Diffuse Midline Glioma, H3K27M-mutant Subtype, Confused for Viral Encephalitis: A Case Report

The diffuse midline glioma, H3K27M-mutant subtype, occurs mainly in children as a result of mutations in the histone H3 (H3F3A) and HIST1H3B (K27M) genes and is characterized by diffuse tumor growth in central nervous system (CNS) midline structures. Due to its nonspecific clinical manifestations, viral encephalitis is often confused with other central nervous system diseases. In this case, we reported a young male patient who was admitted to the hospital chiefly complaining of “diplopia for more than two months and aggravated walking instability for more than 10 days”. After admission, relevant patient blood and cerebrospinal fluid (CSF) tests were completed, and no obvious abnormalities were found. Chest CT suggested pulmonary infection; magnetic resonance imaging (MRI) and contrast-enhanced CT, PET-CT and other imaging examinations of the head all indicated a high possibility of viral encephalitis. Symptoms of fever were improved in the patient after treatment with antiviral therapy and anti-infection therapy. However, symptoms of neurological function loss, such as double vision and adverse right limb movement, persisted. Finally, stereotactic biopsies of deep brain lesions were carried out and sent to the pathology department, which led to a diagnosis of diffuse midline glioma, H3K27M-mutant subtype (WHO IV). His family chose to perform conservative treatment in another hospital, and the patient died four months later. To conclude, when clinical symptoms of suspected viral encephalitis appear in the course of diffuse midline glioma, it can result in confusion regarding clinical diagnosis and treatment. Clinicians should ensure proper early recognition and identification of the disease.

Proteolytic cleavage of Slit by the Tolkin protease converts an axon repulsion cue to an axon growth cue in vivo

ABSTRACTSlit is a secreted protein that has a canonical function of repelling growing axons from the CNS midline. The full-length Slit (Slit-FL) is cleaved into Slit-N and Slit-C fragments, which have potentially distinct functions via different receptors. Here, we report that the BMP-1/Tolloid family metalloprotease Tolkin (Tok) is responsible for Slit proteolysis in vivo and in vitro. In Drosophilatok mutants lacking Slit cleavage, midline repulsion of axons occurs normally, confirming that Slit-FL is sufficient to repel axons. However, longitudinal axon guidance is highly disrupted in tok mutants and can be rescued by midline expression of Slit-N, suggesting that Slit is the primary substrate for Tok in the embryonic CNS. Transgenic restoration of Slit-N or Slit-C does not repel axons in Slit-null flies. Slit-FL and Slit-N are both biologically active cues with distinct axon guidance functions in vivo. Slit signaling is used in diverse biological processes; therefore, differentiating between Slit-FL and Slit fragments will be essential for evaluating Slit function in broader contexts.

Temporal regulation of axonal repulsion by alternative splicing of a conserved microexon in mammalian Robo1 and Robo2

Proper connectivity of the nervous system requires temporal and spatial control of axon guidance signaling. As commissural axons navigate across the CNS midline, ROBO-mediated repulsion has traditionally been thought to be repressed before crossing, and then to become upregulated after crossing. The regulation of the ROBO receptors involves multiple mechanisms that control protein expression, trafficking, and activity. Here, we report that mammalian ROBO1 and ROBO2 are not uniformly inhibited precrossing and are instead subject to additional temporal control via alternative splicing at a conserved microexon. The NOVA splicing factors regulate the developmental expression of ROBO1 and ROBO2 variants with small sequence differences and distinct guidance activities. As a result, ROBO-mediated axonal repulsion is activated early in development to prevent premature crossing and becomes inhibited later to allow crossing. Postcrossing, the ROBO1 and ROBO2 isoforms are disinhibited to prevent midline reentry and to guide postcrossing commissural axons to distinct mediolateral positions.

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.