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SCY1‐like protein 2 (SCYL2) is a member of the SCY1‐like pseudokinase family which regulates secretory protein trafficking. It plays a crucial role in the nervous system by suppressing excitotoxicity in the developing brain. Scyl2 knockout mice have excess prenatal mortality and survivors show severe neurological dysfunction. Bi‐allelic loss‐of‐function (LOF) variants in SCYL2 were recently associated with arthrogryposis multiplex congenita‐4 (AMC4) following the report of 6 individuals from two consanguineous unrelated families. The AMC4 phenotype described included severe arthrogryposis, corpus callosum agenesis, epilepsy and frequently, early death. We describe here two additional similarly affected individuals with AMC4, including one diagnosed in the prenatal period, with bi‐allelic LOF variants in SCYL2, and two individuals homozygous for missense variants in the protein kinase domain of SCYL2 and presenting with developmental delay only. Our study confirms the association of SCYL2 with AMC4 and suggests a milder phenotype can occur, extending the phenotypic spectrum of autosomal recessive SCYL2‐related disorders. [ABSTRACT FROM AUTHOR]

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician's difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic "placenta–cortex" signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ "placenta–cortex" signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that "intercellular communication" was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD. [ABSTRACT FROM AUTHOR]

The occurrence of I TRAF7 i mutations in the normal meninges also questions its intrinsic pathogenic value, since meningiomas frequently harbor a second co-mutation ( I KLF4 i SP I K409Q i sp or one of the main oncogenes of the PI3K pathway, I AKT1 i and I PIK3CA i ) [[1], [5]]. Meningioma oncogenesis is dominated by the occurrence of well-known driver gene mutations that form co-exclusive mutational groups, but 20% of meningiomas do not harbor any somatic mutation [[4]-[6]]. Variants are reported ordered by gene mutation frequency, and colored depending on the consequence of the mutation. d Summary of the four mutations present in the normal meninges in main driver genes for meningioma (NF2 and TRAF7). [Extracted from the article]

Background: Endobronchial ultrasound‐guided (EBUS) transbronchial needle aspiration (TBNA) has significantly improved the diagnostic workup for intrathoracic lymphadenopathies. More recently, EBUS intranodal forceps biopsy (IFB) has been developed in an attempt to maximize diagnostic yield by providing additional tissue. In this study, we aimed to assess the improvement of diagnostic yield with EBUS‐TBNA combined with EBUS‐IFB, compared to EBUS‐TBNA alone. Methods: Consecutive patients who had 19‐G EBUS‐TBNA and EBUS‐IFB from August 30, 2018, to September 28, 2021, were included. Four senior pathologists retrospectively analyzed, independently and blindly, first, only the EBUS‐TBNA samples (cell block), then, at least 1 month later, both samples from EBUS‐TBNA and from EBUS‐IFB together. Results: Fifty patients were included in the study and 52 lymph nodes were analyzed. Diagnostic yield was 77% (40/52) for EBUS‐TBNA alone and 94% (49/52) when combined with EBUS‐IFB (p = 0.023). Malignancy was diagnosed with EBUS‐TBNA combined with EBUS‐IFB in 25/26 cases (96%), versus 22/26 (85%) with EBUS‐TBNA alone (p = 0.35); and 4/5 (80%) versus 2/5 (40%) for lymphoma specifically. Kappa interobserver agreement was 0.92 for EBUS‐IFB and 0.87 for EBUS‐TBNA alone. Nonmalignant condition was diagnosed with EBUS‐TBNA combined with EBUS‐IFB in 24/26 cases (92%), versus 18/26 (69%) for EBUS‐TBNA alone (p = 0.07). Conclusion: The use of EBUS‐IFB combined with 19‐G EBUS‐TBNA improves the mediastinal lymph node diagnostic yield However the benefit appears to be mainly restricted to nonmalignant histology. [ABSTRACT FROM AUTHOR]

Background Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs. Methods We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1. Results Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern. Conclusion These findings expand our understanding of the clinical and imaging features of the 'NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients. [ABSTRACT FROM AUTHOR]

Background: Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC. Methods: Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo. Results: AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement. Conclusion: We show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A. [ABSTRACT FROM AUTHOR]

• Fingerprint bodies are now recognized as non-specific. • They may be observed alone or with other lesions. • Association with rods has never been reported so far. • They may be present in case of mutations in the LMOD3 gene. • And be associated with a milder phenotype than previously reported. Fingerprint bodies are observed in a variety of clinical situations with no definite genetic cause identified so far. We report for the first time the association of fingerprint bodies with rods in a patient who developed a slowly progressive myopathy affecting the face and limb extremities. Ultrastructural examination first disclosed fingerprint bodies and on a second biopsy, associated cytoplasmic bodies and rods. Next Generation Sequencing panel of congenital nemaline myopathy genes allowed the identification of two novel variants, a deleterious missense variant (c.1628G>T, p.Arg543Leu) located in the WASP-homology 2 domain, and a deletion (c.366delG, p.Lys122AsnFs*6) in the LMOD3 gene, generally causing severe nemaline myopathy with antenatal onset and early death. Recently, a less severe phenotype similar to our case has been reported. Our study confirms the existence of milder phenotypes linked to LMOD3 mutations and underlines that fingerprint bodies, though not specific, may be an early ultrastructural marker that could be linked, among others, to nemaline myopathy. [ABSTRACT FROM AUTHOR]

Spinal myxopapillary ependymoma (SP-MPE) is a subgroup of ependymomas in which after initial gross tumor resection, recurrences occur in more than half of the patients. Anaplastic transformation may also occur and contributes to intraneural and extraneural metastatic dissemination. Extraneural metastases from SP-MPE are rare and worsen the prognosis. In this situation, the noninvasive detection of recurrent somatic mutations in the circulating tumor DNA (ctDNA) from plasma is challenging. Telomerase-reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior. We report on a patient with TERTp mutated SP-MPE presenting with an extraneural anaplastic metastatic dissemination after iterative local recurrences. From the initial SP-MPE to pleural anaplastic lesion, TERTp C228T mutation was present with allele frequency varying from 33% to 39%. Interestingly, TERTp mutation was also detected by droplet digital polymerase chain reaction in the plasma with a frequency of 2.1% at the time of pleural metastases, highlighting that ctDNA is released in plasma of patients suffering from SP-MPE with extraneural metastatic dissemination. Despite the rarity of this evolution, plasmatic liquid biopsy appears to be a useful diagnostic and follow-up tool in a subset of primary brain tumors. [ABSTRACT FROM AUTHOR]

Early-onset Alzheimer's disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD. [ABSTRACT FROM AUTHOR]

Purpose: Temozolomide (TMZ) is known to induce thrombocytopenia but no early predictive test has yet been clearly established. The aim of the study was to retrospectively identify and validate a threshold of early platelet variation predicting TMZ-induced thrombocytopenia during the TMZ phase in patients treated according to the Stupp protocol for glioblastoma.Methods: A training set was used to analyze variations in platelet count occurring from the first week (W1) to week 6 (W6) during radiotherapy. Our aim was to identify the most relevant platelet decrease associated with TMZ-induced thrombocytopenia ≤ 100 G/L at day 28 during the TMZ phase. The performance of the threshold was confirmed in an independent validation set.Results: Overall, 147 patients were included, 85 and 62 in the training and validation sets, respectively. Twenty-seven patients (18%) experienced at least one TMZ-induced thrombocytopenia in the TMZ phase. A platelet decrease at W6 ≥ 35% (∆W6 ≥ 35%) was identified as the best predictive variation with an AUC of 0.83, a sensitivity of 65%, and a specificity of 96%. In the validation set, ∆W6 ≥ 35% platelet variation was identified as an independent marker of TMZ-induced thrombocytopenia during the TMZ phase (OR 15.23 (95% CI 3.5-107.5)) corresponding to sensitivity of 77% (66-87%), specificity of 73% (62-84%), a positive predictive value of 42% (29-54%), and a negative predictive value of 92% (86-99%).Conclusion: Platelet decrease at W6 ≥ 35% during the RT-TMZ phase is an early and simple predictive marker of clinically relevant TMZ-induced thrombocytopenia during TMZ maintenance. [ABSTRACT FROM AUTHOR]

Purposes Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming. We have developed a next-generation sequencing (NGS) panel to investigate metabolic causes of NIHF, ascites, and polyhydramnios associated to another fetal abnormality. Methods The hydrops fetalis (HydFet) panel was designed to cover the coding regions and flanking intronic sequences of 41 genes. A retrospective study of amniotic fluid samples from 40 subjects was conducted. A prospective study was subsequently initiated, and six samples were analyzed using the NGS panel. Results Five IEM diagnoses were made using the HydFet panel (Niemann-Pick type C (NPC), Barth syndrome, HNF1Β deficiency, GM1 gangliosidosis, and Gaucher disease). This analysis also allowed the identification of 8p sequence triplication in an additional case. Conclusion NGS combined with robust bioinformatics analyses is a useful tool for identifying the causative variants of NIHF. Subsequent functional characterization of the protein encoded by the altered gene and morphological studies may confirm the diagnosis. This paradigm shift allows a significant improvement of IEM diagnosis in NIHF. [ABSTRACT FROM AUTHOR]

Koolen-de Vries syndrome (MIM# 610443 ) is a rare microdeletion syndrome involving the 17q21.31 region, which was first described by Koolen in 2006. Clinical and behavioral characteristics have been extensively reported from more than 100 postnatal cases including infants, children and young adults. The syndrome is highly clinically heterogeneous, but the main features associate characteristic cranio-facial dysmorphism, heart defects, limb, skeletal, genito-urinary anomalies, along with intellectual disability with early childhood epilepsy and behavioral disturbances. Central nervous system malformations usually consist in hydrocephalus and thin corpus callosum. We report herein an early fetal case with an apparently isolated abnormal corpus callosum diagnosed by ultrasonography, for which a medical termination of the pregnancy was achieved at 22 weeks of gestation. Postmortem examination displayed facial dysmorphism consisting of hypertelorism, short philtrum and flat and broad nose, cleft palate and left duplex ureter. Neuropathological examination revealed a mega corpus callosum that has never been reported so far in this syndrome. Array-CGH performed on thymic DNA tissue revealed a 17q21.31 microdeletion, which allowed for the confirmation of early occurring Koolen-de Vries syndrome. [ABSTRACT FROM AUTHOR]

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla. [ABSTRACT FROM AUTHOR]

Background: A tracheobronchial lesion observed during an endoscopic examination is usually sampled by the pulmonologist and sent to the pathologist for microscopic examination. Adipocytes may be observed in the lamina propria of tracheobronchial biopsies, which may complicate diagnosis of sampled lesions because these adipose cells may be part of the lesion (lipoma or pulmonary hamartoma), but may also be a normal component of the bronchial mucosa. Because endoscopic samples frequently miss their target, adipocytes observed in such biopsies usually lead to uncertainty regarding diagnosis. Both pulmonary hamartomas and lipomas have a high frequency of translocations involving HMGA2, resulting in over expression of the fusion protein. The literature suggests that only 31% of tracheobronchial lipomas are correctly diagnosed on biopsy, sometimes leading to unnecessary aggressive surgical resection. Methods: We performed retrospective study of tracheo-bronchial biopsies containing adipocytes using HMGA2 immunostaining in order to define their nature and to assess the diagnostic utility of this marker. Results: In total, 13 lesions biopsied in 12 patients and containing adipocytes were immunostained for HMGA2. Nuclear immunostaining was detected in 7 out of the 13 lesions (54%), allowing us to diagnose a lipoma or hamartoma. Conclusion: HMGA2 immunostaining is an affordable and straightforward technique for accurate description of biopsies containing adipose cells. When positive, a diagnosis of benign adipose lesion can be made with confidence since well-differentiated liposarcomas have never been described in the tracheobronchial tree. Our work enabled us to diagnose a benign adipose lesion in 54% of cases, above the rate of 31% reported in the literature, based solely on morphological analysis. Overall, HMGA2 immunostaining could help pathologists to provide accurate diagnosis of tracheobronchial adipose lesions, leading to conservative treatment, for the overall benefit of patients. [ABSTRACT FROM AUTHOR]

Pyridoxine-dependent epilepsy (PDE) is a pharmacoresistant epileptogenic encephalopathy controlled by pyridoxine supplementation at pharmacological doses. Despite supplementation, the long-term outcome is often poor possibly because of recurrent seizures and developmental structural brain abnormalities. We report on five patients with PDE from three unrelated families. The diagnosis was confirmed by ALDH7A1 sequencing, which allowed for the characterization of two homozygous variations [NM_001182.3:c.1279G > C - p.(Glu427Gln) and c.834G > A - p.(Val278Val)]. Brain autopsy was conducted for one untreated patient with molecularly confirmed antiquitin deficiency. Macroscopic and histological examination revealed a combination of lesions resulting from recurrent seizures and consisting of extensive areas of cortical necrosis, gliosis, and hippocampic sclerosis. The examination also revealed developmental abnormalities including corpus callosum dysgenesis and corticospinal pathfinding anomalies. This case is the second to be reported in the literature, and our findings show evidence that antiquitin is required for normal brain development and functioning. Despite prophylactic prenatal pyridoxine supplementation during the last trimester of pregnancy in one of the three families and sustained pyridoxine treatment in three living patients, the clinical outcome remained poor with delayed acquisition of neurocognitive skills. Combined therapy (pyridoxine/arginine supplementation and lysine-restricted diet) should be considered early in the course of the disease for a better long-term outcome. Enhanced knowledge of PDE features is required to improve treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung adenocarcinoma is currently the main histological subtype of lung cancer, accounting for more than 60% of diagnosed cases. The most frequent genomic alteration in these tumors is the mutation of the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, which until recently was not accessible to targeted therapy. New phase I, II, and III clinical trials using targeted inhibitors for the specific glycine-to-cysteine mutation at codon 12 (KRAS c.34G>T/KRAS G12C) of the KRAS gene showed promising results in approximately 30% of lung adenocarcinomas harboring a KRAS G12C mutation. In our study, we analyzed the genomic landscape of these tumors using next-generation sequencing technology and characterized new molecular subtypes that could be more susceptible to the new class of KRAS G12C inhibitors. Lung adenocarcinoma (LUAD) is the major subtype of non-small cell lung cancer, accounting for approximately 60% of cases. Molecular analysis of LUADs showed that the KRAS gene is mutated in up to 30% of cases; such cases were previously considered "undruggable". The KRAS G12C mutation has become a hot topic of research after initial, promising, phase I and II trials with targeted inhibitors. We analyzed the morphological and genomic landscape of 202 KRAS G12C mutated LUADs using next-generation sequencing, and identified a specific subtype of patients that could show an improved response to KRAS G12C inhibitors. The main histological subtype was acinar in 29.7% of cases. Tumor-infiltrating lymphocytes (TILs) were highly or moderately abundant in more than 60% of cases. The immunohistochemical profile showed TTF1 positivity in 78.7% of cases and PD-L1 positivity in 44.1% of cases. The molecular profile showed an association between KRAS G12C and STK11 mutations in 25.2% of cases. This subgroup was associated with a statistically significant lower TTF1 (p = 0.0092) and PD-L1 (p < 0.0001) positivity. This type of combined morphological and molecular analysis can improve our understanding of tumor biology, and help us to identify specific patient subgroups that can achieve the best treatment response. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to explore metabolic remodeling in plasma and tissue samples in patients with glioblastoma through an integrated targeted and untargeted metabolomics-based strategy. We report phospholipids, sphingomyelins, acylcarnitines, and acylglycerols as key impaired metabolic classes in glioblastoma. (1) Background: Glioblastoma is the most common malignant brain tumor in adults. Its etiology remains unknown in most cases. Glioblastoma pathogenesis consists of a progressive infiltration of the white matter by tumoral cells leading to progressive neurological deficit, epilepsy, and/or intracranial hypertension. The mean survival is between 15 to 17 months. Given this aggressive prognosis, there is an urgent need for a better understanding of the underlying mechanisms of glioblastoma to unveil new diagnostic strategies and therapeutic targets through a deeper understanding of its biology. (2) Methods: To systematically address this issue, we performed targeted and untargeted metabolomics-based investigations on both tissue and plasma samples from patients with glioblastoma. (3) Results: This study revealed 176 differentially expressed lipids and metabolites, 148 in plasma and 28 in tissue samples. Main biochemical classes include phospholipids, acylcarnitines, sphingomyelins, and triacylglycerols. Functional analyses revealed deep metabolic remodeling in glioblastoma lipids and energy substrates, which unveils the major role of lipids in tumor progression by modulating its own environment. (4) Conclusions: Overall, our study demonstrates in situ and systemic metabolic rewiring in glioblastoma that could shed light on its underlying biological plasticity and progression to inform diagnosis and/or therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common malignant primary brain tumor in adults. Glioblastoma accounts for 2 to 3 cases per 100,000 persons in North America and Europe. Glioblastoma classification is now based on histopathological and molecular features including isocitrate dehydrogenase (IDH) mutations. At the end of the 2000s, genome-wide sequencing of glioblastoma identified recurrent somatic genetic alterations involved in oncogenesis. Among them, the alterations in the promoter region of the telomerase reverse transcriptase (TERTp) gene are highly recurrent and occur in 70% to 80% of all glioblastomas, including glioblastoma IDH wild type and glioblastoma IDH mutated. This review focuses on recent advances related to physiopathological mechanisms, diagnosis, and clinical implications. Glioblastoma, the most frequent and aggressive primary malignant tumor, often presents with alterations in the telomerase reverse transcriptase promoter. Telomerase is responsible for the maintenance of telomere length to avoid cell death. Telomere lengthening is required for cancer cell survival and has led to the investigation of telomerase activity as a potential mechanism that enables cancer growth. The aim of this systematic review is to provide an overview of the available data concerning TERT alterations and glioblastoma in terms of incidence, physiopathological understanding, and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Rhombencephalosynapsis is a rare cerebellar malformation developing during embryogenesis defined by vermian agenesis or hypogenesis with fusion of the cerebellar hemispheres. It occurs either alone or in association with other cerebral and/or extracerebral anomalies. Its association with microlissencephaly is exceedingly rare and to date, only a heterozygous de novo missense variant in ADGRL2 , a gene encoding Adhesion G-Protein-Coupled Receptor L2, has been identified. We report on two siblings of Roma origin presenting with severe growth retardation, fetal akinesia, microlissencephaly and small cerebellum with vermian agenesis. Neuropathological studies revealed extreme paucity in pontine transverse fibres, rudimentary olivary nuclei and rhombencephalosynapsis with vanishing spinal motoneurons in both fetuses. Comparative fetus-parent exome sequencing revealed in both fetuses a homozygous variant in exon 1 of the EXOSC3 gene encoding a core component of the RNA exosome, c.92G > C; p.(Gly31Ala). EXOSC3 accounts for 40%–75% of patients affected by ponto-cerebellar hypoplasia with spinal muscular atrophy (PCH1B). The c.92G > C variant is a founder mutation in the Roma population and has been reported in severe PCH1B. PCH1B is characterized by a broad phenotypic spectrum, ranging from mild phenotypes with spasticity, mild to moderate intellectual disability, pronounced distal muscular and cerebellar atrophy/hypoplasia, to severe phenotypes with profound global developmental delay, progressive microcephaly and atrophy of the cerebellar hemispheres. In PCH1B, the usual cerebellar lesions affect mainly the hemispheres with relative sparing of vermis that radically differs from rhombencephalosynapsis. This unusual foetal presentation expands the spectrum of PCH1B and highlights the diversity of rhombencephalosynapsis etiologies. [ABSTRACT FROM AUTHOR]

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4 -deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC. [ABSTRACT FROM AUTHOR]