Spalt-like 4 (SALL4) maintains vertebrate embryonic stem cell identity and is required for the development of multiple organs, including limbs. Mutations in SALL4 are associated with Okihiro syndrome, and SALL4 is also a known target of thalidomide. SALL4 protein has a distinct preference for AT-rich sequences, recognised by a pair of zinc fingers at the C-terminus. However, unlike many characterised zinc finger proteins, SALL4 shows flexible recognition with many different combinations of AT-rich sequences being targeted. SALL4 interacts with the NuRD corepressor complex which potentially mediates repression of AT-rich genes. We present a crystal structure of SALL4 C-terminal zinc fingers with an AT-rich DNA sequence, which shows that SALL4 uses small hydrophobic and polar side chains to provide flexible recognition in the major groove. Missense mutations reported in patients that lie within the C-terminal zinc fingers reduced overall binding to DNA but not the preference for AT-rich sequences. Furthermore, these mutations altered association of SALL4 with AT-rich genomic sites, providing evidence that these mutations are likely pathogenic.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Individuals affected by the disease gradually lose their capacity for abstract thinking, understanding, communication and memory. As populations age, declining cognitive abilities will represent an increasing global health concern. While AD was first described over a century ago, its pathogenesis remains to be fully elucidated. It is believed that cognitive decline in AD is caused by a progressive loss of neurons and synapses that lead to reduced neural plasticity. AD is a multifactorial disease affected by genetic and environmental factors. The molecular hallmarks of AD include formation of extracellular β amyloid (Aβ) aggregates, neurofibrillary tangles of hyperphosphorylated tau protein, excessive oxidative damage, an imbalance of biothiols, dysregulated methylation, and a disproportionate inflammatory response. Recent reports have shown that viruses (e.g., Herpes simplex type 1, 2, 6A/B; human cytomegalovirus, Epstein-Barr virus, hepatitis C virus, influenza virus, and severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), bacteria (e.g., Treponema pallidum, Borrelia burgdorferi, Chlamydia pneumoniae, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, Fusobacterium nucleatum, Aggregatibacter actinomycetemcmitans, Eikenella corrodens, Treponema denticola, and Helicobacter pylori), as well as eukaryotic unicellular parasites (e.g., Toxoplasma gondii) may factor into cognitive decline within the context of AD. Microorganisms may trigger pathological changes in the brain that resemble and/or induce accumulation of Aβ peptides and promote tau hyperphosphorylation. Further, the mere presence of infectious agents is suspected to induce both local and systemic inflammatory responses promoting cellular damage and neuronal loss. Here we review the influence of infectious agents on the development of AD to inspire new research in dementia based on these pathogens.

Cerebral palsy (CP) is associated with the non‑progressive damage of upper motor neurons, which is manifested by a variety of symptoms, particularly motor and functional deficits. During the rehabilitation of patients with CP, attention is paid to improving mobility which can have a significant impact on the child's development. The effectiveness of rehabilitation depends on the plasticity of the nervous system, which may be genetically determined. Of importance are the various polymorphisms of the brain derived neurotrophic factor (BDNF) gene. It has been shown that the Val/Val genotype may predispose children to greater improvements in function and its maintenance. However, subjects with the Met allele showed a reduced tendency to improve their motor functions but had significantly better results on indirect tests assessing gait function. Fifty subjects with CP participated in this study. They were divided into two groups by genotype and examined on their rehabilitation progress in terms of improved gait function. The results correlated with other studies describing the relationship between the BDNF genotype and learning motor functions in CP, and with numerous studies on the relationship between BDNF genotype and neuroplasticity in stroke patients. This research provides a basis for the identification of genetic biomarkers in patients with CP which can be used to predict the effects of rehabilitation therapy and help with the development of personalized treatments.

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel.

Alzheimer's disease (AD) is a dementia disease with a pathomechanism that is not fully understood. There are currently over 20 known genes associated with AD. These genes are involved in metabolism, the removal of abnormal products, including Aβ. Exosomes may be involved in removing abnormal proteins in AD. It is believed that the APOE, RAB11A and TSG101 genes may influence the functioning of exosomes. APOE E4 gene reduces ability to clear Aβ by affecting microglia function. TREM2, acts as a receptor for the Aβ oligomers and mediates its degradation by microglia. Both the CD33 and MS4A4A genes are also responsible for maintaining the efficiency of the immune system. So far, the correlation between these genes has not been studied in AD. The aim of the study was to analyze of genetic variants RAB11A (exon 2), TSG101 (exons 8, 9), CD33 (rs3865444), MS4A4A (rs6591561), TREM2 (rs75932628 and rs143332484) in AD patients, control subjects related to AD cases (CR), and controls subjects without family history of AD (CU).The studies were conducted on 170 individuals (AD and controls). The APOE genotype was determined by real-time PCR. The RAB11A, TSG101, CD33, MS4A4A, TREM2 genetic variants were determined by HRM and sequencing.The C/T variant of the TREM2 rs143332484 was a probable risk factor for AD. People carrying the pathogenic TREM2 rs143332484-C/T variant tended to have earlier onset of symptoms and faster progression of AD (p<0.05). Variant C/A CD33 rs3865444 was more frequent in patients with AD. The CD33 gene, a very rare polymorphism was detected: rs562148996-C/T. The C/A + C/T CD33 gene tended to occur more frequently in controls. The presence of the CD33 rs3865444-A/A might have indicated a protective effect in AD. The MS4A4A rs6591561-A variant was probably associated with the progression of dementia in patients with AD. Dementia tended to develop faster in A/A homozygotes, and slower in patients with the G/G genotype. Conversely, mutations in the RAB11A and TSG101 genes did not appear to affect the onset of AD.Genes associated with removal of pathogenic Aβ deposits seem to be involved in the pathogenesis of AD.

Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.

Alzheimer’s disease is the most common neurodegenerative disease and the cause of dementia. Although the pathomechanisms underlying Alzheimer’s disease have not been fully elucidated, there is evidence that genetic and environmental factors contribute to its development. Immune system changes, both environmentally-induced and, as a result of predisposing genetics, are implicated in Alzheimer’s disease etiopathogenesis. Genes associated with immune system dysfunction in Alzheimer’s disease include CLU, BIN1, CR1, ABCA7, HLA-DRB1, TREM2, EPHA1, and CD2AP. In particular, BIN1 and CLU, aberrations in which are thought to promote neurodegeneration by dysregulating exocytosis and immune processes, together with the E4 variant of the APOE gene, are among the most common genetic risk factors for Alzheimer’s disease. While the relationships between these genes in Alzheimer’s disease have been examined, little information exists regarding their role as variables predisposing first or second-degree relatives of Alzheimer’s disease patients to the illness. The rationale of this review is to suggest that individuals with a family history of Alzheimer’s disease who have the BIN1-T/T variant may be at significant risk of developing Alzheimer’s disease. Also, the unfavorable BIN1-T variant is independent of APOE E4-associated risk. People at risk of developing Alzheimer’s disease are more often carriers of the protective C-variant of the CLU gene, the presence of which might be associated with later-onset dementia observable within this high-risk group. It seems BIN1 and CLU together with, albeit independent of APOE E4, may be among the factors predisposing individuals with a family history of Alzheimer’s disease to developing the illness.

INTRODUCTION Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, progressive ischemic disease of small vessels of the brain characterized by migraine with aura (MA), recurrent subcortical ischemic episodes, cognitive decline and psychiatric disorders. CADASIL is caused by mutations in the NOTCH3 gene. We identified the NOTCH3 Y189C mutation as a genetic cause of CADASIL in a Polish family and provided its first clinical manifestation. MATERIAL AND METHODS The study included twelve subjects from one family. The NOTCH3 mutation, APOE and MTHFR polymorphisms were determined by high-resolution melting analyses (HRMA) and Sanger sequencing. Neuroimaging included CT and MRI. Ultrastructural examination of skin-muscle biopsy material of the proband was performed. RESULTS The NOTCH3 Y189C mutation was present in a 36-year-old woman and her two sisters (aged 40 and 27) from 6 siblings. The MA was found in all of them, and started or became more severe after childbirth. The numerous T2/FLAIR hyperintense lesions were shown in the brain MRI. The deposition of granular osmiophilic material in the wall of small vessels of the proband observed in histopathological analysis confirmed the high degree of CADASIL severity. CONCLUSIONS Patients with the Y189C mutation of NOTCH3 from the same family display a similar phenotype of CADASIL.

In an aging society, the number of people suffering from Alzheimer's disease (AD) is still growing. Currently, intensive research is being carried out on the pathogenesis of AD. The results of these studies indicated that oxidative stress plays an important role in the onset and development of this disease. Moreover, in AD, oxidative stress is generated by both genetic and biochemical factors as well as the functioning of the systems responsible for their formation and removal. The genetic factors associated with the regulation of the redox system include TOMM40, APOE, LPR, MAPT, APP, PSEN1 and PSEN2 genes. The most important biochemical parameters related to the formation of oxidative species in AD are p53, homocysteine (Hcy) and a number of others. The formation of reactive oxygen species (ROS) is also related to the efficiency of the DNA repair system, the effectiveness of the apoptosis, autophagy and mitophagy processes as well as the antioxidant potential. However, these factors are responsible for the development of many disorders, often with similar clinical symptoms, especially in the early stages of the disease. The discovery of markers of the early diagnosis of AD may contribute to the introduction of pharmacotherapy and slow down the progression of this disease.

Mitochondria play an important role in numerous processes, including energy generation, regulating ion homeostasis, and cell signaling. Mitochondria are also the main source of reactive oxygen species (ROS). Due to the oxidative environment within mitochondria, the macromolecules therein, for example, mtDNA, proteins, and lipids are more susceptible to sustaining damage. During aging, mitochondrial functions decline, partly as a result of an accumulation of mtDNA mutations, decreased mtDNA copy number and protein expression, and a reduction in oxidative capacity. The aim of this study was to summarize the knowledge on DNA oxidative damage in aging and age-related neurodegenerative diseases. It has been hypothesized that various ROS may play an important role not only in physiological senescence but also in the development of neurodegenerative diseases, for example, Alzheimer's disease and Parkinson's disease. Thus, mitochondria seem to be a potential target of novel treatments for neurodegenerative diseases.

Background Migraine is a polygenetic disease, considered as a channelopathy. The dysregulation of ion functioning due to genetic changes may activate the trigeminovascular system and induce migraine attack both migraine with aura (MA) and without aura (MO). Objectives The aim of the study was to analyze the following variants of genes encoding ion channels and associated protein: c.3199G>A SCN1A, c.56G>A SCN2A, c.28A>G and c.328T>C KCNK18, c.3053A>G TRPA1, c.31-1811C>T STX1A in migraine patients. Patients and Methods The study included 170 migraine patients and 173 controls. HRMA and Sanger sequencing were used for genotyping. Meta-analysis was performed for c.28A>G, c.328T>C KCNK18, and c.31-1811C>T STX1A. Results AA genotype of c.56G>A SCN2A was found only in migraine patients. Patients with c.328T>C KCNK18 mutation had an increased risk of developing migraine before the age of 18. Moreover, individuals with AA/TC haplotype of KCNK18 had higher attack frequency than those with AA/TT (p<0.05). T allele of c.31-1811C>T STX1A was more frequent in MA patients than MO (p<0.05). The c.3053A>G TRPA1 polymorphism was more common in patients with migraine onset before the age of 15 (p<0.05), while c.31-1811C>T STX1A and c.3199G>A SCN1A before the age of 10 (p<0.01). Meta-analysis showed a significant association of c.31-1811C>T STX1A polymorphism with migraine overall (OR=1.22, p=0.0086), MA, and MO. No association was found for c.28A>G KCNK18, c.328T>C KCNK18, and migraine overall. Conclusion Changes in genes encoding ion channels or proteins regulating their functioning may increase the risk of migraines and correlate with clinical features of disease, e.g. age of onset and attack frequency.

Purpose: Thyroid-associated orbitopathy (TAO) is an autoimmune disease that typically occurs in the course of Graves' disease. VDR gene has been tested for its association with autoimmune thyroid diseases, with conflicting results. The study aimed to evaluate the association of selected VDR polymorphisms (rs2228570, rs1544410, rs7975232, rs731236, and rs11568820) with susceptibility to TAO. Methods: 108 TAO patients and 130 control subjects were enrolled. Polymorphisms were studied by PCR-RFLP or TaqMan real-time PCR. Results: Genotype distributions of rs2228570 differed significantly between TAO and controls under a dominant model (OR = 2.05; 95% CI: 1.03-4.08; p = .04). TAO patients also had slightly increased frequency of C allele of rs2228570 comparing to controls (p = .05). However, the study failed to find any associations between VDR polymorphisms and the analyzed clinical features of the disease. Conclusions: These preliminary results have shown that C allele of rs2228570 may contribute to the development of TAO in patients of Caucasian Polish origin.

: Dementia is an important issue in western societies, and in the following years, this problem will also rise in the developing regions, such as Africa and Asia. The most common types of dementia in adults are Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD) and Vascular Dementia (VaD), of which, AD accounts for more than half of the cases. : The most prominent symptom of AD is cognitive impairment, currently treated with four drugs: Donepezil, rivastigmine, and galantamine, enhancing cholinergic transmission; as well as memantine, protecting neurons against glutamate excitotoxicity. Despite ongoing efforts, no new drugs in the treatment of AD have been registered for the last ten years, thus multiple studies have been conducted on genetic factors affecting the efficacy of antidementia pharmacotherapy. The researchers investigate the effects of variants in multiple genes, such as ABCB1, ACE, CHAT, CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22A1/2/5, SLC47A1, UGT1A6, UGT1A9 and UGT2B7, associated with numerous pathways: the development of pathological proteins, formation and metabolism of acetylcholine, transport, metabolism and excretion of antidementia drugs and transcription factors regulating the expression of genes responsible for metabolism and transport of drugs. The most promising results have been demonstrated for APOE E4, dementia risk variant, BCHE-K, reduced butyrylcholinesterase activity variant, and CYP2D6 UM, ultrarapid hepatic metabolism. Further studies investigate the possibilities of the development of emerging drugs or genetic editing by CRISPR/Cas9 for causative treatment. : In conclusion, the pharmacogenetic studies on dementia diseases may improve the efficacy of pharmacotherapy in some patients with beneficial genetic variants, at the same time, identifying the carriers of unfavorable alleles, the potential group of novel approaches to the treatment and prevention of dementia.

Currently, Alzheimer disease (AD) risk polymorphisms include among others APOE, TOMM40, CLU, and BIN1genes. APOE possess 3 alleles: protective (E2), neutral (E3) and pathogenic (E4). Similar to APOE, the clusterin (CLU) gene also known as apolipoprotein J is present in amyloid plaques and binds to Aβ peptides. Moreover, the CLU gene plays an important role in lipid transport, apoptosis, immune system, and neurogenesis. BIN1 gene is also involved in the regulation of apoptosis and immune response. It is also implicated in synaptic vesicle endocytosis, intracellular APP trafficking. APOE, CLU, and BIN1 are associated with late-onset AD (LOAD) risk. So far, the correlation between these genes has not been studied in the Polish population. The aim of the study was to analyze the CLU and BIN1 polymorphisms in carriers and non-carriers of APOE4 allele: AD patients and related (CR), and unrelated (CU) controls with AD patients. The studies were conducted on 40 patients with AD. The control group included 47 CR and 39 CU. The APOE genotype was determined by real-time PCR. The CLU and BIN1 genotypes were determined by HRM and sequencing. The study showed that incorrect CLU TT homozygous genotype occurred with the same frequency in CR and CU, and 3-times less often than in AD patients. However, incorrect BIN1 TT homozygous genotype occurred 5-times less often in CU than in CR and AD. At the same time, in the non-carriers of APOE4 allele: CLU TT occurred only in CU and AD, and in AD patients appear 2-times more often than in CU and BIN1 TT occurred 3-times less often in CU, AD than in CR. In the carriers of APOE4 allele: CLU TT occurred with the same frequency in CR and AD, and in AD patients appear 3-times more often than in CU. However, BIN1 TT occurred only in CR and AD, and in AD patients appear 2-times more often than in CR. It seems that AD is a complex neurodegenerative disease with a strong genetic component such as APOE, CLU and BIN1.

BACKGROUND:Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system. The clinical phenotype is probably modified by interactions from genetic and environmental factors. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease. NF1 gene mutations lead to clinical manifestation in the peripheral and central nervous system. Coexistence of MS and NF1 is a rare condition.OBJECTIVE:To report the case of the patient with primary progressive MS (PPMS) and NF1.METHODS:A retrospective analysis of a patient who has undergone whole exome sequencing confirmed by Sanger sequencing.RESULTS:We reported a novel de novo c.6817delC deletion and rs1801052 polymorphism in NF1 gene associated with NF1 symptoms, as well as numerous polymorphisms in SPG7, SPG15, SPG39 genes responsible for benign spastic paraplegia.CONCLUSION:Co-occurrence of PPMS and NF1 may be a consequence of genetic changes.

Alzheimer's disease (AD) is a progressive neurodegenerative dementia in adults. Pathogenesis of AD depends on various factors, including APOE genetic variants, apolipoprotein E (apoE) phenotype and oxidative stress, which may promote both DNA and RNA damage, including non-coding RNA (ncRNA). Among ncRNAs, microRNA (miRNA) is known to contribute to pathologic processes in AD. The aim of the study was to analyse the plasma concentration of apoE by ELISA as well as the plasma levels of miR-107 and miR-650 by qPCR in relation to APOE genetic variants and clinical features including the age of onset and dementia severity in 64 AD patients and 132 controls. Our data showed that a low apoE plasma concentration was a risk factor for developing AD (OR = 5.18, p = 6.58E-06) and was particularly pronounced in severe dementia (p < 0.001) and correlated with cognitive functions (R = 0.295, p = 0.020), similarly as the level of miR-650 (R = 0.385, p = 0.033). The presence of APOE E4 allele in both AD patients and controls led to a reduction in apoE, while APOE E3/E3 genotype was associated with an increased apoE concentration and level of miR-107 in AD (p < 0.05) which was inversely correlated with the number of APOE E4 alleles (R = -0.448, p = 0.009). Additionally, patients with the onset at 60-69 years of age showed a reduced level of miR-107 (p < 0.05, as compared to AD above 80 years of age). Changed levels of plasma apoE, miR-107 and miR-650 may be a marker of the neurodegenerative process in the course of AD, associated with amyloid β metabolism and inordinate cell cycle.

Alzheimer’s disease (AD) is a progressive disease, with frequently observed improper biothiols turnover, homocysteine (Hcy) and glutathione (GSH). GSH protects cells from oxidative stress and may be determined by 8-oxo-2’-deoxyguanosine (8-oxo2dG) level and its repair enzyme 8-oxoguanine DNA glycosylase (OGG1). The presence of unfavorable alleles, e.g., in APOE cluster, TOMM40 or APOC1 is known to facilitate the dementia onset under oxidative stress. The aim of the study was to analyze rs1052452, rs2075650 TOMM40 polymorphisms, rs4420638 APOC1, and their correlation with Hcy, GSH, 8-oxo2dG, OGG1 levels in plasma of AD patients and controls. We recruited 230 individuals: 88 AD, 80 controls without (UC), 62 controls with (RC) positive family history of AD. The TOMM40 genotype was determined by HRM and capillary electrophoresis, while APOC1 by HRM. The concentrations of OGG1, 8-oxo2dG were determined by ELISA, whereas Hcy, GSH by HPLC/EC. We showed that over 60% of AD patients had increased Hcy levels (p<0.01 vs. UC, p<0.001 vs. RC), while GSH (p<0.01 vs. UC), 8-oxo2dG (p<0.01 vs. UC, p<0.001 vs. RC) were reduced. Minor variants: rs10524523-L, rs4420638-G, rs2075650-G were significantly overrepresented in AD. For rs4420638-G, rs2075650-G variants, the association remained significant in APOE E4 non-carriers. The misbalance of analyzed biothiols, and 8-oxo2dG, OGG1 were more pronounced in carriers of major variants: rs10524523-S/VL, rs4420638-A, rs2075650-A. We showed, for the first time, that APOC1 and TOMM40 rs2075650 polymorphisms may be independent risk factors of developing AD, whose major variants are accompanied by disruption of biothiols metabolism and inefficient removal of DNA oxidation.