ser55Phe missense mutation in the myotilin gene. The mutation was identified in his older brother, who presented a mild hypertrophic appearance and had a myopathic pattern in EMG, despite not presenting any of the complaints of the proband and having normal muscle strength. This finding, and his deceased father and paternal aunt's similar gait disorders, suggest that this is in fact a new autosomal dominant kindred. The present observations further expand the spectrum of clinical manifestations associated with mutations in the myotilin gene

Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations

Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy

Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRY A B, M YOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 M FM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in M YOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis. (C) 2011 Elsevier B.V. All rights reserved

Numerical modeling of induction heating systems with load of azimuthal periodicity

The paper presents developed numerical modelling methodology of induction heating problems of disks with a simple and complex profile in 3D for calculating the coupled electromagnetic and thermal tasks in the parametric design language (ANSYS APDL). We demonstrate that the developed tools can be used for products of various sizes, as well as for other metal engineering components using the example of local electromagnetic processing of a metal disk and a diaphragm spring. The authors used development for parametric research and design of induction heaters. The described methodology has particular specificity, due to which it is possible to expand the scope for a number of engineering units with azimuthal periodicity property

Does thrombosis play a causal role in lacunar stroke and cerebral small vessel disease?

Objective: The importance of thromboembolism in the pathogenesis of lacunar stroke (LS), resulting from cerebral small vessel disease (cSVD), is debated, and although antiplatelets are widely used in secondary prevention after LS, there is limited trial evidence from well-subtyped patients to support this approach. We sought to evaluate whether altered anticoagulation plays a casual role in LS and cSVD using two-sample Mendelian randomization. Methods: From a recent genome-wide association study (n=81,190), we used 119 genetic variants associated with venous thrombosis at genome-wide significance (P<5*10−8) and with a linkage disequilibrium r2 <0.001 as instrumental variables. We also used genetic associations with stroke from the GIGASTROKE consortium (62,100 ischemic stroke cases: 10,804 cardioembolic stroke; 6,399 large-artery stroke; 6,811 LS). In view of the lower specificity for LS with the CT-based phenotyping mainly used in GIGASTROKE, we also used data from patients with MRI-confirmed LS (n=3,199). We also investigated associations with more chronic MRI features of cSVD, namely white matter hyperintensity (n=37,355) and diffusion tensor imaging metrics (n=36,533). Results: Mendelian randomization analyses showed that genetic predisposition to venous thrombosis was associated with an increased odds of any ischemic stroke (OR=1.19, 95% CI=1.13–1.26), cardioembolic stroke (OR=1.32, 95% CI=1.21–1.45), and large-artery stroke (OR=1.41, 95% CI=1.26–1.57), but not with LS (OR=1.07, 95% CI=0.99–1.17) in GIGASTROKE. Similar results were found for MRI-confirmed LS (OR=0.94, 95% CI=0.81–1.09). Genetically predicted risk of venous thrombosis was not associated with imaging markers of cSVD. Interpretation: These findings suggest that altered thrombosis plays a role in the risk of cardioembolic and large artery stroke but is not a causal risk factor for LS or imaging markers of cSVD. This raises the possibility that antithrombotic medication may be less effective in cSVD and underscores the necessity for further trials in well-subtyped cohorts with LS to evaluate the efficacy of different antithrombotic regimens in LS.This research was funded a British Heart Foundation programme grant (RG/F/22/110052). Infrastructural support was provided the Cambridge British Heart Foundation Centre of Research Excellence (RE/18/1/34212) and by the Cambridge University Hospitals National Institute for Health and Care Research (NIHR) Biomedical Research Centre (NIHR203312). ELH is supported by the Alzheimer’s Society (AS-RF-21-017). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care