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Intermediate filaments are 10 nm structures that interact with actin and microtubules to form the cytoskeletal scaffolding of the cells. They share a common structure of a dimer with 2 alpha helical chains intertwined in a coiled-coil highly conserved rod structure. In the muscle, intermediate filaments constitute 1% of the total proteins and include lamin A/C, emerin, desmin, paranemin, nestin, vimentin, peripherin and possibly syncoilin. Together with various proteins associated with them, such as plectin and αB crystalline, the intermediate filaments play a fundamental role in the structural resilience of the myofibres. A group of neuromuscular diseases that selectively affect intermediate filaments, has now emerged that can be collectively called "filamentopathy". The prototypic filamentopathy causing myopathy is the one due to mutations in the desmin gene (desmin myopathy); others may be due to defects in nuclear intermediate filaments such as lamin A/C and emerin, causing dilated cardiomyopathy or Emery-Dreifuss muscular dystrophy; and still others due to mutations in plectin or αB crystallin causing myofibrillar myopathy, as discussed later. The prototypic filamentopathy affecting nerves is the one due to mutations in gigaxonin that results in an axonal neuropathy; the prototypic filamentopathy affecting skin is caused by mutations in the keratin gene. Finally, mutations in neurofilament subunits may lead to motor neuron cell death.

OBJECTIVE: The current pathological diagnostic criteria for sporadic inclusion body myositis (IBM) lack sensitivity. Using immunohistochemical techniques abnormal protein aggregates have been identified in IBM, including some associated with neurodegenerative disorders. Our objective was to investigate the diagnostic utility of a number of markers of protein aggregates together with mitochondrial and inflammatory changes in IBM. DESIGN: Retrospective cohort study. The sensitivity of pathological features was evaluated in cases of Griggs definite IBM. The diagnostic potential of the most reliable features was then assessed in clinically typical IBM with rimmed vacuoles (n=15), clinically typical IBM without rimmed vacuoles (n=9) and IBM mimics-protein accumulation myopathies containing rimmed vacuoles (n=7) and steroid-responsive inflammatory myopathies (n=11). SETTING: Specialist muscle services at the John Radcliffe Hospital, Oxford and the National Hospital for Neurology and Neurosurgery, London. RESULTS: Individual pathological features, in isolation, lacked sensitivity and specificity. However, the morphology and distribution of p62 aggregates in IBM were characteristic and in a myopathy with rimmed vacuoles, the combination of characteristic p62 aggregates and increased sarcolemmal and internal major histocompatibility complex class I expression or endomysial T cells were diagnostic for IBM with a sensitivity of 93% and specificity of 100%. In an inflammatory myopathy lacking rimmed vacuoles, the presence of mitochondrial changes was 100% sensitive and 73% specific for IBM; characteristic p62 aggregates were specific (91%), but lacked sensitivity (44%). CONCLUSIONS: We propose an easily applied diagnostic algorithm for the pathological diagnosis of IBM. Additionally our findings support the hypothesis that many of the pathological features considered typical of IBM develop later in the disease, explaining their poor sensitivity at disease presentation and emphasising the need for revised pathological criteria to supplement the clinical criteria in the diagnosis of IBM.

Common elements: Primary inflammatory myopathies consist of dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). They have certain characteristics in common: progressive muscle weakness and mononuclear inflammatory infiltrates in the muscle. Different mechanisms: They may be distinguished by their histological features which also reflect their different underlying pathogeneses. The mechanism of DM would be complement-mediated microangiopathy, the inflammatory infiltrate of which would be secondary to ischemic phenomena, whereas in PM the muscle fibres are damaged by cytotoxic CD8 T lymphocytes. The factors triggering-off these two forms of myositis remain unknown. IBM may be a degenerative disease with accumulation of a variety of proteins within the fibres. The inflammatory infiltrate, which is similar to that seen in PM, may be a reaction to accumulated proteins.

OBJECTIVE: Polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) are two developmental brain malformations that have been described independently in multiple syndromes. Clinically, they present with epilepsy and developmental handicaps in both children and adults. Here we describe their occurrence as the two major findings in a new cortical malformation syndrome with several distinct subtypes. METHODS: Twenty-seven patients were identified as having both PNH and PMG on brain imaging. Their brain imaging characteristics and clinical data were reviewed. Mutation analysis for FLN1 was carried out on six patients. RESULTS: The group was divided into two main subtypes based on brain imaging findings. The posterior PNH-PMG subtype had 16 patients and was characterized by PNH in the posterior and inferior lateral ventricles, and by PMG that was most severe in the temporo-parietooccipital regions. The perisylvian PNH-PMG subtype had eight patients and was characterized by PNH lining the lateral body and frontal horns of the lateral ventricles, and by PMG that was most severe in the perisylvian areas, occasionally with extension to the frontal and parietal lobes. Two variants were distinguished that were distinct from the two main subtypes. Key differences in the clinical characteristics of the two main subtypes were distinguished, including differences in developmental outcome and seizures. No FLN1 mutations were identified. CONCLUSIONS: The PNHPMG subtypes and variants we describe have distinct imaging and clinical phenotypes, suggesting multiple genetic etiologies involving defects in a gene or genes. Delineation of these syndromes will aid in providing more accurate diagnosis and prognostic information for patients with these malformations.