Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.

peer reviewedNemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation

Severe asymmetric muscle weakness revealing glycogenin-1 polyglucosan body myopathy

International audienceWe recently identified polyglucosan body myopathy-2, a pure skeletal myopathic form of glycogen storage disease type XV, caused by glycogenin-1 deficiency, the primingenzyme of glycogen synthesis. To date 22 patients have been reported. They have juvenile to late-onset clinical symptoms with a variable distribution of muscle weakness. Muscle biopsies show the accumulation of polyglucosan bodies, consisting of hyper-intense periodic acid-Schiff (PAS)-positive material with a variable resistance to alpha-amylase treatment. Although cardiacinvolvement has been reported in 4 patients with glycogenin-1 gene (GYG1) mutations, these patients did not show any clear evidence of skeletal muscle disease.Here, we describe a 63-year-old woman born to consanguineous French parents, who developed right shoulder pain, difficulty climbing stairs and left foot weakness causing stumbling episodes at 46 years of age. Over time, the patient reported increasing difficulty elevating the right arm. At 61 years of age she also developed slight difficulty with left shoulder movement, and more recently she reported rare forearm fasciculations and nocturnal cramps in her thighs, calves, and toes

A Heterozygous Mutation in the Filamin C Gene Causes an Unusual Nemaline Myopathy With Ring Fibers

Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies

ALZHEIMER RISK FACTOR PICALM IS INVOLVED IN TAU PATHOLOGY IN ALZHEIMER AND OTHER TAUOPATHIES

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Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas

Pola NetworkInternational audienceThe integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3id) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3id. Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3id overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3id is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3id recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3id and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3id. A better understanding of spatial and temporal intratumor cell heterogeneity in O3id will open new therapeutic avenues overcoming resistance to current antitumor treatments

Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies

Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains.

PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65-75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe