Neonatal Seizures: An Overview of Genetic Causes and Treatment Options

Seizures are the most frequent neurological clinical symptoms of the central nervous system (CNS) during the neonatal period. Neonatal seizures may be ascribed to an acute event or symptomatic conditions determined by genetic, metabolic or structural causes, outlining the so-called ‘Neonatal Epilepsies’. To date, three main groups of neonatal epilepsies are recognised during the neonatal period: benign familial neonatal epilepsy (BFNE), early myoclonic encephalopathy (EME) and ‘Ohtahara syndrome’ (OS). Recent advances showed the role of several genes in the pathogenesis of these conditions, such as KCNQ2, KCNQ3, ARX, STXBP1, SLC25A22, CDKL5, KCNT1, SCN2A and SCN8A. Herein, we reviewed the current knowledge regarding the pathogenic variants most frequently associated with neonatal seizures, which should be considered when approaching newborns affected by these disorders. In addition, we considered the new possible therapeutic strategies reported in these conditions.

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The Role of Lymphatic Marker Prox-1 in Relation to Brain Tumours

Folia Veterinaria ◽

10.2478/fv-2021-0040 ◽

2021 ◽

Vol 65 (4) ◽

pp. 72-78

Author(s):

J. Teleky ◽

J. Király

Keyword(s):

Brain Tumours ◽

Current Knowledge ◽

Treatment Options ◽

Lymphatic Vessels ◽

Homeobox Gene ◽

Lymphatic Vasculature ◽

Lymphatic Development ◽

The Central Nervous System ◽

The Brain

Abstract The homeobox gene, Prox-1 is a transcription factor essential for lymphatic development (lymphangiogenesis) during embryogenesis. It also performs different functions in various tissues such as: retina, lens, liver, pancreas and the central nervous system. Intense expression of Prox-1 has been demonstrated in the developing spinal cord and brain. In adulthood its expression continues in the hippocampus and cerebellum. In adult tissues the process of lymphatic vasculature formation is accompanied under certain pathological conditions such as inflammation, tissue repair and tumour growth. Prox-1 expression is typical for lymphatic vessels; thus it belongs to one of the most specific and widely used mammalian lymphatic endothelial marker in the detection of lymphangiogenesis and lymphatic vessel invasion in oncogenesis. It has been shown that Prox-1 is involved in cancer development and progression. It’s tumour suppressive and oncogenic properties are proven in several human cancers, including brain tumours. Among all body cancers the brain tumours represent the most feared tumours with very limited treatment options and a poor diagnosis. The aim of this paper was to show the current knowledge of the gene Prox-1 with an emphasis on brain tumours, especially in gliomas.

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Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽

10.3390/cancers13040909 ◽

2021 ◽

Vol 13 (4) ◽

pp. 909

Author(s):

Krzysztof Kotowski ◽

Jakub Rosik ◽

Filip Machaj ◽

Stanisław Supplitt ◽

Daniel Wiczew ◽

...

Keyword(s):

Current Knowledge ◽

Treatment Options ◽

Protein Structures ◽

New Drugs ◽

Proliferating Cells ◽

Cancer Tissues ◽

The Impact ◽

Rate Limiting ◽

Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

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Case Report: Clinical Features of Congenital Portosystemic Shunts in the Neonatal Period

Frontiers in Pediatrics ◽

10.3389/fped.2021.778791 ◽

2021 ◽

Vol 9 ◽

Author(s):

Suhua Xu ◽

Peng Zhang ◽

Liyuan Hu ◽

Wenhao Zhou ◽

Guoqiang Cheng

Keyword(s):

Liver Transplantation ◽

Conservative Treatment ◽

Liver Enzyme ◽

Neonatal Period ◽

Elevated Liver Enzyme ◽

Clinical Symptoms ◽

Treatment Options ◽

Type Ii ◽

Neonatal Cholestasis ◽

Portosystemic Shunts

Objective: The aim of this single-center retrospective study was to analyze the clinical characteristics, treatment options, and course of neonatal-onset congenital portosystemic shunts (CPSS).Methods: We included all patients with CPSS who presented with clinical symptoms within the neonatal period in our institution between 2015 and 2020.Results: Sixteen patients were identified, including 13 patients with intrahepatic portosystemic shunts (IPSS) and three patients with extrahepatic portosystemic shunts (EPSS). The median age of diagnosis was 16 days (range prenatal 24 weeks−12 months). Hyperammonemia (60%), neonatal cholestasis (44%), elevated liver enzyme (40%), hypoglycemia (40%), thrombocytopenia (38%), and coagulation abnormalities (23%) appeared in neonatal CPSS. Twelve patients (75%) presented with congenital anomalies, of which congenital heart disease (CHD) (44%) was the most common. Thirteen patients with IPSS initially underwent conservative treatment, but two of them were recommended for the catheter interventional therapy and liver transplantation, respectively, due to progressive deterioration of liver function. Spontaneous closure occurred in nine patients with IPSS. The shunt was closed using transcatheter embolization in one patient with EPSS type II. Another patient with EPSS type II underwent surgical treatment of CHD firstly. The remaining patient with EPSS type Ib received medical therapy and refused liver transplantation.Conclusion: Hyperammonemia, neonatal cholestasis, elevated liver enzyme, hypoglycemia, and thrombocytopenia are the main complications of neonatal CPSS. Moreover, CPSS is associated with multiple congenital abnormalities, especially CHD. Intrahepatic portosystemic shunts may close spontaneously, and conservative treatment can be taken first. Extrahepatic portosystemic shunts should be closed to prevent complications.

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CMV AND INFANTILE SPASMS

PEDIATRICS ◽

10.1542/peds.63.2.285 ◽

1979 ◽

Vol 63 (2) ◽

pp. 285-285

Author(s):

R. Riikonen

Keyword(s):

Neonatal Period ◽

Clinical Symptoms ◽

Congenital Toxoplasmosis ◽

Infantile Spasms ◽

Early Years ◽

Cmv Infection ◽

Slow Virus ◽

Congenital Cmv Infection ◽

The Central Nervous System ◽

Slow Virus Infection

At the Children's Hospital, University of Helsinki, 205 children with infantile spasms who were born between 1960 and 1976 were studied in a search for the factors responsible. In 11 children (5%) the infantile spasms were possibly associated with cytomegalovirus (CMV) infection. The number may actually have been considerably higher, as no systematic search was made for CMV, especially in the early years. In four of the 11 children, the infection was probably congenital, and was the most likely cause of the spasms. One of the remaining seven children had congenital toxoplasmosis and the simultaneous CMV infection was probably also congenital. The children with congenital CMV infection exhibited severe clinical symptoms in the neonatal period or in early infancy. Two frequent symptoms were persistent tremor and meningoencephalitis. Later, all five children were severely mentally retarded and had spastic tetraplegia and small heads; three of them had optic atrophy and were blind. In the other six children, the CMV infection was probably acquired, the clinical symptoms being less severe, and the spasms may have been caused by another factor. In two of the 11 cases, immunosuppressive therapy (ACTH treatment generally given for infantile spasms) seems to have caused a fulminant CMV infection. Two children with CMV infection still show signs of a slow virus infection in the central nervous system many years later.

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Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Biomolecules ◽

10.3390/biom10121648 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1648

Author(s):

Daniel Liedtke ◽

Christine Hofmann ◽

Franz Jakob ◽

Eva Klopocki ◽

Stephanie Graser

Keyword(s):

Alkaline Phosphatase ◽

Clinical Symptoms ◽

Current Knowledge ◽

Systemic Disease ◽

Loss Of Function ◽

Inorganic Pyrophosphate ◽

Wide Range ◽

Mineralization Processes ◽

Tissue Nonspecific Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

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The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer

Journal of Immunology Research ◽

10.1155/2017/5150678 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 34

Author(s):

Jie Yin ◽

Katherine L. Valin ◽

Michael L. Dixon ◽

Jianmei W. Leavenworth

Keyword(s):

Current Knowledge ◽

Complex Function ◽

Cell Types ◽

First Line ◽

Cns Disorders ◽

Cns Autoimmunity ◽

The Face ◽

The Central Nervous System ◽

Macrophage Subsets

Macrophages are major cell types of the immune system, and they comprise both tissue-resident populations and circulating monocyte-derived subsets. Here, we discuss microglia, the resident macrophage within the central nervous system (CNS), and CNS-infiltrating macrophages. Under steady state, microglia play important roles in the regulation of CNS homeostasis through the removal of damaged or unnecessary neurons and synapses. In the face of inflammatory or pathological insults, microglia and CNS-infiltrating macrophages not only constitute the first line of defense against pathogens by regulating components of innate immunity, but they also regulate the adaptive arms of immune responses. Dysregulation of these responses contributes to many CNS disorders. In this overview, we summarize the current knowledge regarding the highly diverse and complex function of microglia and macrophages during CNS autoimmunity—multiple sclerosis and cancer—malignant glioma. We emphasize how the crosstalk between natural killer (NK) cells or glioma cells or glioma stem cells and CNS macrophages impacts on the pathological processes. Given the essential role of CNS microglia and macrophages in the regulation of all types of CNS disorders, agents targeting these subsets are currently applied in preclinical and clinical trials. We believe that a better understanding of the biology of these macrophage subsets offers new exciting paths for therapeutic intervention.

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Neuroinflammation as Fuel for Axonal Regeneration in the Injured Vertebrate Central Nervous System

Mediators of Inflammation ◽

10.1155/2017/9478542 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 47

Author(s):

Ilse Bollaerts ◽

Jessie Van houcke ◽

Lien Andries ◽

Lies De Groef ◽

Lieve Moons

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Axonal Regeneration ◽

Current Knowledge ◽

Cord Injury ◽

The Central Nervous System ◽

Novel Therapeutic Strategies ◽

The Impact ◽

Vertebrate Central Nervous System

Damage to the central nervous system (CNS) is one of the leading causes of morbidity and mortality in elderly, as repair after lesions or neurodegenerative disease usually fails because of the limited capacity of CNS regeneration. The causes underlying this limited regenerative potential are multifactorial, but one critical aspect is neuroinflammation. Although classically considered as harmful, it is now becoming increasingly clear that inflammation can also promote regeneration, if the appropriate context is provided. Here, we review the current knowledge on how acute inflammation is intertwined with axonal regeneration, an important component of CNS repair. After optic nerve or spinal cord injury, inflammatory stimulation and/or modification greatly improve the regenerative outcome in rodents. Moreover, the hypothesis of a beneficial role of inflammation is further supported by evidence from adult zebrafish, which possess the remarkable capability to repair CNS lesions and even restore functionality. Lastly, we shed light on the impact of aging processes on the regenerative capacity in the CNS of mammals and zebrafish. As aging not only affects the CNS, but also the immune system, the regeneration potential is expected to further decline in aged individuals, an element that should definitely be considered in the search for novel therapeutic strategies.

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Association of HMGB1, S100A12 and IL-17A Expression with IVIG-Resistant Kawasaki Disease and Treatment Options

10.21203/rs.3.rs-51161/v1 ◽

2020 ◽

Author(s):

Deying Liu ◽

Pan Liu ◽

Fan Liu ◽

Wei Yin ◽

Yan Ding

Keyword(s):

Kawasaki Disease ◽

Coronary Arteries ◽

Adjunctive Therapy ◽

Clinical Symptoms ◽

Treatment Options ◽

Poor Response ◽

Serum Levels ◽

Laboratory Parameters ◽

Molecular Pattern

Abstract Background: Kawasaki disease (KD) is a medium vessel vasculitis of unknown aetiology that predominantly affecting coronary arteries. The damage-associated molecular pattern molecules (DAMPs) such as HMGB1, S100A12 and IL-17A have been reported to predict poor response to IVIG. Here, we explored the the role of HMGB1, S100A12 and IL-17A in the detection of intravenous immunoglobulin (IVIG)-resistant in KD patients, and to investigate the value of different adjunctive therapy.Method: 126 KD patients and as well as age- and sex-matched 16 febrile control subjects were enrolled in our study. The fresh peripheral blood were collected from KD patients and febrile controls, analyzed the demographic or clinical data and various laboratory parameters. We also measured changes in serum levels of IL-17A and mRNA expression levels of HMGB1 and S100A12 were tested in IVIG-resistant KD patients. Further we explored the association between coronary arteries lesions and different treatment options about IVIG retreatment, methylprednisolone and infliximab for IVIG-resistant KD patients. Result: Regarding laboratory parameters, KD individuals were found to have lower levels of lymphocyte(L)%, prealbumin, CD4+, CD8+ and higher levels of WBC, neutrophil (N)%, CRP, ESR, NT-proBNP, ALT, CD4+/CD8+ (P<0.05 or P<0.01). For KD group, the 53 IVIG-resistant patients had significantly higher levels of S100A12, HMGB1, serum IL-17A, N%, CRP, NT-proBNP, TBIL, ALT, AST and lower levels of L%, PLT (P<0.05 or P<0.01) in comparison to the IVIG-responsive patients. For patients with IVIG-resistant, IVIG retreatment, methylprednisolone or infliximab were used. Methylprednisolone showed better in improving clinical symptoms and CRP than the IVIG retreatment and infliximab (P> 0.05).Conclusion: IVIG-resistant was associated with overreaction of inflammation.The levels of HMGB1,S100A12 and IL-17A suggested to be reliable predictors for IVIG-resistant in KD. In addition, the adjunctive therapy of methylprednisolone and infliximab showed more effective in relieving clinical symptoms than IVIG retreatment.

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Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

Biomedicines ◽

10.3390/biomedicines9121895 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1895

Author(s):

Max Jonathan Stumpf ◽

Nadjib Schahab ◽

Georg Nickenig ◽

Dirk Skowasch ◽

Christian Alexander Schaefer

Keyword(s):

Current Knowledge ◽

Treatment Options ◽

Pseudoxanthoma Elasticum ◽

Skin Lesions ◽

Arterial Calcification ◽

Future Perspectives ◽

Strong Inhibitor ◽

New Therapeutic Approaches ◽

Pathogenic Variants ◽

Abcc6 Gene

Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease with an estimated prevalence of between 1 per 25,000 and 56,000. Its main hallmarks are characteristic skin lesions, development of choroidal neovascularization, and early-onset arterial calcification accompanied by a severe reduction in quality-of-life. Underlying the pathology are recessively transmitted pathogenic variants of the ABCC6 gene, which results in a deficiency of ABCC6 protein. This results in reduced levels of peripheral pyrophosphate, a strong inhibitor of peripheral calcification, but also dysregulation of blood lipids. Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them. In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and development, and future perspectives.

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A Review of Vascular Disease Risk Factors and Multiple Sclerosis

US Neurology ◽

10.17925/usn.2017.13.02.90 ◽

2017 ◽

Vol 13 (02) ◽

pp. 90

Author(s):

Meena R Kannan ◽

Vijayshree Yadav ◽

◽

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Vascular Disease ◽

Type Ii Diabetes ◽

Demyelinating Disease ◽

Disease Risk ◽

Current Knowledge ◽

Type Ii Diabetes Mellitus ◽

The Central Nervous System

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system and the most common non-traumatic cause of disability in young adults. Recent research shows that vascular disease risk factors (VDRFs) such as obesity, smoking, hyperlipidemia, hypertension, type II diabetes mellitus, and metabolic syndrome, can influence MS on its onset, disease activity, progression, and resultant disability. This review evaluates the current knowledge on the role of VDRFs on outcomes among people with MS (PwMS) and shows that while VDRF prevalence may or may not be higher among PwMS compared with the general population, its presence can influence MS in myriad ways. Management of VDRFs through early detection and treatment may be a promising approach to improving outcomes in PwMS.

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