mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development: Novel Variants, Topographic Mapping, and Clinical Outcomes.

Background and Objectives: Somatic and germline pathogenic variants in genes of the mammalian target of rapamycin (mTOR) signaling pathway are a common mechanism underlying a subset of focal malformations of cortical development (FMCDs) referred to as mTORopathies, which include focal cortical dysplasia (FCD) type II, subtypes of polymicrogyria, and hemimegalencephaly. Our objective is to screen resected FMCD specimens with mTORopathy features on histology for causal somatic variants in mTOR pathway genes, describe novel pathogenic variants, and examine the variant distribution in relation to neuroimaging, histopathologic classification, and clinical outcomes. Methods: We performed ultra-deep sequencing using a custom HaloPlexHS Target Enrichment kit in DNA from 21 resected fresh-frozen histologically confirmed FCD type II, tuberous sclerosis complex, or hemimegalencephaly specimens. We mapped the variant alternative allele frequency (AAF) across the resected brain using targeted ultra-deep sequencing in multiple formalin-fixed paraffin-embedded tissue blocks. We also functionally validated 2 candidate somatic MTOR variants and performed targeted RNA sequencing to validate a splicing defect associated with a novel DEPDC5 variant. Results: We identified causal mTOR pathway gene variants in 66.7% (14/21) of patients, of which 13 were somatic with AAF ranging between 0.6% and 12.0%. Moreover, the AAF did not predict balloon cell presence. Favorable seizure outcomes were associated with genetically clear resection borders. Individuals in whom a causal somatic variant was undetected had excellent postsurgical outcomes. In addition, we demonstrate pathogenicity of the novel c.4373_4375dupATG and candidate c.7499T>A MTOR variants in vitro. We also identified a novel germline aberrant splice site variant in DEPDC5 (c.2802-1G>C). Discussion: The AAF of somatic pathogenic variants correlated with the topographic distribution, histopathology, and postsurgical outcomes. Moreover, cortical regions with absent histologic FCD features had negligible or undetectable pathogenic variant loads. By contrast, specimens with frank histologic abnormalities had detectable pathogenic variant loads, which raises important questions as to whether there is a tolerable variant threshold and whether surgical margins should be clean, as performed in tumor resections. In addition, we describe 2 novel pathogenic variants, expanding the mTORopathy genetic spectrum. Although most pathogenic somatic variants are located at mutation hotspots, screening the full-coding gene sequence remains necessary in a subset of patients.

Myositis with prominent B cell aggregates may meet classification criteria for sporadic inclusion body myositis.

The objective of this study was to report the clinical, serological and pathological features of patients with autoimmune myositis other than dermatomyositis, who displayed both muscle weakness on physical examination and prominent B cell aggregates on muscle pathology, defined as ≥ 30 CD20+ cells/aggregate. Specifically, the presence of a brachio-cervical inflammatory myopathies or a sporadic inclusion body myositis (sIBM) phenotype was recorded. Over a three-year period, eight patients were identified from two university neuropathology referral centers. Seven of 8 (88%) patients had an associated connective tissue disease (CTD): rheumatoid arthritis (n=3), systemic sclerosis (n=2), Sjögren's syndrome (n=1) and systemic lupus erythematosus (n=1), while one patient died on initial presentation without a complete serological and cancer investigation. A brachio-cervical phenotype, i.e. neck weakness, proximal weakness more than distal and shoulder abduction weakness greater than hip flexors, was seen in two patients (25%), while one patient had both proximal and diaphragmatic weakness. In contrast, an IBM-like clinical phenotype was seen in the last five patients (63%), who either had finger flexor weakness and/or quadriceps weakness ≤ 4 on the manual muscle testing MRC-5 scale. Although these 5 patients met at least one set of classification criteria for sIBM, an integrated clinico-sero-pathological approach argued against a diagnosis of sIBM. In summary, in a weak patient with myositis plus an associated CTD and lymphoid aggregates at muscle pathology, B cell predominant aggregates may represent a morphological biomarker against a diagnosis of sIBM.

IgG4-Related Disease of the Central Nervous System: A Case Series.

IgG4-related disease (IgG4-RD) is a rare and often misdiagnosed disorder with limited literature that highlights the different neurological presentations of this treatable disease. The diagnosis of IgG4-RD could be challenging, while imaging is fundamental for the diagnosis, biopsy is considered the gold standard. Most cases respond well to steroids and immunosuppressive therapy. This is a case series study that illustrates the varied neurological presentations of IgG4-RD through three different patients that were followed at the Montreal Neurological Institute. This paper takes you through the diagnostic strategy that we followed to accurately diagnose and treat those patients.

Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data.

BACKGROUND: Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF's auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. METHODS: To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. RESULTS: Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions. CONCLUSIONS: We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs.

Detection of temozolomide-induced hypermutation and response to PD-1 checkpoint inhibitor in recurrent glioblastoma.

Background: Despite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide (TMZ) as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has yet to be described. Methods: We combined GBM patient and derive GBM stem cells (GSCs) from tumors following TMZ to explore response of hypermutant and non-hypermutant emergent phenotypes and explore the immune relevance of hypermutant and non-hypermutant states in vivo. Results: Hypermutation emerges as one of two possible mutational subtypes following TMZ treatment in vivo and demonstrates distinct phenotypic features compared to non-hypermutant recurrent GBM. Hypermutant tumors elicited robust immune rejection in subcutaneous contexts which was accompanied by increased immune cell infiltration. In contrast, immune rejection of hypermutant tumors were stunted in orthotopic settings where we observe limited immune infiltration. Use of anti-PD-1 immunotherapy showed that immunosuppression in orthotopic contexts was independent from the PD-1/PD-L1 axis. Finally, we demonstrate that mutational burden can be estimated from DNA contained in extracellular vesicles (EVs). Conclusion: Hypermutation post-TMZ are phenotypically distinct from non-hypermutant GBM and requires personalization for appropriate treatment. The brain microenvironment may be immunosuppressive and exploration of the mechanisms behind this may be key to improving immunotherapy response in this subtype of recurrent GBM.

Capillary pathology with prominent basement membrane reduplication is the hallmark histopathological feature of scleromyositis.

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.

Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report.

BACKGROUND: Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. CASE PRESENTATION: A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren's syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. CONCLUSION: Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.

Autoantibody profiles delineate distinct subsets of scleromyositis.

OBJECTIVE: Scleromyositis remains incompletely characterized owing in part to its heterogeneity. The purpose of this study was to explore the role of autoantibody profiles to define subsets of scleromyositis. METHODS: Subjects with scleromyositis from a prospective cohort were divided into three groups based on autoantibody profiles: subjects with SSc-specific autoantibodies (anti-centromere, -topoisomerase 1, -RNA polymerase III, -Th/To, -fibrillarin), subjects with SSc-overlap autoantibodies (anti-PM/Scl, -U1RNP, -Ku) and subjects without SSc-related autoantibodies. Clinical features, laboratory tests and histopathological findings were retrieved and compared between groups. RESULTS: Of 42 scleromyositis subjects (79% female, mean age at diagnosis 55 years, mean disease duration 3.5 years), 8 (19%) subjects had SSc-specific autoantibodies, 14 (33%) SSc-overlap autoantibodies and 20 (48%) had no SSc-related autoantibodies. One-third had no skin involvement, a finding more frequent in the SSc-overlap subjects and those without SSc-related autoantibodies. Proximal and distal weakness was common and head drop/bent spine was found in 50% of the SSc-specific and 35% of the subjects without SSc-related autoantibodies. Of note, the group without SSc-related autoantibodies had the only cases of severe cardiac systolic dysfunction (n = 1) and scleroderma renal crisis (n = 1), as well as three out of the four cancers and three out of the four deaths. CONCLUSION: In this carefully phenotyped series of scleromyositis subjects, absence of SSc-related autoantibodies was common and associated with distinct features and poor prognosis. Future studies are needed to validate these results and possibly identify novel autoantibodies or other biomarkers associated with scleromyositis.

Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated ß-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone.

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1+ osteoblast-like progenitor population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.See related commentary by Licht, p. 1794.This article is highlighted in the In This Issue feature, p. 1775.

Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.

OBJECTIVE: Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy. METHODS: Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype. RESULTS: Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so. INTERPRETATION: This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.

BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblastoma.

Despite advances in therapy, glioblastoma remains an incurable disease with a dismal prognosis. Recent studies have implicated cancer stem cells within glioblastoma (glioma stem cells, GSCs) as mediators of therapeutic resistance and tumor progression. In this study, we investigated the role of the transforming growth factor-ß (TGF-ß) superfamily, which has been found to play an integral role in the maintenance of stem cell homeostasis within multiple stem cell systems, as a mediator of stem-like cells in glioblastoma. We find that BMP and TGF-ß signaling define divergent molecular and functional identities in glioblastoma, and mark relatively quiescent and proliferative GSCs, respectively. Treatment of GSCs with BMP inhibits cell proliferation, but does not abrogate their stem-ness, as measured by self-renewal and tumorigencity. Further, BMP pathway activation confers relative resistance to radiation and temozolomide chemotherapy. Our findings define a quiescent cancer stem cell population in glioblastoma that may be a cellular reservoir for tumor recurrence following cytotoxic therapy.

Rheumatoid Meningitis Presenting With Acute Parkinsonism and Protracted Non-convulsive Seizures: An Unusual Case Presentation and Review of Treatment Strategies.

Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA). It is associated with substantial morbidity and mortality. The condition may present in a variety of ways and is therefore diagnostically challenging. Uncertainty still exists regarding the optimal treatment strategy. Herein, we describe the case of a 74-year-old man with a history of well-controlled seropositive RA on low-dose prednisone, hydroxychloroquine, and methotrexate. The patient presented with a several-month history of multiple prolonged episodes of expressive aphasia, right hemiparesis, and encephalopathy. Although no epileptiform activity was recorded on repeated electroencephalography, the symptoms fully resolved following treatment with antiepileptic drugs. He subsequently developed acute asymmetrical parkinsonism of the right hemibody. Magnetic resonance imaging revealed subtle enhancement of the leptomeninges over the left frontoparietal convexity. Cerebrospinal fluid analysis revealed a mild lymphocytic pleocytosis and elevated proteins. Histopathologic analysis of a meningeal biopsy revealed nodular rheumatoid meningitis. The patient was treated with corticosteroids and cyclophosphamide, following which he incompletely recovered. This is the first description of rheumatoid meningitis manifesting with acute parkinsonism and protracted non-convulsive seizures. A summary of cases reported since 2005, including data on pathology, therapy and outcomes, along with a discussion on the efficacy of different treatment strategies are provided.

DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.

Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. In this study, we describe the TERT hypermethylated oncological region (THOR), a 433-bp genomic region encompassing 52 CpG sites located immediately upstream of the TERT core promoter, as a cancer-associated epigenetic mechanism of TERT upregulation. Unmethylated THOR repressed TERT promoter activity regardless of TPM status, and hypermethylation of THOR counteracted this repressive function. THOR methylation analysis in 1,352 human tumors revealed frequent (>45%) cancer-associated DNA hypermethylation in 9 of 11 (82%) tumor types screened. Additionally, THOR hypermethylation, either independently or along with TPMs, accounted for how approximately 90% of human cancers can aberrantly activate telomerase. Thus, we propose that THOR hypermethylation is a prevalent telomerase-activating mechanism in cancer that can act independently of or in conjunction with TPMs, further supporting the utility of THOR hypermethylation as a prognostic biomarker.

Angiocentric lymph proliferative disorder (lymphomatoid granulomatosis) in a person with newly-diagnosed HIV infection: a case report.

BACKGROUND: Angiocentric lymph proliferative disorder (ALPD) is a granulomatous lymphoproliferative condition associated with various primary and secondary immunodeficiency states. ALPD is so rare that its prevalence has not been established. Typically affecting middle-aged adults, this condition is often found in the context of Epstein Bar Virus infection and consists of angiocentric and angioinvasive pulmonary infiltrates. Herein, we present a biopsy-proven case of a patient manifesting with a viral meningoencephalomyelitis-like picture with brain, spinal cord, renal and splenic lesions. The diagnosis was confirmed to be ALPD in the context of newly diagnosed HIV infection. CASE PRESENTATION: A 35 year-old homosexual man presented with a 5-week history of headaches followed by a 3-week history of horizontal diplopia, limb weakness and right 6th cranial nerve palsy. Lumbar puncture revealed a lymphocytic pleocytosis, high protein and low glucose. Magnetic Resonance Imaging showed scattered lesions throughout the brain and spinal cord and Computed Tomography of the abdomen and pelvis revealed hypodensities involving the kidneys and spleen. HIV testing was positive, with a viral load of 11,096 copies/mL and CD4 count of 324 cells/µL. Serum Epstein Bar virus PCR was positive with 12,434 copies/ml. Right frontal brain biopsy revealed gray matter containing angiogentric cerebritis with organizing infarction but Epstein Bar Virus-in situ preparations were negative and no viral inclusions were identified. A diagnosis of ALPD (also known as lymphomatoid granulomatosis) was made. The patient was initiated on antiretroviral therapy and treated with intravenous rituximab every 3 weeks for 4 cycles and made progressive improvements. By the time of discharge his strength had improved and he was ambulating again although with a walker. Within 2 months, his HIV viral load was suppressed. Magnetic Resonance Imaging of the brain 6 months later revealed interval improvement. At his most recent follow-up, 34 months later, his neurological symptoms had almost completed resolved. CONCLUSION: Albeit rare, ALPD should be considered in the differential diagnosis of central nervous system lesions in persons with HIV once common etiologies have been eliminated. Furthermore, ALPD involving the central nervous system may occur in in the absence of documented EBV infection in the central nervous system.

Recessive mutations in VPS13D cause childhood onset movement disorders.

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.

Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas.

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.