Björn Lindvall

Myosin storage myopathy associated with a heterozygous missense mutation in MYH7

Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/β‐cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/β‐cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/β‐cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/β‐cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/β‐cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

Extensive inflammatory cell infiltration in human skeletal muscle in response to an ultraendurance exercise bout in experienced athletes

The impact of a 24-h ultraendurance exercise bout on systemic and local muscle inflammatory reactions was investigated in nine experienced athletes. Blood and muscle biopsies were collected before (Pre), immediately after the exercise bout (Post), and after 28 h of recovery (Post28). Circulating blood levels of leukocytes, creatine kinase (CK), C-reactive protein (CRP), and selected inflammatory cytokines were assessed together with the evaluation of the occurrence of inflammatory cells (CD3(+), CD8(+), CD68(+)) and the expression of major histocompatibility complex class I (MHC class I) in skeletal muscle. An extensive inflammatory cell infiltration occurred in all athletes, and the number of CD3(+), CD8(+), and CD68(+) cells were two- to threefold higher at Post28 compared with Pre (P < 0.05). The inflammatory cell infiltration was associated with a significant increase in the expression of MHC class I in muscle fibers. There was a significant increase in blood leukocyte count, IL-6, IL-8, CRP, and CK at Post. At Post28, total leukocytes, IL-6, and CK had declined, whereas IL-8 and CRP continued to increase. Increases in IL-1β and TNF-α were not significant. There were no significant associations between the magnitude of the systemic and local muscle inflammatory reactions. Signs of muscle degenerative and regenerative events were observed in all athletes with various degrees of severity and were not affected by the 24-h ultraendurance exercise bout. In conclusion, a low-intensity but very prolonged single-endurance exercise bout can generate a strong inflammatory cell infiltration in skeletal muscle of well-trained experienced ultraendurance athletes, and the amplitude of the local reaction is not proportional to the systemic inflammatory response.

Childhood onset tubular aggregate myopathy associated with de novo STIM1 mutations

Abstract We investigated three unrelated patients with tubular-aggregate myopathy and slowly progressive muscle weakness manifesting in the first years of life. All patients showed type 1 muscle fiber predominance and hypotrophy of type 2 fibers. Tubular aggregates were abundant. In all three patients mutations were identified in the gene STIM1, and the mutations were found to be de novo in all patients. In one of the patients the mutation was identified by exome sequencing. Two patients harbored the previously described mutation c.326A>G p.(His109Arg), while the third patient had a novel mutation c.343A>T p.(Ile115Phe). Taking our series together with previously published cases, the c.326A>G p.(His109Arg) seems to be a hotspot mutation that is characteristically related to early onset muscle weakness.

The expression of adhesion molecules in muscle biopsies: the LFA-1/VLA-4 ratio in polymyositis.

Objectives– The expression of three pairs of adhesion receptors and ligands was examined in 22 consecutive muscle biopsies showing morphological signs of inflammation. Material and methods– The following groups were studied: patients with polymyositis (PM) (n=7), patients with myositis that did not fulfil criteria for PM, i.e. suspected PM (n=5), patients with other diseases, with no clinical signs of inflammatory myopathy (n=6), and a small group of non‐PM inflammatory myopathies (n=4). The endothelial expression of ICAM‐1, VCAM‐1 and E‐selectin was evaluated, as was the cellular expression of LFA‐1, VLA‐4 and SLex. In addition, the expression of MHC class I and II was studied. Results– The ratio between the number of cells expressing LFA‐1 and VLA‐4 showed significant differences between the groups, with the lowest values in PM. Conclusion– The LFA‐1/VLA‐4 ratio should be suitable for diagnostic purposes. Our findings also indicate that the VLA‐4/VCAM‐1 system is important for chronic T cell inflammation in muscle, in line with findings in other “hidden” organs like joints and the central nervous system.

Classification and Diagnostic Investigation in Inflammatory Myopathies: A Study of 99 Patients

Objective. Insights into the pathogenesis of inflammatory myopathies have led to new diagnostic methods. The aims of our study were (1) to evaluate the consequences of using the classification of Amato/European Neuromuscular Centre Workshop (ENMC) compared to that of Bohan and Peter; and (2) to evaluate any diagnostic benefit in using an extended pathological investigation. Methods. From a consecutive retrospective database, we evaluated 99 patients for classification. Patients with inclusion body myositis (IBM) were classified according to Griggs, et al. In addition to routine stainings and immunohistochemistry, a multilevel serial sectioning procedure was performed on paraffin-embedded material, to identify scarce pathological findings. Results. Classification according to Bohan and Peter could be performed for 83 of the 99 patients, whereas only 60 patients met the Amato/ENMC criteria, the latter resulting in the following diagnostic groups: IBM (n = 18), nonspecific myositis (n = 14), polymyositis (n = 12), dermatomyositis (n = 10), dermatomyositis sine dermatitis (n = 5), and immune-mediated necrotizing myopathy (n = 1). Most of the Amato/ENMC diagnostic groups harbored patients from several of the Bohan and Peter groups, which included a substantial group lacking proximal muscle weakness. The serial sectioning procedure was essential for classification of 9 patients (15%), and led to a more specific diagnosis for 13 patients (22%) according to Amato/ENMC. Conclusion. The classification of Amato/ENMC was more restrictive, forming groups based on clinical criteria and specified myopathological findings, which clearly differed from the groups of the Bohan and Peter classification. An extended pathological investigation increased the diagnostic yield of a muscle biopsy and highlights the quantity and specificity of certain pathological findings.

Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle

The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle, we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

Increased prevalence of celiac disease in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM) are often associated with other immune‐mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of Östergötland, Sweden.

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease

BackgroundMyotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania).ResultsThe registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact.ConclusionsThe community should consider how to maximise this collective resource in future therapeutic programmes.

Epidemiology and Screening for Pompe Disease in Sweden

Pompe disease (PD; acid maltase defi ciency or glycogen storage disease type II) is an autosomal recessive inherited, potentially treatable metabolic myopathy with heterogeneous clinical presentations and with considerable overlap of signs and symptoms found in other neuromuscular disorders. According to previous reports, patients with PD have been incorrectly diagnosed for several years as limb–girdle muscular dystrophies (LGMDs). To diagnose both entities is challenging, and a diagnostic delay of several years seems to be common. The frequency of misdiagnosis is unknown. No epidemiologic studies have been carried out on PD in the nordic countries.

Subacute neuronopathy in a young man: a possible association with tetracycline treatment

A young man with subacute neuronopathy following tetracycline treatment is described. The symptoms started as a sensory dorsal root affection but by time also involved motor nerves. He developed a severe sensory ataxia with pseudoathetotic movements. Other possible aetiologies were scrutinized and excluded. Tetracycline induced neuronopathy is hitherto not reported in the literature. We propose a possible association between treatment with tetracycline and the development of sensory neuronopathy in this patient.