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• W1999160290 abstract "1. IntroductionThis international ENMC workshop assembled 18 clinicians and scientists from Europe, the United States of America, South America, Japan and Australia to discuss “Rare Structural Congenital Myopathies (CM)”. This workshop can be considered a follow-up to an earlier one [[1]Goebel H.H. Anderson J. Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies). 56th European Neuromuscular Centre (ENMC)-sponsored International Workshop, December 12–14, 1997, Naarden, The Netherlands.Neuromuscul Disord. 1999; 9: 50-57Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar], then and now excluding classical CM on which separate workshops have repeatedly been held at ENMC and respective consortia exist such as on nemaline myopathies, centronuclear myopathies, core myopathies, as well as protein aggregate myopathies. CM can be classified according to CM-specific morphological features, certain epidemiological aspects or on molecular grounds. This workshop addressed those rare CM which, to date, have not been assigned to any known genes by virtue of identifying disease causing mutations. Of the approximately 10 CM discussed at the earlier workshop [[1]Goebel H.H. Anderson J. Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies). 56th European Neuromuscular Centre (ENMC)-sponsored International Workshop, December 12–14, 1997, Naarden, The Netherlands.Neuromuscul Disord. 1999; 9: 50-57Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar] seven have now been clarified molecularly. The workshop concentrated on the remaining three and other rare CM, i.e., tubular aggregates myopathy, cylindrical spirals myopathy, crystalline body myopathy, as well as fingerprint and Zebra bodies myopathies with the goal to characterise them nosologically and to develop further strategies towards their molecular clarification. Since these CM are very rare, it was crucial to perform archival searches in major large neuromuscular centres across the globe and to obtaining relevant clinical findings from patients and their families in preparation for this workshop. Moreover, the suitability of various investigative techniques and pathways to gene discovery was reviewed to apply them to rare CM within individual working groups that were formed amongst the participants of this consortium.2. Background and available techniquesAngela Hübner (Dresden, Germany) presented a linkage facility for a screening of unclassified families with CM and other neuromuscular disorders, which is one of the service structures of the German Muscular Dystrophy network MD-NET.Within the last two decades the application of molecular genetic strategies has led to a delineation of subgroups of clinically indistinguishable neuromuscular disorders and disclosed marked disease overlap. The expanding number of molecularly defined NMDs requires new strategies to classify overlapping and clinical indistinguishable phenotypes. To date, more than 84 different gene loci have been linked to the different forms of muscular dystrophies (MD), CM, congenital myasthenic syndromes (CMS) and myotonias, and for many of them the responsible genes have been cloned and characterised. This has already led to a partial reclassification of NMD, now guided by genotypes rather than phenotypes. Determining the genotype for an individual patient has important implications for prognosis, management, genetic counselling and the potential for prenatal diagnosis. The knowledge about additional gene loci underlying neuromuscular diseases is rapidly increasing so that it becomes more and more difficult for physicians to meet the justified expectations of patients and relatives for professional counselling. Furthermore, the financial and methodological resources required to achieve a diagnosis have increased in a way that new and more economical diagnostic strategies are warranted.Good examples for the validity of this approach are the genetically heterogeneous limb girdle muscular dystrophies (LGMD) or the myofibrillar myopathies (MFM) which present with a marked phenotypical overlap and are difficult to differentiate in early stages. The recent mapping and cloning of a number of novel genes involved in neuromuscular function such as the genes for Dok-7 (DOK7), cofilin 2 (CFL2) and amphiphysin 2 (BIN1) have substantially widened our understanding of the pathogenesis of NMD. Mutations in muscle-specific transcription factors may modify the phenotype and hence become relevant in the molecular genetic diagnosis of MD and myopathies.The MD-NET linkage facility at the Technical University Dresden has developed DNA microsatellite marker sets for 84 gene loci (including MD, MDC, CMS and ion channel muscle diseases) which is ready for use and can be applied for linkage and haplotype analyses in families with unclassified NMDs. This group represents the largest linkage centre specifically dedicated to neuromuscular diseases and has made a substantial contribution to the detection rate of disease-causing mutations in patients and families with yet unclassified NMDs. Quick and large scale linkage and haplotype analyses are provided for most of the currently known neuromuscular diseases. The facility provides a high level of flexibility to include novel genes and gene loci into the screening sets just within a couple of days. The method is based on family analyses of the inheritance of about six genetic markers (microsatellites) in close proximity to each of the candidate genes. Dependent on the size of the families, approximately 40–50 families per year have been investigated so far. This marker set has been proved highly effective for the narrowing of the number of differential diagnoses and for the characterisation of the molecular defect in informative families with extensively prediagnosed but yet unclassified NMDs. So far, 390 informative families were investigated and it was possible to reduce the number of candidate genes to one or two gene loci in 40% of the families, while in about 30% of all families the disease-causing mutation was subsequently identified by direct sequencing. Informative families in whom all known candidate genes are excluded have been transferred to a genome wide linkage scan and in one family the genome scan allowed the identification of a new candidate gene, filamin c (FLNC), for a novel myofibrillar myopathy. The method is universally applicable and can be extended to other diseases with overlapping phenotypes. So far, the investigation is done on a collaborative basis (free of charge) as the project is supported by a grant of the German Federal Ministry of Education and Research (BMBF). In conjunction with this approach other modern genomic approaches were discussed as well, in particular the possibility of sequencing the entire or partial exome in a single patient. This approach would be greatly facilitated by prior haplotype analysis narrowing down the genomic regions to be covered, by affected and unaffected family members to compare discovered alterations, by independent clearly similarly affected patients with similar morphology who likely have the same disease and who therefore then also should have a mutation in the same genes suspected in the initial case; and by clear ideas about possible candidate genes, facilitated by careful morphological and immunohistochemical examination.Caroline Sewry (London, UK) discussed specific aspects of immunohistochemistry that need to be considered when studying biopsies form patients within this group of disorders. Antibodies to numerous muscle proteins localizing to various subcellular regions, are widely available, however, immunohistochemistry likely will only be of value if the structures are numerous and already visible at the light microscopic level with histochemical techniques. Immunohistochemical reduction or absence of a protein caused by a primary gene defect in the gene encoding for the protein is well recognised in recessive disorders (e.g. dystrophin), and secondary abnormalities, such as a reduction, accumulation, or post-translational modification, are also of diagnostic importance. Accumulation of a primarily affected mutant protein can also occur (e.g. actin and desmin). It is not always known if the immunoreactivity of certain structures such as inclusion with a particular antibody accurately reflects the presence of the protein the antibody is supposed to recognise, or if non-specific binding to unusual structures could also occur. Laser capture of specific structures, followed by mass spectrometry could help answer this. Other aspects to consider when applying immunohistochemistry were also discussed. These included studies of interacting proteins, fibre type differences in the localisation of proteins (some structures under consideration are fibre type-specific), and studies of microtubules. The use of different types of microscopic techniques useful for the characterisation of histological phenomena was also discussed, in particular fluorescence methods, as some structures such as cylindrical spirals are autofluorescent. In addition, neither the menadione-NBT technique that stains reducing bodies, nor the stain for myoadenylate deaminase which stains tubular aggregates requires the use of the enzyme substrate and are thus useful additional stains to use in the full histological characterisation of unusual inclusions and bodies found in a muscle biopsy.Carsten Bönnemann (Philadelphia, USA) decribed the laser microdissection mass spectrometry approach used by his laboratory in biopsies from two sporadic patients to identify FHL1 as the most prominent component of reducing bodies, leading to the identification of mutations in FHL1 as underlying the disorder. Reducing body myopathy is the first example for which this type of approach has been successful, potentially making it a model for analysis of other myopathies with prominent inclusions. Several features of reducing body myopathy made this an ideal situation for the laser microdissection mass spectroscopy approach to work: The inclusions are readily visible by light microscopy on eosin staining as condensed material, even without the application of a cover slip and they were frequent and quite uniform. Laser microdissection in the reducing body analysis was done using a Zeiss microscope and P.A.L.M. catapult system on 10 micron frozen sections stained with eosin but not coverslipped. 3000–5000 “shots”, i.e. individual laser punches, were obtained from two sections and captured in 40 μl water, digested with trypsin after intermediary steps, and run on C18 reversed phase HPLC and submitted for mass spectrometry analysis first obtaining a full scan MS, followed by the acquisition of raw MS/MS spectra (tandem mass spectrometry), which were then assigned and annotated. Carsten Bonnemann’s lab has now also verified the technique on sections stained with modified Gomori trichrome, obtaining clean spectra for expected muscle proteins. It was also found that modifications of this stain that result in crosslinking of proteins will interfere with the mass spectrometry analysis. Further developments in the lab will be directed at decreasing the material needed by increasing sensitivity of the mass spectrometry, expanding the technique to other histochemical stains and to immunostained material, exploration of different proteases to capture trypsin resistant proteins, and to consider work on archival material.Hans H. Goebel (Mainz, Germany) reported on the use of electron microscopy to facilitate direct gene analysis, which is possible in certain CM. Cytoplasmic bodies are the crucial morphological hallmark of cytoplasmic body myopathy and other protein aggregate myopathies. They consist of intermediate filaments, separated from a rather electron-dense amorphous core. Another morphological hallmark of protein aggregate myopathies is granulofilamentous material originally considered a morphological equivalent of a distinct type of CM, but now known to be less specific. The granular component of this material is more conspicuous, mixed with myofilaments and beneath the plasma membrane while filaments are often difficult to identify. Nevertheless, the typical components of intermediate filament aggregation, i.e. granular amorphous material and intermediate filaments, are present in such granulofilamentous material as well. Hence, it is of no surprise that certain patients with granulofilamentous material in their diseased muscle fibres have been found to carry heterozygous mutations in the desmin DES gene itself. Rosenthal fibres represent accumulation of granular amorphous electron-dense material and GFAP-positive intermediate filaments of astrocytes. Mutations in the GFAP gene, occurring in Alexander disease, are morphologically marked by innumerable Rosenthal fibres. While filamentous bodies consisting of actin filaments within muscle fibres are a non-specific feature in many different neuromuscular conditions, larger aggregates of actin filaments, are demonstrated by positivity to antibodies to sarcomeric actin at both the electron and light microscopic levels, are found in patients who have heterozygous mutations in the ACTA1 gene. Nemaline myopathies are characterized by sarcoplasmic rods on the basis of possible mutations in genes of Z-band-related proteins such as sarcomeric actin (ACTA1), and tropomyosins 2 and 3 (TPM 2 and 3), and nebulin (NEB), while the marker protein of Z disks, alpha-actinin 2, has not been found to be mutant in nemaline myopathies. Moreover, a subgroup of nemaline myopathies is marked by the presence of intranuclear rods with or without sarcoplasmic rods. These intranuclear rods if not demonstrating a criss-cross pattern of Z-disks may be identified by antibodies against sarcomeric actin by light microscopy and at the ultrastructural level. So far, nemaline myopathies with intranuclear rods have almost exclusively been demonstrated to show heterozygous dominant mutations in the ACTA1 gene.3. Rare structural congenital myopathiesAna-Lia Taratuto (Buenos Aires, Argentina) reported on familial cylindrical spirals myopathy. Cylindrical spirals (CS) have been reported in a few sporadic cases, five of these were associated with myalgia and/or cramps, while two cases, belonging to one family, were associated with a myotonic disorder. Cylindrical spirals were the main pathological finding in muscle biopsies from a 72-year-old mother (case 1) and her 52-year-old son (case 2) who both exhibited myopathic facies and diffuse weakness of late onset [[2]Taratuto A.L. Matteucci M. Barreiro C. Saccolitti M. Sevlever G. Autosomal dominant neuromuscular disease with cylindrical spirals.Neuromuscul Disord. 1991; 1: 433-441Abstract Full Text PDF PubMed Scopus (23) Google Scholar]. At least 10 other family members spanning five generations were variously affected by muscular weakness, gait disorders, motor impairment, and/or scoliosis suggesting an autosomal-dominant trait with variable expression, although these additional family members had not undergone a muscle biopsy yet. In the two biopsies cylindrical spirals were observed in type-2 fibres as sub-sarcolemmal or intermyofibrillar clusters. They appeared bluish with haematoxylin, bright red with Gomori and strongly reactive for non-specific esterase and myoadenylate deaminase. Cylindrical spirals stained faintly with NADH-TR and were non-reactive for succinate dehydrogenase and myofibrillar ATPase. Immunostaining was negative for desmin, actin, and dystrophin. Electron microscopy revealed concentrically wrapped lamellae of 1–2 nm in diameter merging into tubular vesicular structures, some closely resembling tubular aggregates. Dilatation of adjacent lateral sacs suggests an origin of the cylindrical spirals from the sarcoplasmic reticulum. In an innervated muscle tissue culture obtained from case 2 cylindrical spirals were identified within lateral sacs [1Goebel H.H. Anderson J. Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies). 56th European Neuromuscular Centre (ENMC)-sponsored International Workshop, December 12–14, 1997, Naarden, The Netherlands.Neuromuscul Disord. 1999; 9: 50-57Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 3Askanas V. Alvarez R.B. Taratuto A.L. Mc Ferrin J. Angel K. Cylindrical spirals expressed in innervated muscle culture from a patient with autosomal dominant neuromuscular disease.Neurology. 1991; 41: 1070PGoogle Scholar]. A cousin of case 2 with three daughters and one son had been identified more recently, all of them clinically presenting facioscapulohumeral (FSH) involvement of variable severity. A muscle biopsy of the more severely affected daughter at the age of 26 years (case 3, 6th generation) also showed cylindrical spirals together with myopathic features and inflammatory infiltration [[1]Goebel H.H. Anderson J. Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies). 56th European Neuromuscular Centre (ENMC)-sponsored International Workshop, December 12–14, 1997, Naarden, The Netherlands.Neuromuscul Disord. 1999; 9: 50-57Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Frozen tissue from this case is available for possible laser capture micro dissection. DNA studies (Marc Jean-Pierre Cochin/Paris, personal communication) performed in both parents and 3 out of the 4 siblings, showed in all of them a pathologic fragment of 5 D4Z4 repeat units (except the father who had more than 20) consistent with FSHD. After a 13-year follow-up of the clinical evolution in this family, a repeat haplotype analyses at the FSHD1A locus on chromosome 4q35.2 by Angela Hübner, Dresden/Germany involving mother and her children (paternal DNA was not available) showed that the affected proband female (Case 3, 6th generation) had a haplotype that was identical to that of her affected mother and affected siblings, thus supporting linkage to the FSHD locus. Interestingly, a biceps muscle biopsy (although other muscles were clinically more severely affected) of the affected male sibling showed dilatation of the sub-sarcolemmal sarcoplasmic reticulum as well as some vesicles and tubules suggestive of early CS formation, thus supporting the notion of a sarcoplasmic reticulum origin of the the spirals.This family raises the enticing notion, that CS formation could be a direct result of the FSHD mutation. It was thus suggested to study other members of this large family from a morphologic as well as genetic point of view.Janice Holton (London, UK) presented a review of tubular aggregates in skeletal muscle. Tubular aggregates were first described in hypokalaemic periodic paralysis and myotonia congenita. Subsequently four clinical syndromes have been described in which tubular aggregates are the major abnormality in the muscle biopsy: weakness with exercise-induced cramps, pain and stiffness; autosomal recessive limb girdle myasthenia with or without cardiomyopathy; progressive limb girdle weakness which may be sporadic or inherited with an autosomal dominant or recessive pattern; gyrate atrophy of the retina and choroid due to autosomal recessive inheritance of mutations in the gene encoding ornithine aminotransferase. In addition tubular aggregates may be observed in the context of hypokalaemic periodic paralysis, myotonia congenita, inflammatory myopathies, malignant hyperthermia, alcoholic myopathy, Whipple’s disease and porphyria cutanea tarda [[4]Morgan-Hughes J.A. Tubular aggregates in skeletal muscle: their functional significance and mechanisms of pathogenesis.Curr Opin Neurol. 1998; 11: 439-442Crossref PubMed Scopus (45) Google Scholar]. A number of case reports have also been published describing tubular aggregates as a feature in other clinical syndromes. These include distal myopathy in association with multiple mitochondrial DNA mutations in which both ragged red fibres and fibres containing tubular aggregates were a pathological feature [[5]Garrard P. Blake J. Stinton V. et al.Distal myopathy with tubular aggregates: a new phenotype associated with multiple deletions in mitochondrial DNA?.J Neurol Neurosurg Psychiatry. 2002; 73: 207-208Crossref PubMed Scopus (9) Google Scholar]. Cases associated with pupillary abnormalities suggest that smooth muscle dysfunction may occur in some cases in which tubular aggregates are present in skeletal muscle [6Jacques T.S. Holton J. Watts P.M. Wills A.J. Smith S.E. Hanna M.G. Tubular aggregate myopathy with abnormal pupils and skeletal deformities.J Neurol Neurosurg Psychiatry. 2002; 73: 324-326Crossref PubMed Scopus (12) Google Scholar, 7Shahrizaila N. Lowe J. Wills A. Familial myopathy with tubular aggregates associated with abnormal pupils.Neurology. 2004; 63: 1111-1113Crossref PubMed Scopus (20) Google Scholar]. The characteristic morphological appearances of tubular aggregates were described and illustrated. In haematoxylin and eosin preparations tubular aggregates are represented by basophilic regions of varying size, often with an angular profile in the muscle fibre. These may have a sub-sarcolemmal location or be more centrally placed within the fibre. Tubular aggregates are typically bright red in the Gomori trichrome preparation, are darkly stained in the reduced nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR) histochemical reaction and also show strong activity for myoadenylate deaminase. They show no histochemical activity for cytochrome oxidase, succinic dehydrogenase or ATPase. In most cases tubular aggregates are found in type-2 fibres although they have been described in type-1 fibres in familial cases. Ultrastructural studies have demonstrated that tubular aggregates arise from the sarcoplasmic reticulum. In the most commonly observed form they are composed of regular arrays of tubules 50–70 nm in diameter with a smaller central tubule although a number of different forms have been described [[8]Pavlovicova M. Novotova M. Zahradnik I. Structure and composition of tubular aggregates of skeletal muscle fibres.Gen Physiol Biophys. 2003; 22: 425-440PubMed Google Scholar]. Immunohistochemical studies have confirmed the origin of tubular aggregates from the sarcoplasmic reticulum by the demonstration of a number of proteins derived from the sarcoplasmic reticulum within tubular aggregates [[9]Chevessier F. Bauche-Godard S. Leroy J.P. et al.The origin of tubular aggregates in human myopathies.J Pathol. 2005; 207: 313-323Crossref PubMed Scopus (68) Google Scholar]. Preliminary data from a review of the archive of the Division of Neuropathology, UCL Institute of Neurology were also presented. Examination of the database containing details of muscle biopsies performed from 1975 to 2009 identified 27 muscle biopsies from 24 cases in which tubular aggregates were recorded as a feature. The biopsies were reviewed and it was observed that there was a wide range in the number of affected fibres between different cases. Tubular aggregates were present in type-2 fibres in all cases examined. Future analysis will be undertaken to ascertain whether there is any correlation between the clinical syndrome and pathological features such as the proportion of affected fibres and the ultrastructural features of the tubular aggregates. In view of the rarity of tubular aggregates myopathy, a multi-centre approach may facilitate future studies.Caroline Sewry (London, UK) presented data from the original case of zebra body myopathy published in 1975 by Lake and Wilson [[10]Lake B.D. Wilson J. Zebra body myopathy.J Neurol Sci. 1975; 24: 437-446Abstract Full Text PDF PubMed Scopus (44) Google Scholar]. The clinical phenotype was consistent with a congenital myopathy and she had suggested the ACTA1 gene as a candidate gene after the observation that patients homozygous for null ACTA1 mutations showed a higher number of zebra bodies than usually encountered in diseased muscle. In addition, the case of Lake and Wilson also showed nemaline rods, as did the only other reported case of zebra body myopathy [[11]Reyes M.G. Goldbarg H. Fresco K. Bouffard A. Zebra body myopathy: a second case of ultrastructurally distinct congenital myopathy.J Child Neurol. 1987; 2: 307-310Crossref PubMed Scopus (11) Google Scholar]. Molecular studies of the Lake and Wilson case have now confirmed a novel ACTA1 mutation. Thus zebra body myopathy is not a separate disease entity but is part if the nemaline, ACTA1 spectrum.She also presented a review of the literature on fingerprint body myopathy that was first published in 1972 by A G Engel [[12]Engel A.G. Angelini C. Gomez M.R. Fingerprint body myopathy. A newly recognized congenital muscle disease.Mayo Clin Proc. 1972; 47: 377-388PubMed Google Scholar]. All reported cases had hypotonia from birth, and most were sporadic cases, although a few familial cases suggest a possible genetic basis. The fingerprint bodies are only visible with electron microscopy and can occur in association with other pathologies, such as central cores, rimmed vacuoles and type-1 hypotrophy. They can also occur in association with various disorders and in normal foetal muscle. One paper suggested that they may be restricted to type-1 fibres, based on ultrastructural measurements of Z and M lines.Kristl Claeys (Paris, France) reported four unrelated patients with a myopathy with hexagonally cross-linked tubular arrays [13Bourque P.R. Lach B. Carpenter S. Rippstein P. Myopathy with hexagonally cross-linked tubular arrays: a new autosomal dominant or sporadic congenital myopathy.Ann Neurol. 1999; 45: 512-515Crossref PubMed Scopus (17) Google Scholar, 14Lach B. Tarnopolsky M. Nguyen C. Sarcoplasmic hexagonally cross-linked tubular arrays immunostain for caveolin-3: an excess caveolinopathy?.Acta Neuropathol. 2009; 117: 339-341Crossref PubMed Scopus (6) Google Scholar]. Two patients had a familial history, one of which was suggestive of dominant inheritance, and two occurred sporadically. Age at onset varied between 13 and 56 years. Patients experienced exercise intolerance with exercise-induced muscle pain and weakness, without rhabdomyolysis. One patient additionally presented mild permanent pelvic girdle muscle weakness. Serum creatine kinase levels varied between normal and five times the normal value. Electromyography showed myopathic changes in one patient, and was normal in the others. Muscle imaging and respiratory function were normal. Minor cardiac abnormalities were found in two patients. The inclusions were eosinophilic and slightly refractile at haematoxylin and eosin, and bright red after modified Gomori trichrome staining. They were selectively present in type-2 fibres, with a frequency varying from 13% to 28% on transverse sections. The inclusions revealed immunoreactivity exclusively for the antibody directed against caveolin-3. Ultrastructurally, the inclusions showed a highly organised, hexagonally cross-linked crystalloid structure at transverse sections. Mutations in the caveolin-3 encoding gene were excluded. Biochemical assessment of glycogenolysis in muscle of two patients did not reveal any abnormality. This myopathy should be differentiated from a myopathy with tubulin-reactive crystalloid inclusions [15Vu T.H. Hays A.P. Tanji K. et al.Myopathy with tubulin-reactive crystalline inclusions.Neurology. 2001; 57: 149-152Crossref PubMed Scopus (11) Google Scholar, 16Shelton G.D. Sturges B.K. Lyons L.A. et al.Myopathy with tubulin-reactive inclusions in two cats.Acta Neuropathol. 2007; 114: 537-542Crossref PubMed Scopus (9) Google Scholar], and from non-specific myopathic changes with crystalline aggregates of protein–glycogen complexes, also called virus-like particles [17Palmucci L. Anzil A.P. Luh S. Crystalline aggregates of protein-glycogen complexes (alias ‘virus-like particles’) in skeletal muscle: report of a case and review of the literature.Neuropathol Appl Neurobiol. 1983; 9: 61-71Crossref PubMed Scopus (7) Google Scholar, 18Ho K.L. Crystalloid bodies in skeletal muscle of hypothyroid myopathy. Ultrastructural and histochemical studies.Acta Neuropathol. 1987; 74: 22-32Crossref PubMed Scopus (8) Google Scholar]. We concluded that myopathy with hexagonally cross-linked crystalloid inclusions is associated with a homogeneous clinical and histopathological phenotype.Joachim Schessl (Munich, Germany) reported on reducing body myopathy (RBM), a rare structural disorder of muscle, first described more than 35 years ago as a severe progressive myopathy in two girls [[19]Brooke M.H. Neville H.E. Reducing body myopathy.Neurology. 1972; 22: 829-840Crossref PubMed Google Scholar], and subsequently in other sporadic and small familial occurrences. The typical muscle histopathological findings are intracytoplasmic inclusions staining strongly with the menadione-NBT stain. Working in Carsten Bonnemann’s group at the Children’s Hospital of Philadelphia he recently established the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for RBM by using laser microdissection of the inclusions out of biopsy material followed by proteomic analysis [[20]Schessl J. Zou Y. McGrath M.J. et al.Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy.J Clin Invest. 2008; 118: 904-912PubMed Google Scholar]. Twenty-one sporadic patients and eight familial cases with RBM have been documented in the literature so far, at this point mostly without molecular confirmation. All mutations underlying RBM have so far been located in the second LIM domain of FHL1. The mutations reported have been seen in patients with variable, but more often with severe disease symptoms. While females can be severely affected, males show even more severe symptoms compared to females car" @default.
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• W1999160290 title "169th ENMC International Workshop Rare Structural Congenital Myopathies 6–8 November 2009, Naarden, The Netherlands" @default.
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