The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case.

Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course.

POLG gene mutation. Clinico-neuropathological study.

We present a female patient with a mutation of the POLG gene (POLG DNA polymerase gamma, catalytic subunit; *174763) in which the clinical course suggested a mitochondrial disease, a neuropathological examination identified the syndrome more closely, and a genetic test confirmed the disease. Apart from the morphological lesions typical of Alpers-Huttenlocher syndrome, rarely observed symmetrical degenerative changes in the accessory olivary nuclei were found. It was unusual in the clinical course of the disease that pancreatitis was diagnosed before symptoms of liver failure appeared.

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4).

Clinico-pathological correlation in case of BRAT1 mutation.

The clinical picture of BRCA1-associated protein required for ATM activation-1 (BRAT1) comprises retractable early-onset epileptic encephalopathy, progressive microcephaly, and early demise. Both, inter- and intrafamilial variations of features of BRAT1-associated disease have been described. Here, the familial case of a brother and sister with homozygous pathogenic variants in BRAT1 is presented with special emphasis on differences in seizure type/onset and central nervous system lesions.

Commitment of protein p53 and amyloid-beta peptide (Aβ) in aging of human cerebellum.

Protein p53 is known to induce the cell cycle arrest and apoptosis in response to a variety of cellular distress signals and DNA damage. A recent study has demonstrated that in blood cells of aging subjects, p53 may induce early pathological changes that precede the amyloidogenic cascade. However, it is not clear whether p53 participates in the local deposition of amyloid-beta peptide (Aβ) in the nerve tissue of normal aging subjects.

Holoprosencephaly with agenesia of the prosencephalic ventricle.

Malformations of the forebrain are characterized by abnormalities in size, shape, and arrangement of the cerebral hemispheres and ventricles. We present the morphological picture of a brain with failure of the forebrain complementary to holoprosencephaly coexisting with absence of the anterodorsal part of the prosencephalic ventricles. The anomaly can be graded within the holoprosencephalic spectrum due to the main morphological features.

Toll-like receptor 2 (TLR2) is a marker of angiogenesis in the necrotic area of human medulloblastoma.

Angiogenesis plays a key role in the progression of malignant tumors. In recent years, anti-angiogenic drugs have been shown to be effective against tumors. However, some tumors are able to adopt escape mechanisms, suggesting that the vascular network in these tumors may be formed or may function in a different way.

Methyl-CpG binding protein 2, receptors of innate immunity and receptor for advanced glycation end-products in human viral meningoencephalitis.

Inflammation is a normal host defense reaction to infections and tissue injury. In pathology, the process of inflammation is deregulated by various environmental factors, prolonged activation of Toll-like receptors (TLRs), induction of epigenetic machinery or expression of receptors for advanced glycation end-products (RAGE). In the present study, we examined immunoexpression of proteins participating in the above-mentioned mechanisms, in the brain of patients with viral meningoencephalitis.

Congenital glioblastoma coexisting with vascular developmental anomaly.

Congenital central nervous tumours form a unique group of neoplasms. They are different from other tumour groups not only due to the onset time but also to their histopathology, anatomic location, and biologic behaviour. Congenital glioblastoma is one of the rarest types of congenital brain tumours and is uncommon in the prenatal period.

Morphological evidence of the beneficial role of immune system cells in a rat model of surgical brain injury.

The blood-brain barrier prevents infiltration of peripheral immunocompetent cells into the CNS under physiological conditions. Following brain trauma there is reported a rapid and massive immunological response. Our earlier data indicated that surgical brain injury causes breaking of brain parenchyma integrity and results in cell changes and death, astrogliosis and disruption of blood vessels.

Crosstalk in human brain between globoid cell leucodystrophy and zinc-α-2-glycoprotein (ZAG), a biomarker of lipid catabolism.

Zinc-alpha-2-glycoprotein (ZAG) is a protein identified as a lipid-mobilizing factor participating in a lipid catabolism. In spite of intensive studies conducted during last five decades, the role of this protein in processes of neurodegeneration remains unclear. The aim of our study was to examine the presence of ZAG protein in the brain of patients with Krabbe's disease, which is considered as a psychosine lipidosis caused by a mutation of a known gene.

Toll-like receptors as an innate immunity bridge to neuroinflammation in medulloblastoma.

The relationship between inflammation, immunity and cancer is widely accepted but mechanisms mediating this relationship remain unknown. Our present study was undertaken to examine the presence and distribution of Toll-like receptors (TLRs) in necrotic areas of medulloblastoma. These receptors fulfil the criteria postulated for the receptors of innate immunity and signalling from TLRs induces synthesis of various pro-inflammatory cytokines, enzymes and mediators.

Diagnostic difficulties in Krabbe disease: a report of two cases and review of literature.

Globoid cell leukodystrophy (GLD, also known as Krabbe disease), whose pathophysiology is still not completely elucidated, is an inherited, metabolic, and neurodegenerative disease, caused by the deficiency of β-galactocerebrosidase (GALC) or in very rare cases by lack of active saposin A. We describe two patients, in whom first MRI changes were not suggestive of GLD. Additionally, in Patient 1, the residual β-galactocerebrosidase activity was rather high leading to difficulties in the diagnosing process.

Immunodistribution of amyloid beta protein (Aβ) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients.

RAGE (receptor for advanced glycation end-products) participates in the influx transport of glycated Aβ (amyloid beta) from the blood to the brain. Because little is known of the RAGE operating in brain barriers such as those in the choroid plexus and ependyma, the aim of the present study was to examine the immunodistributions of RAGE and Aβ peptides in the choroid plexus where the blood-cerebrospinal fluid barrier (B-CSF) is located, and in ependyma of the brain ventricles associated with functions of the cerebrospinal fluid-brain barrier (CSF-B). The study was performed on patients over 65 years successfully resuscitated after cardiac arrest with survival a few weeks.

Cerebellar cortical neurons misplaced in the white matter due to disturbed migration during development of human brain.

The normal laminar organisation of the cerebellar cortex is the result of the precisely controlled migration, differentiation and maturation of the neurons. Occasionally the migrating neurons lose their proper way of migration and form nests of grey matter in the improper place. The aim of this study was to investigate the morphological features of the lost neurons in the cerebellar white matter during development, with particular emphasis on their localisation, arrangement and differentiation.

Association of mast cells with calcification in the human pineal gland.

Increased pineal calcifications and decreased pineal melatonin biosynthesis, both age related, support the notion of a pineal bio-organic timing mechanism. The role of calcification in the pathogenesis of pineal gland dysfunction remains unknown but the available data document that calcification is an organized, regulated process, rather than a passive aging phenomenon. The cellular biology and micro-environmental conditions required for calcification remain poorly understood but most studies have demonstrated evidence that mast cells are strongly implicated in this process.

Calbindin positive Purkinje cells in the pathology of human cerebellum occurring at the time of its development.

Development of cerebellum continues over an extremely long period of time extending from the early embryonic phase until the first postnatal years. During an extended time of maturation the cerebellum is vulnerable to harmful agents. A group of cytoplasmic proteins that may protect cells against injury are the calcium binding proteins, among others calbindin.

Astroglia and microglia in cerebellar neuronal migration disturbances.

Between the neuronal and glial cells there is a close relationship conditioning a tight morphological correlation and proper functional interplay. Disturbed interaction between glial and neuronal components leads to inappropriate neural circuits. The reflection of the failure of neural circuit organisation is the picture of morphological changes of neurons and glia.

Faulty position of cerebellar cortical neurons as a sequel of disturbed neuronal migration.

The object of our report is the presentation of the morphological picture of cerebellar cortex malformation as a sequel of disturbed neuronal migration. In the disarranged tissue, cavities with a network of meningeal tissue and embedded pathological vessels were noted. The external granule cells did not form a proper external granule layer, but moved deeper, forming irregular aggregates.

Effects of ischaemia and hypoxia on the development of the nervous system in acardiac foetus.

The twin-reversed arterial perfusion (TRAP) sequence and development of an acardius are rare and severe complications in monozygotic twin pregnancy. Haemodynamic disturbances in placental perfusion via abnormal vascular anastomoses allow inter-twin transfusion to occur. Because of blood perfusion, one of the twins is poorly oxygenated and contains metabolic waste products.

Inflammatory and reparative tissue reaction in developing human central nervous system.

Morphologic features of inflammatory reactions in the immature central nervous system (CNS) develop in the second half of pregnancy. The cells composing the infiltrations arise early during development but their presence in circulation and final localization in fully mature inflammatory reactions is prolonged in time. The aim of this work was to compare the picture of inflammatory infiltrations in a group of fetal brains following various infections and aseptic injuries.

Toll-like receptors in rat brains injured by hypoxic-ischaemia or exposed to staphylococcal alpha-toxin.

Some data suggest that the central nervous system (CNS) is the main target of Staphylococcus alpha-toxin. Since this pathogen cannot penetrate the blood-brain barrier (BBB), the exact mechanism by which alpha-toxin affects the CNS remains unclear. Recent studies on the role of the innate immune system have shed light on how bacterial infections initiate inflammatory responses within the CNS.

Morphology of pineal glands in human foetuses and infants with brain lesions.

The pineal gland is an organ involved in regulation of homeostasis and body rhythms. It plays an important role in the growth foetuses and adaptation of newborns to new environmental conditions. The requirements of foetuses and newborns progressively change during development.

Discrete glioneuronal malformative lesions in the foetal and infantile cerebral cortex.

Microdysgenesis is a term describing microscopic cortical cytoarchitectural abnormalities. Histologically this change shows an irregular glioneuronal tissue combination forming an abnormal structure of the cortex. The pathological features of this malformation are subtle and less well defined than other more distinctive cortical malformations.

Proinflammatory cytokines in injured rat brain following perinatal asphyxia.

In contrast to astrogliosis, which is common to injuries of the adult CNS, in the developing brain this process is minimal. Reasons postulated for this include the relative immaturity of the immune system and the consequent insufficient production of cytokines to evoke astrogliosis. To explore this hypothesis, the study was undertaken to detect the presence of some proinflammatory cytokines in the injured rat brain following perinatal asphyxia (ischaemia/hypoxia).