Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder.

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell-cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with "Pitt-Hopkins-like syndrome-1" (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype-phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype-phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

Characterization of M116.1p, a Murine Cytomegalovirus Protein Required for Efficient Infection of Mononuclear Phagocytes.

Broad tissue tropism of cytomegaloviruses (CMVs) is facilitated by different glycoprotein entry complexes, which are conserved between human CMV (HCMV) and murine CMV (MCMV). Among the wide array of cell types susceptible to the infection, mononuclear phagocytes (MNPs) play a unique role in the pathogenesis of the infection as they contribute both to the virus spread and immune control. CMVs have dedicated numerous genes for the efficient infection and evasion of macrophages and dendritic cells. In this study, we have characterized the properties and function of M116, a previously poorly described but highly transcribed MCMV gene region that encodes M116.1p, a novel protein necessary for the efficient infection of MNPs and viral spread in vivo. Our study further revealed that M116.1p shares similarities with its positional homologs in HCMV and RCMV, UL116 and R116, respectively, such as late kinetics of expression, N-glycosylation, localization to the virion assembly compartment, and interaction with gH-a member of the CMVs fusion complex. This study, therefore, expands our knowledge about virally encoded glycoproteins that play important roles in viral infectivity and tropism. IMPORTANCE Human cytomegalovirus (HCMV) is a species-specific herpesvirus that causes severe disease in immunocompromised individuals and immunologically immature neonates. Murine cytomegalovirus (MCMV) is biologically similar to HCMV, and it serves as a widely used model for studying the infection, pathogenesis, and immune responses to HCMV. In our previous work, we have identified the M116 ORF as one of the most extensively transcribed regions of the MCMV genome without an assigned function. This study shows that the M116 locus codes for a novel protein, M116.1p, which shares similarities with UL116 and R116 in HCMV and RCMV, respectively, and is required for the efficient infection of mononuclear phagocytes and virus spread in vivo. Furthermore, this study establishes the α-M116 monoclonal antibody and MCMV mutants lacking M116, generated in this work, as valuable tools for studying the role of macrophages and dendritic cells in limiting CMV infection following different MCMV administration routes.

Are Parkinson's disease patients referred too late for device-aided therapies and how can better informed and earlier referrals be encouraged?

In the advanced Parkinson's disease, motor and non-motor symptoms become more severe and more difficult to treat. Oral therapy may become insufficient in controlling a patient´s motor complications, which results in a substantial deterioration of the patient's quality of life, ability to work and self-reliance. This is when device-aided treatments should be considered and offered, if suitable for a given patient. They include subcutaneous and intestinal infusion therapies, deep brain stimulation and, more recently, MRI-guided focussed ultrasound. Device-aided treatments should be offered in accordance with guidelines and treatment standardization. Also there is a need to ensure availability of treatment and education of patients and physicians.

Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure.

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence.

Prophylactic therapeutic plasma exchange in pregnant woman with Familial Chylomicronemia Syndrome - A case report.

CONTEXT: Familial Chylomicronemia Syndrome (FCS) is an inherited disease where lack of lipoprotein lipase results in severe hypertriglyceridemia that frequently leads to recurrent acute pancreatitis. Pregnancy in patients with familial chylomicronemia syndrome (FCS) post a risk for mother and baby with potential complications (pancreatitis, miscarriage and death). Therapeutic approach includes strict dietary measures and plasma exchange. Despite the development of new drugs for FCS, their safety in pregnancy has not yet been confirmed. CASE DESCRIPTION: We present a case of a young, pregnant female with FCS who had miscarriage in the past during one episode of acute pancreatitis. Due to the inability to achieve lower TG levels with current therapy, from 27-th week of pregnancy we have started prophylactic therapeutic plasma exchange (two times per week). Patient was followed up until the delivery of a healthy baby boy and did not experience an episode of acute pancreatitis. CONCLUSIONS: With adequate supervision and monitoring therapeutic plasma exchange represents a safe approach in pregnant women with FCS in order to reduce TGs and prevent pancreatitis. Therefore, we prevented potential complications for both mother and child.

Heavy Metals and Essential Metals Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease.

Various metals have been associated with the pathogenesis of Alzheimer's disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is needed on their mechanisms of toxicity. To further assess the involvement of heavy and essential metals in AD pathogenesis, we compared cerebrospinal fluid (CSF) AD biomarkers to macro- and microelements measured in CSF and plasma. We tested if macro- and microelements' concentrations (heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Na, Mg, K, Ca, Fe, Co, Mn, Cu, Zn, and Mo), essential non-metals (B, P, S, and Se), and other non-essential metals (Al, Ba, Li, and Sr)) are associated with CSF AD biomarkers that reflect pathological changes in the AD brain (amyloid ß1-42, total tau, phosphorylated tau isoforms, NFL, S100B, VILIP-1, YKL-40, PAPP-A, and albumin). We used inductively coupled plasma mass spectroscopy (ICP-MS) to determine macro- and microelements in CSF and plasma, and enzyme-linked immunosorbent assays (ELISA) to determine protein biomarkers of AD in CSF. This study included 193 participants (124 with AD, 50 with mild cognitive impairment, and 19 healthy controls). Simple correlation, as well as machine learning algorithms (redescription mining and principal component analysis (PCA)), demonstrated that levels of heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Ca, Co, Cu, Fe, Mg, Mn, Mo, Na, K, and Zn), and essential non-metals (P, S, and Se) are positively associated with CSF phosphorylated tau isoforms, VILIP-1, S100B, NFL, and YKL-40 in AD.

Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein.

Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known. Here, we investigated the mechanisms underlying aSyn-mediated transcription deregulation by assessing its effects in the nucleus and the impact of phosphorylation in these dynamics. We found that aSyn induced severe transcriptional deregulation, including the downregulation of important cell cycle-related genes. Importantly, transcriptional deregulation was concomitant with reduced binding of aSyn to DNA. By forcing the nuclear presence of aSyn in the nucleus (aSyn-NLS), we found the accumulation of high molecular weight aSyn species altered gene expression and reduced toxicity when compared with the wild-type or exclusively cytosolic protein. Interestingly, nuclear localization of aSyn, and the effect on gene expression and cytotoxicity, was also modulated by phosphorylation on serine 129. Thus, we hypothesize that the role of aSyn on gene expression and, ultimately, toxicity, may be modulated by the phosphorylation status and nuclear presence of different aSyn species. Our findings shed new light onto the subcellular dynamics of aSyn and unveil an intricate interplay between subcellular location, phosphorylation and toxicity, opening novel avenues for the design of future strategies for therapeutic intervention in PD and other synucleinopathies.

A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor.

BACKGROUND: Li-Fraumeni is a rare autosomal dominant cancer predisposition syndrome. The basis is a germline mutation of TP53 gene which encodes tumor suppressor protein resulting in early onset of tumors, most often breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinomas, and leukemia. CASE REPORT: We present a case of a young woman with a positive family history for cancer diagnosed with malignant solitary fibrous tumor and luminal B-like invasive breast cancer. Breast cancer and sarcomas account for the majority of tumors associated with Li-Fraumeni syndrome, yet solitary fibrous tumor is a rare clinical entity with no established guidelines for treatment. Even though both primary tumors were successfully resected, the sarcoma relapsed in the form of lung metastases. The NGS analysis revealed single nucleotide variant (c.1101-1G>A) in TP53 gene, affecting the acceptor splice site at intron 10. Until now, only one case of this genetic variant has been documented with conflicting interpretations of pathogenicity. CONCLUSIONS: The knowledge of TP53 mutation status is essential since the management of these patients requires different approach to avoid excessive toxicity due to the risk of developing secondary malignancy. Using the clinical criteria to screen for affected individuals facilitates appropriate early genetic counseling of patients and their families. Following the American College of Medical Genetics criteria, we believe that the reported single nucleotide variant (c.1101-1G>A) in TP53 gene should be considered pathogenic.

Psychiatric Comorbidities in Parkinson's Disease Seen through the Prism of Genomics and Epigenetics.

Parkinson's disease (PD) is a neurodegenerative disorder clinically characterized by motor dysfunctions due to progressive loss of dopaminergic neurons and a broad spectrum of non-motor symptoms. Interestingly, non-motor symptoms like depression, anxiety and psychosis are often present several years before the occurrence of classic motor features seriously affecting patient quality of life. Their presence is often misleading, delaying the correct diagnosis of PD. Despite its high incidence, the pathophysiology and aetiology of neuropsychiatric symptoms associated with PD remains unclear. Currently, a lot of interest lays in research looking for genetic predictors of motor and non-motor symptoms in PD. The availability of next-generation sequencing technology for genome, epigenetic and transcriptional analysis opens the door to a new way of studying multifactorial diseases like PD and their comorbidities. In this review we will present new insights in the genomic and epigenetic background of psychiatric comorbidity in Parkinson's disease.

Could Mental and Physical Exercise Alleviate Alzheimer's Disease?

The aim of this review is to emphasize the importance of mental activity and aerobic physical exercise as one of the most important health-related activities which may delay the onset or slow down the progression of Alzheimer's dementia. Studies have shown that the elderly who regularly engage in mental and physical activities have a lower risk of dementia development. Performing mental and physical activities regularly has a synergistic effect on the improvement of cognitive functions. Complex mental activity during life is associated with a reduction in the hippocampal atrophy rate, which is a sensitive early-stage biomarker of dementia while regular physical exercise can slow down the progressive reduction of the cortical brain volume which occurs during aging. Mental activity increases a person's "cognitive reserve" and promotes the formation of new communications between brain cells. Since it is not possible to influence genetic components of Alzheimer's dementia, preventative interventions such as encou¬raging regular engagement in mental and physical activities are extremely important. Activities need to be safe, moderate, comfortable, and adapted as to type, duration, and especially the health and functional status of the patient. In the near future, it is expected that genome analysis in personalized medicine will guide us in the right direction on certain types of physical and mental exercise.

DIAGNOSTIC AND THERAPEUTIC DILEMMAS IN THE MANAGEMENT OF INTRACRANIAL ANEURYSMS.

Intracranial aneurysms have a prevalence of about 2% of the population. They are a common incidental finding of noninvasive neuroimaging methods, raising the question of the necessity of treatment of patients with an asymptomatic intracranial aneurysm. For long, the only treatment option was surgical clipping of aneurysm neck. In the last 25 years, endovascular techniques have been developed as an alternative solution for patients who are not eligible for neurosurgical procedures. Research has shown better results of embolization procedures with lower rates of complications, but a higher rate of recanalization is still a major drawback of endovascular coiling. There are no strict protocols and the treatment of choice for intracranial aneurysms should be agreed upon by both the physician and the patient. This review aims to provide an insight into the management of intracerebral aneurysms with emphasis on the decision making problems faced by clinicians.

GliMR: Cross-Border Collaborations to Promote Advanced MRI Biomarkers for Glioma.

Purpose: There is an annual incidence of 50,000 glioma cases in Europe. The optimal treatment strategy is highly personalised, depending on tumour type, grade, spatial localization, and the degree of tissue infiltration. In research settings, advanced magnetic resonance imaging (MRI) has shown great promise as a tool to inform personalised treatment decisions. However, the use of advanced MRI in clinical practice remains scarce due to the downstream effects of siloed glioma imaging research with limited representation of MRI specialists in established consortia; and the associated lack of available tools and expertise in clinical settings. These shortcomings delay the translation of scientific breakthroughs into novel treatment strategy. As a response we have developed the network "Glioma MR Imaging 2.0" (GliMR) which we present in this article. Methods: GliMR aims to build a pan-European and multidisciplinary network of experts and accelerate the use of advanced MRI in glioma beyond the current "state-of-the-art" in glioma imaging. The Action Glioma MR Imaging 2.0 (GliMR) was granted funding by the European Cooperation in Science and Technology (COST) in June 2019. Results: GliMR's first grant period ran from September 2019 to April 2020, during which several meetings were held and projects were initiated, such as reviewing the current knowledge on advanced MRI; developing a General Data Protection Regulation (GDPR) compliant consent form; and setting up the website. Conclusion: The Action overcomes the pre-existing limitations of glioma research and is funded until September 2023. New members will be accepted during its entire duration.

Management of idiopathic normal pressure hydrocephalus (iNPH) - a retrospective study.

Background: Normal pressure hydrocephalus (NPH) is communicating hydrocephalus characterised by normal intraventricular pressures. It presents with the triad of gait impairment, cognitive decline, and urinary incontinence. The term idiopathic normal pressure hydrocephalus (iNPH) is used in cases where the etiology is unknown. The aim of this study was to assess the prevalence and management of iNPH in our institution.Method: This was a retrospective study carried out at a tertiary health care center. Retrospective case series analysis was conducted using the existing electronic medical record data (2009-2017) on patients with hydrocephalus.Results: Forty-two (6.7%) patients with iNPH were identified, mean age 71.5 ± 8.8 years, 21 male (mean age 71.5 ± 9.3 years) and 21 female (mean age 71.5 ± 8.5 years). Ataxia was recorded in 39, symptoms of dementia in 31, and urinary incontinence in 29 patients. Forty patients were treated surgically by placing a ventriculoperitoneal (VP) shunt. One of the two patients treated by endoscopic third ventriculostomy (ETV) was subsequently treated by placing a VP shunt due to clinical deterioration. Significant improvements were noticed in cognitive and urinary symptoms, in the triad symptom sum score on the Japanese NPH scale, as well as in Evans' index and callosal angle (CA) on brain MRI (p < 0.05). Significant positive correlation was found between age and gait disturbance (Spearman's rho = 49.86% p = 0.0017), age and incontinence (Spearman's rho = 35.22%, p = 0.0351), age and triad symptom sum score (Spearman's rho = 44.67%, p = 0.0056), female gender and dementia (Spearman's rho = 34.94%, p = 0.0367), and among all three variables on the Japanese NPH scale (p < 0.0001).Conclusions: Treatment of iNPH with VP shunt showed significant improvement. A properly designed study is required to address the efficacy of ETV in the treatment of iNPH.

Congenital factor XI deficiency caused by a novel F11 missense variant: a case report.

Hereditary factor XI (FXI) deficiency is a mild bleeding disorder, rare in the general population but relatively common among Ashkenazi Jews. The human F11 gene comprises 15 exons, spanning over 23 kb of the long arm of chromosome 4 (4q35). Homozygotes or compound heterozygotes typically show severe FXI deficiency, whereas heterozygotes show partial or mild deficiency. However, the genotype-phenotype relationship is difficult to establish, even among individuals within the same family. We report on a female patient with a heterozygous variant in F11 and FXI deficiency (49 IU/dL), who suffers from menorrhagia since menarche and easy bruising. She experienced excessive bleeding during thyroidectomy and after a cesarean section. Her younger sister, who carries the same heterozygous variant in F11 and has mild FXI deficiency (47 IU/dL), has menorrhagia without other bleeding difficulties although she has undergone several surgeries. Their father, who carries the same missense variant, has not experienced any bleeding difficulties (but he has not undergone any surgeries either). The family study revealed that the A428C mutation was inherited from the father. This variant has not previously been described in the literature and is the first F11 variant described in the Croatian population. Our study showed that even when family members have the same germline F11 variant, they still may experience phenotypic variability, making disease prognosis more complex.

Attenuation of ALS progression during pregnancy-lessons to be learned or just a coincidence?

ALS is the most frequent motor neuron disorder in adults with suggested complex relationship regarding gender. Studies investigating ALS and hormones have provided varying results. ALS onset during pregnancy is uncommon and pregnancy after the ALS symptom onset is even rarer. We present three patients with the onset of ALS symptoms before or during pregnancy and propose a putative disease modifying mechanism leading to attenuation of disease progression that we observed during the pregnancies.

Comparable Genomic Copy Number Aberrations Differ across Astrocytoma Malignancy Grades.

A collection of intracranial astrocytomas of different malignancy grades was analyzed for copy number aberrations (CNA) in order to identify regions that are driving cancer pathogenesis. Astrocytomas were analyzed by Array Comparative Genomic Hybridization (aCGH) and bioinformatics utilizing a Bioconductor package, Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0.23 and DAVID software. Altogether, 1438 CNA were found of which losses prevailed. On our total sample, significant deletions affected 14 chromosomal regions, out of which deletions at 17p13.2, 9p21.3, 13q12.11, 22q12.3 remained significant even at 0.05 q-value. When divided into malignancy groups, the regions identified as significantly deleted in high grades were: 9p21.3; 17p13.2; 10q24.2; 14q21.3; 1p36.11 and 13q12.11, while amplified were: 3q28; 12q13.3 and 21q22.3. Low grades comprised significant deletions at 3p14.3; 11p15.4; 15q15.1; 16q22.1; 20q11.22 and 22q12.3 indicating their involvement in early stages of tumorigenesis. Significantly enriched pathways were: PI3K-Akt, Cytokine-cytokine receptor, the nucleotide-binding oligomerization domain (NOD)⁻like receptor, Jak-STAT, retinoic acid-inducible gene (RIG)-I-like receptor and Toll-like receptor pathways. HPV and herpex simplex infection and inflammation pathways were also represented. The present study brings new data to astrocytoma research amplifying the wide spectrum of changes that could help us identify the regions critical for tumorigenesis.

EEG Analysis and Spect Imaging in Alzheimer's Disease, Vascular Dementia and Mild Cognitive Impairment.

BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) represent a leading public-health problem given the rising age of the population. Early diagnosis of dementia, especially at the stage of mild cognitive impairment (MCI) has become an important goal of the modern patient work-up. Brain perfusion single-photon emission computed tomography (SPECT) has become a mainstay of diagnostic algorithms in patients with dementia showing specific patterns of hypoperfusion in temporal and parietal lobes. Clinical electroencephalography (EEG) is a relatively simple and inexpensive diagnostic tool showing potential in assessing cortical thinning and lower perfusion in temporoparoetal regions. SUBJECTS AND METHODS: Our study was a cross sectional and included retrospective analysis of the group of patients diagnosed with AD, VaD and MCI. The study group consisted of 50 patients - 29 females and 21 males. All patients underwent EEG and SPECT analysis as part of regular work-up. RESULT: Patients with AD exhibit EEG changes mostly in the form of theta waves, focal abnormalities and spike-and-wave complexes in frontotemporal regions with the reduction in the amplitude of alpha waves. SPECT in most patients exhibited hypoperfusion in temporoparietal regions with occasional unilateral abnormalities in frontotemporal region. EEG changes in patients with VaD are predominantly in the form of theta waves while SPECT findings show mostly "patchy" abnormalities. EEG readings are normal or exhibit minimal changes in the group of patients with MCI, while SPECT imaging exhibits mostly normal CBF. CONCLUSION: EEG and SPECT are diagnostic methods which show specific changes, especially in AD. EEG can be used to monitor the therapeutic effect and progression of AD as well as the possible transition from MCI to early stage AD. SPECT on the other hand, being a more expensive and less available method, can be utilized as an add-on method to increase the specificity and sensitivity of the diagnostic algorithm.

Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function.

Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.