Kaya Bilguvar

Aim: This study was designed to examine patients who underwent surgery for arachnoid cysts and compare surgical treatment options in terms of clinical, radiological and histopathological outcomes. Methods: Data obtained from 47 patients who underwent surgery for arachnoid cysts at 3 neurosurgery institutions between November 2002 and January 2020 were retrospectively reviewed. As the surgical interventions, two methods were performed; cyst fenestration with craniotomy, and cystoperitoneal shunt. Results: The mean age of the patients was 12.7 ± 11.3 years. Among them, 18 (38.3%) were female and 29 (61.7%) were male. 40 were pediatric and 7 were adult patients. In the study group, 32 patients (68%) underwent fenestration with craniotomy, while 15 patients (32%) underwent cystoperitoneal shunt application. The mean reduction rates of the cyst volume were determined as 51.4%. When comparing the surgeries performed, no statistically significant difference was found between the reduction rates (p>0.05). The group with the highest reduction rates was detected as convexity cysts treated with fenestration with a rate of 73.9%. In the postoperative period, the symptoms of 29 patients (62%) completely resolved, while the symptoms of 14 patients (30%) improved. Symptoms did not change in 3 patients (6%), and worsening was observed in 1 patient (2%). When comparing the surgeries performed, the rate of complete resolution of symptoms was found to be statistically significantly higher in the fenestration group (p=0.01). Postoperative cyst volumes were found higher in the patients with edema positivity (p=0.031) and thickening of basal lamina negativity (p=0.046). Preoperative mass effect was found statistically significant in the patients with edema positivity (p=0.006) and thickening of basal lamina negativity (p=0.013). Postoperative mass effect reduction was also found statistically significant in the patients with edema positivity (p=0.024) and thickening of basal lamina negativity (p=0.002). Conclusions: The present study revealed that fenestration with craniotomy seems to be a favorable technique as the first step in the treatment of arachnoid cysts. The rate of complete resolution of symptoms was higher in the fenestration group and complication rates were higher in the cystoperitoneal shunt group. However, we think that the patients with coexistence of arachnoid cyst and hydrocephalus should be treated with cystoperitoneal shunt application. We also found that the membrane thickness of arachnoid cysts and the amount of collagen increases as the patients’ age increases and tissue edema increases in younger patients. Preoperative mass effect, and postoperative reduction in mass effect correlated positively with tissue edema and negatively with basal lamina thickness.

Meningiomas are the most common primary tumors of the central nervous system and are typically treated with surgery or radiation, as targeted therapies remain limited. Despite extensive study, seventeen percent of meningiomas lack known genetic drivers. Our analysis of meningiomas without driver mutations or major chromosomal alterations identifies a subset with recurrent genomic rearrangements involving the FOS and FOSB genes. These tumors exhibit elevated FOS/FOSB protein levels and retain meningothelial lineage. Here we show that FOS/FOSB fusion-positive meningiomas represent a distinct molecular subgroup, defined by unique gene expression patterns, including activation of AP-1 target genes and signatures resembling preadipocyte-like and mast cell–associated profiles. Clinically, these tumors display low-grade behavior and DNA methylation profiles consistent with benign subtypes. Our findings identify a meningioma subgroup with distinct genetic, transcriptomic, and clinical features, expanding the molecular classification of meningiomas and opening new avenues for targeted treatment strategies.

Essential Tremor (ET) is a common movement disorder characterized by action tremors, primarily affecting the hands and head. lthough previous studies have suggested potential links between ET and aging-related diseases, its relationship with longevity remains unclear, with conflicting evidence in the literature. To investigate this association, we analyzed data from 1,493 individuals across 145 families, encompassing both ET-positive (ET+) and ET-negative (ET−) participants. Using comprehensive statistical methods, including survival function estimation and regression modeling, we examined the potential influence of ET on lifespan. The median age of our participants was 67 years (IQR 54–77). Among deceased individuals, those with ET had a higher median age at death (80 years, IQR 70–86) compared to their ET− counterparts (70 years, IQR 59–77). Living ET+ participants also demonstrated slightly higher median ages (63 years, IQR 53–74) than living ET− individuals (60 years, IQR 49–71). Survival analysis revealed a significantly prolonged lifespan for ET+ individuals compared to ET− individuals (log-rank p = 1.11 × 10 ⁻²³). Furthermore, hazard ratio (HR) calculations indicated a reduced risk of mortality for the ET+ group (HR = 0.44, CI95% = 0.37–0.52), particularly among males. These findings suggest that ET may be associated with increased longevity, though the underlying biological mechanisms remain unclear. Further research is essential to elucidate the processes contributing to this relationship and to explore its implications for understanding aging and neurodegenerative disorders.

Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions¹. Lissencephaly (‘smooth brain’) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability². However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1 , OAS2 , or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)–sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the single-stranded RNA–degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L–deficient cells. Cytokine production in RNase L–deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Objective: The study aimed to show the clinical characteristics and prognosis of the L1 syndrome in patients with L1CAM mutations in the extracellular region. Materials and Methods: Three affected boys and their siblings and parents from a large family were included in this study. Genetic etiology was investigated by whole-exome sequencing in the index patient. The pathogenic variant was detected by whole-exome sequencing and was validated by Sanger sequencing in 3 patients and other family members. Results: We present 2 brothers and their cousin with prenatal onset hydrocephalus, severe developmental and speech delay, corpus callosum agenesis/hypogenesis, epilepsia, and adducted thumbs. A hemizygous missense mutation NM_024003 (c.A2351G:p.Y784C) on exon 18 of L1CAM gene was found in the 3 patients and their carrier mother. This missense mutation in the conserved region of the second fibronectin type III-like repeats located in the extracellular region of L1CAM resulted in the severe phenotype of X-linked inherited L1 syndrome in the patients. Conclusion: L1 syndrome should be considered in the differential diagnosis of male children with intellectual disability, hydrocephalus, and adducted thumbs. While truncating mutations of L1CAM may cause a more severe phenotype, missense mutations cause milder forms. However, pathogenic missense mutations affecting key amino acid residues lead to severe phenotype likely Cite this article as: Tüysüz B, Ercan-Şençiçek AG, Özer E, Goc N, Yalçınkaya C, Bilguvar K. Severe phenotype in patients with X-linked hydrocephalus caused by a missense mutation in L1CAM. Turk Arch Pediatr. 2022;57(5):521-525.

To determine whether mutations reported for ZDHHC15 can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models. We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a Drosophila model. Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in Drosophila. Our findings support a functional expansion of this gene to a role in motor dysfunction. Although ZDHHC15 mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

Improved molecular screening and diagnostic tools are needed to substantially increase SARS-CoV-2 testing capacity and throughput while reducing the time to receive test results. Here we developed multiplex reverse transcriptase polymerase chain reaction (m-RT-PCR) for detection of SARS-CoV-2 using rapid DNA electrophoresis and alternatively using multiplex viral sequencing (mVseq). For RNA specimens extracted from nasopharyngeal (NP) swabs in viral transport media (VTM), our assays achieved a sensitivity for SARS-CoV-2 detection corresponding to cycle threshold (Ct) of 37.2 based on testing of these specimens using quantitative reverse transcription PCR (RT-qPCR). For NP swab-VTM specimens without prior RNA extraction, sensitivity was reduced to Ct of 31.6, which was due to lower concentration of SARS-CoV-2 genome copies in VTM compared to RNA-extracted samples. Assay turnaround time was 60 minutes using rapid gel electrophoresis, 90 minutes using Agilent Bioanalyzer, and 24-48 hours using Illumina sequencing, the latter of which required a second PCR to produce a sequence-ready library using m-RT-PCR products as the template. Our assays can be employed for high-throughput sequencing-based detection of SARS-CoV-2 directly from a clinical specimen without RNA isolation, while ease-of-use and low cost of the electrophoresis-based readout enables screening, particularly in resource-constrained settings.