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TIA1/SQSTM1 myopathy is one of the few myopathies with a true digenic inheritance. Our goal was to define the phenotype presentation of the disease, genotype-phenotype correlations, and to study the prevalence of the TIA1 -N357S variant in distal myopathy. We describe four new adult male patients carrying the TIA1 -N357S and SQSTM1 -P392L variant and review the literature to include 20 additional cases. We reviewed the results of the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort for the TIA1 -N357S variant. Twenty-four patients (75% males) were included, with late-onset (52,6±10,1years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and EMG myopathic changes. Two of the four French patients also had a sensorimotor axonal polyneuropathy and an additional one had neurogenic features in tibialis anterior biopsy. Most commonly, muscle histopathology showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 -N357S variant was present in all patients and the SQSTM1-P392L was the most frequent (68%) of the four reported SQSTM1 variants. The TIA1 -N357S variant was carried by 11/414=2.7% of distal myopathy patients and two had an alternative diagnosis (TTN and MYH7) with atypical phenotypes. TIA1/SQSTM1 myopathy has a homogenous and characteristic phenotype reinforcing the pathogenicity of its digenic variants. Furthermore, sensorimotor axonal polyneuropathy may be an additional feature of the disease. Finally, we confirm an increased burden of the TIA1 -N357S variant in distal myopathy patients which could act as a genetic modifier. [ABSTRACT FROM AUTHOR]

Amyloid angiopathy represents 20% of causes of intraparenchymal hematoma. The histopathological examination must carefully look for characteristic vascular abnormalities and the immunohistochemistry for the βA4 peptide must be carried out systematically. In practice, the evacuation products of an intracerebral hematoma must be fully included, because the lesions may be focal. The existence of a neurosurgical history may suggest an iatrogenic etiology when patients are less than 55 years-old., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

TIA1/SQSTM1 myopathy is one of the few digenic myopathies. We describe four new French adult male patients carrying the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variant and review the literature to include 20 additional cases to define the spectrum of the disease. These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG. Two of the four French patients had sensorimotor axonal polyneuropathy and an additional one had neurogenic changes in muscle biopsy. Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1 p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1 variants. We reviewed the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort finding a prevalence of 11/414=2.7% of the TIA1 p.Asn357Ser variant, with two patients having an alternative diagnosis (TTN and MYH7) with atypical phenotypes, resembling some of the features seen in TIA1/SQSTM1 myopathy. Overall, TIA1/SQSTM1 myopathy has a homogenous phenotype reinforcing the pathogenicity of its digenic variants. We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Filamin C-related disorders include myopathies and cardiomyopathies linked to variants in the FLNC gene. Filamin C belongs to a family of actin-binding proteins involved in sarcomere stability. This study investigates the pathogenic impact of the FLNC c.3557C > T (p.Ala1186Val) pathogenic variant associated with an early-onset cytoplasmic body myopathy and cardiomyopathy in three unrelated patients. We performed clinical imaging and myopathologic and genetic characterization of three patients with an early-onset myopathy and cardiomyopathy. Bioinformatics analysis, variant interpretation, and protein structure analysis were performed to validate and assess the effects of the filamin C variant. All patients presented with a homogeneous clinical phenotype marked by a severe contractural myopathy, leading to loss of gait. There was prominent respiratory involvement and restrictive or hypertrophic cardiomyopathies. The Ala1186Val variant is located in the interstrand loop involved in intradomain stabilization and/or interdomain interactions with neighbor Ig-like domains. 3D modeling highlights local structural changes involving nearby residues and probably impacts the protein stability, causing protein aggregation in the form of cytoplasmic bodies. Myopathologic studies have disclosed the prominent aggregation and upregulation of the aggrephagy-associated proteins LC3B and p62. As a whole, the Ala1186Val variant in the FLNC gene provokes a severe myopathy with contractures, respiratory involvement, and cardiomyopathy due to protein aggregation in patients' muscles.

Objective: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers., Methods: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease., Results: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded., Conclusion: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Aims: We aim to perform ultrastructural and histopathological analysis of muscle biopsies from a large group of systemic sclerosis (SSc) patients, including some with early/mild SSc features, and examine whether capillary pathology differentiates 'scleromyositis' (SM) from other auto-immune myositis (AIM) subsets., Methods: Muscle biopsies from a total of 60 SM patients and 43 AIM controls from two independent cohorts were examined by electron microscopy, collagen-4 immunofluorescence (Col4IF) and routine light microscopy., Results: Ultrastructural examination revealed prominent capillary basement membrane (BM) reduplication (4+ layers in >50% of capillaries) in 65% of SM vs 0% of AIM controls (p < 0.001). In SM cases without prominent BM reduplication, capillary dilation was the most distinctive feature, present in 8% of capillaries in SM vs 2% in controls (p = 0.001). Accumulation of ensheathed pericyte processes was another characteristic feature of SM and closely correlated with the degree of BM reduplication (r = 0.833, p < 0.001). On light microscopy, BM marker Col4IF revealed more frequent capillary enlargement in SM than in controls (84% vs 21%, p < 0.001). SM cases were classified as non-inflammatory myopathy (36%), non-specific myositis (33%) or immune-mediated necrotizing myopathy (31%), but despite this histopathological heterogeneity, prominent BM reduplication remained a constant finding. In the 16 SM patients with early/mild SSc features, 63% showed prominent BM reduplication., Conclusions: These results show that capillary pathology, and in particular prominent capillary BM reduplication, is the hallmark histopathological feature of SM even in patients with early/mild SSc and support the concept of SM as an organ manifestation of SSc and a distinct subset of AIM., (© 2022 British Neuropathological Society.)

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., (© 2022. The Author(s).)

Background: The dystonias are a heterogeneous group of hyperkinetic disorders characterized by sustained or intermittent muscle contractions that cause abnormal movements and/or postures. Although more than 200 causal genes are known, many cases of primary dystonia have no clear genetic cause., Objectives: To identify the causal gene in a consanguineous family with three siblings affected by a complex persistent generalized dystonia, generalized epilepsy, and mild intellectual disability., Methods: We performed exome sequencing in the parents and two affected siblings and characterized the expression of the identified gene by immunohistochemistry in control human and zebrafish brains., Results: We identified a novel missense variant (c.142G>A (NM&#95;032192); p.Glu48Lys) in the protein phosphatase 1 regulatory inhibitor subunit 1B gene (PPP1R1B) that was homozygous in all three siblings and heterozygous in the parents. This gene is also known as dopamine and cAMP-regulated neuronal phosphoprotein 32 (DARPP-32) and has been involved in the pathophysiology of abnormal movements. The uncovered variant is absent in public databases and modifies the conserved glutamate 48 localized close to the serine 45 phosphorylation site. The PPP1R1B protein was shown to be expressed in cells and regions involved in movement control, including projection neurons of the caudate-putamen, substantia nigra neuropil, and cerebellar Purkinje cells. The latter cells were also confirmed to be positive for PPP1R1B expression in the zebrafish brain., Conclusions: We report the association of a PPP1R1B/DARPP-32 variant with generalized dystonia in man. It might be relevant to include the sequencing of this new gene in the diagnosis of patients with otherwise unexplained movement disorders. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Ethylene glycol poisoning is relatively rare, with around a hundred cases reported each year in France. Its diagnosis is often challenging and delayed because of a several hours' free interval between ingestion of the toxic and the onset of the first symptoms. Ethylene glycol is a colorless and odorless liquid primarily found in automotive coolants, whose toxicity is linked to its hepatic metabolites. Histologically, ethylene glycol poisoning is characterized by abundant tissular deposits of calcium oxalate crystals. Under polarized light, these crystals appear birefringent and iridescent. Their microscopic appearance and their distribution are pathognomonic of oxalosis. Due to its frequent misleading presentation, the diagnosis of ethylene glycol poisoning is sometimes only made after an autopsy. Hereafter, we report the case of a 59-year-old man diagnosed with ethylene glycol intoxication after a post-mortem histopathological examination of organs., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)