Genetic Neurological Disorders Research Articles

A Highly Selective Fluorescent Probe for Monitoring the Thyroid Hormone Transporter Activity in Mammalian Cells.

Monocarboxylate transporter 8 (MCT8) is a trans-membrane transporter, which mediates the cellular delivery of thyroid hormones, L-thyroxine (T4) and 3,5,3 '-triiodo-L-thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene and mutations in the transporter cause a genetic neurological disorder known as Allan-Herndon-Dudley syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain. Radiolabelled T4 and T3 or LC/MS-MS methods have been used to monitor the thyroid hormone uptake through MCT8. Herein, we developed a fluorescent based assay to monitor the thyroid hormone uptake through MCT8. A dansyl-based fluorescent probe having L-thyroxine moiety is found to be highly selective towards MCT8 in living cells. The high selectivity of the probe towards MCT8 can be attributed to the halogen bond-mediated recognition by the transporter protein. The presence of a free carboxylic acid group is essential for the specificity of the probe towards MCT8. Additionally, the selectivity of the probe for MCT8 is abolished upon esterification of the carboxylic group. Similarly, MCT8 does not recognize the probe when it contains a free amine group.

A Review of the CACNA Gene Family: Its Role in Neurological Disorders.

Calcium channels are specialized ion channels exhibiting selective permeability to calcium ions. Calcium channels, comprising voltage-dependent and ligand-gated types, are pivotal in neuronal function, with their dysregulation is implicated in various neurological disorders. This review delves into the significance of the CACNA genes, including CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1G, and CACNA1H, in the pathogenesis of conditions such as migraine, epilepsy, cerebellar ataxia, dystonia, and cerebellar atrophy. Specifically, variants in CACNA1A have been linked to familial hemiplegic migraine and epileptic seizures, underscoring its importance in neurological disease etiology. Furthermore, different genetic variants of CACNA1B have been associated with migraine susceptibility, further highlighting the role of CACNA genes in migraine pathology. The complex relationship between CACNA gene variants and neurological phenotypes, including focal seizures and ataxia, presents a variety of clinical manifestations of impaired calcium channel function. The aim of this article was to explore the role of CACNA genes in various neurological disorders, elucidating their significance in conditions such as migraine, epilepsy, and cerebellar ataxias. Further exploration of CACNA gene variants and their interactions with molecular factors, such as microRNAs, holds promise for advancing our understanding of genetic neurological disorders.

Detection of Parkinson’s Disease using Deep learning algorithms

Parkinson’s illness is an advancing genetic neurological chronic disease impacts people mostly in old age but still might infect very few young people. This disease slowly eats up a part of the brain which is responsible for body movement, resulting in a steady loss of muscle control of the entire body. For example, frequent hand and leg tremors, body stiffness, loss of speech, bradykinesia, and dystonia. The treatments available don’t entirely cure PD as there is no medication, but on the other side, clinicians are trying to improve the patient’s lifetime. As the pattern recognition region of the brain is related to PD, we are using a dataset with healthy and PD hand-drawn images from a small test conducted. Here we have proposed a combination of deep learning algorithms of ANN and CNN with a machine learning algorithm of Random Forest classifier to improve the accuracy rate by “74” in finding out the person with PD. Hence, it is inferred that the expected results benefit clinicians in identifying and treating patients with PD in an operative way.

Trofinetide in Rett syndrome: A brief review of safety and efficacy.

Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 (MECP2) gene, leading to critical issues in normal brain function. The condition has a global prevalence of 5 to 10 cases per 100,000 females, and there is currently no cure for RTT. However, therapy is available to manage the symptoms and improve quality of life. Trofinetide, an insulin-like growth factor 1, was originally developed as a stroke medication and progressed to Phase II clinical trials, where it exhibited favorable safety and efficacy profiles by improving several core RTT symptoms. Recently, Trofinetide received the US Food and Drug Administration (FDA) approval and orphan drug designation for the treatment of RTT, making it the first approved drug for this rare genetic disorder. It has also shown to be safe, well-tolerated and with no known drug interactions. These findings suggest that Trofinetide is a promising treatment option for individuals with RTT.

52 Stable Cognitive Impairment and Increased Psychiatric Symptoms in a Patient with Neuropathologically Progressive Fahr’s Disease After 2-Year Repeated Neuropsychological Assessment

Objective:Fahr’s disease is a rare genetic neurological disorder characterized by abnormal idiopathic calcification of the basal ganglia, typically with extrapyramidal symptoms, speech difficulty, behavioral disturbances, and progressive neurologic dysfunction. A small number of case reports have explored the neuropsychological profile of Fahr’s disease patients, and even fewer have followed the course of neuropsychological functioning over time.Participants and Methods:A 53-year-old Asian woman presented for a neuropsychological reevaluation (2021) after experiencing a recurrence of memory difficulties and mood changes. Relevant medical history was significant for systemic lupus erythematosus (SLE) and Fahr’s disease. Following an episode of acute confusion, the patient underwent a head CT (2019) which revealed extensive calcification throughout the cerebellum, central pons, and periventricular and subcortical white matter, suggestive of Fahr’s disease. Two months later, she underwent an initial neuropsychological evaluation (2019), which demonstrated prominent attention and processing speed deficits contributing to variably impaired new learning and memory along with spatial planning and problem-solving difficulties. The etiology of her cognitive deficits was determined to likely reflect metabolic and immune instability, consistent with her history of SLE and Fahr’s disease. An updated CT (2021) revealed increased calcification throughout the bilateral corona radiata, basal ganglia, cerebellar hemispheres, and midbrain, which was determined to be compatible with progressive Fahr’s disease.Results:The patient’s neurocognitive profile from current neuropsychological testing (2021) was marked by notable deficits in attention and processing speed, delayed memory, problem solving, visuospatial reasoning, and motor dexterity. Compared to her initial evaluation, her cognitive profile remained stable save for a slight decline in processing speed. The largest change was seen within the psychiatric domain. Self-reported depressive symptoms involving anhedonia, concentration difficulties, and anxiety symptoms involving nervousness and tension were more pronounced in her current evaluation. In addition, she endorsed an increase in apathy compared to her initial evaluation.Conclusions:The cognitive profile seen in this patient is consistent with the current literature relating to the clinical sequelae of Fahr’s disease in patients that eventually went on to develop dementia. Despite an increase in brain calcification seen on CT imaging over an 18-month interval, the patient’s neurocognitive profile remained relatively stable. An increase in psychiatric symptoms appeared to be the most prominent change over repeated neuropsychological assessment, which elucidates the heterogenous course of Fahr’s disease from a neuropsychological perspective. Further exploration of this disorder is warranted to better understand the clinical progression of symptoms over time.

In depth characterization of midbrain organoids derived from wild type iPSC lines.

The ability to model human neurological tissues in vitro has been a major hurdle to effective drug development for neurological disorders. iPSC-derived brain organoids have emerged as a compelling solution to this problem as they have the potential to relevantly model the protein expression pattern and physiology of specific brain regions. Although many protocols now exist for the production of brain organoids, few attempts have been made to do an in-depth kinetic evaluation of expression of mature regiospecific markers of brain organoids. To address this, we differentiated midbrain-specific brain organoids from iPSC-lines derived from three apparently healthy individuals using a matrix-free, bioreactor method. We monitored the expression of midbrain-specific neuronal markers from 7 to 90-days using immunofluorescence and immunohistology. The organoids were further characterized using electron microscopy and RNA-seq. In addition to serving as a potential benchmark for the future evaluation of other differentiation protocols, the markers observed in this study can be useful as control parameters to identify and evaluate the disease phenotypes in midbrain organoid derived from patient iPSC-lines with genetic neurological disorders.

The state of the art in treating patients with a dual diagnosis of chronic migraine and medication-overuse headache

Migraine is a common, highly prevalent genetic neurological disorder. Its most burdensome form is the chronic migraine, which is clinically defined by the presence of headache on ≥15 days/month for longer than three months, with eight or more typical migraine days. Medication-overuse headache (MOH) is a secondary headache disorder associated with the overuse of symptomatic headache medications on ≥10 days/month for longer than 3 months. Chronic migraine and medication-overuse headache often coexist and most chronic migraineurs have medication overuse headache. Despite that, general practitioners and health professionals do not know about MOH. This review aims at presenting insights, recent knowledge, and guidance regarding the approach and treatments for patients with a dual diagnosis of chronic migraine and medication-overuse headache.

Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration.

The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by pathologic variants in the PANK2 gene codifying the enzyme pantothenate kinase 2 (PANK2). To date, there are no effective treatments to stop the progression of these diseases. This review discusses the utility of patient-derived cell models as a valuable tool for the identification of pharmacological or natural compounds for implementing polytarget precision medicine in PKAN. Recently, several studies have described that PKAN patient-derived fibroblasts present the main pathological features associated with the disease including intracellular iron overload. Interestingly, treatment of mutant cell cultures with various supplements such as pantothenate, pantethine, vitamin E, omega 3, α-lipoic acid L-carnitine or thiamine, improved all pathophysiological alterations in PKAN fibroblasts with residual expression of the PANK2 enzyme. The information provided by pharmacological screenings in patient-derived cellular models can help optimize therapeutic strategies in individual PKAN patients.

News from the European Journal of Therapeutics: A new issue and a new editorial board

News from the European Journal of Therapeutics: A new issue and a new editorial board

Antisense drugs for rare and ultra-rare genetic neurological diseases

The regulatory approvals of nusinersen and tofersen, plus the large body of clinical and preclinical data from other drugs, have significantly de-risked antisense technology for neurological diseases. The platform learnings over the last 2 decades can be applied to subsequent drugs to improve the efficiency of discovering effective neuro-therapeutics.

HSD101 The Key Role of Therapeutic Professionals in Rett Syndrome Care Pathway

Rett syndrome (RTT) is a rare genetic neurological and developmental disorder that predominantly affects females. Most children with RTT experience rapid regression affecting motor and communication skills and become severely disabled. This study aimed to describe the care pathway for RTT in the United States, particularly the role of therapeutic professionals (TPs).

EPH127 Understanding the Burden of Aromatic L-Amino Acid Decarboxylase Deficiency (AADCD): Results from a Clinician Expert Survey

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a life-limiting and acutely debilitating rare genetic neurological disorder that causes widespread central nervous system dysfunction and developmental delay. Eladocagene exuparvovec is a gene therapy, approved in Europe, which bilaterally delivers a functional DDC gene directly into the putamen improving patient motor function. Due to the disease rarity and paucity of surrounding data, clinician experts were surveyed on evaluating the importance of motor development in AADC deficiency progression and outcomes.

Spinocerebellar ataxia type 14 (SCA14) in an Argentinian family: a case report

BackgroundHereditary spinocerebellar ataxias are a group of genetic neurological disorders that result in degeneration of the cerebellum and brainstem, leading to difficulty in controlling balance and muscle coordination.Case presentationA family affected by spinocerebellar ataxia was identified in Argentina and investigated using whole exome sequencing to determine the genetic etiology. The proband, a female white Hispanic aged 48, was noted to have slowly progressive gait ataxia, dysarthria, nystagmus, and moderate cerebellar atrophy. Whole exome sequencing was performed on three affected and two unaffected family members and revealed a dominant pathogenic variant, p.Gln127Arg (19:54392986 A>G), in the protein kinase C gamma gene, and the family was diagnosed with spinocerebellar ataxia type 14.ConclusionsTo our knowledge, no previous cases of spinocerebellar ataxia type 14 have been reported in Argentina, expanding the global presence of this neurological disorder. This diagnosis supports whole exome sequencing as a high-yield method for identifying coding variants causing cerebellar ataxias and emphasizes the importance of broadening the clinical availability of whole exome sequencing for undiagnosed patients and families.

Oleic Acid-Containing Phosphatidylinositol Is a Blood Biomarker Candidate for SPG28

Hereditary spastic paraplegia is a genetic neurological disorder characterized by spasticity of the lower limbs, and spastic paraplegia type 28 is one of its subtypes. Spastic paraplegia type 28 is a hereditary neurogenerative disorder with an autosomal recessive inheritance caused by loss of function of DDHD1. DDHD1 encodes phospholipase A1, which catalyzes phospholipids to lysophospholipids such as phosphatidic acids and phosphatidylinositols to lysophosphatidic acids and lysophoshatidylinositols. Quantitative changes in these phospholipids can be key to the pathogenesis of SPG28, even at subclinical levels. By lipidome analysis using plasma from mice, we globally examined phospholipids to identify molecules showing significant quantitative changes in Ddhd1 knockout mice. We then examined reproducibility of the quantitative changes in human sera including SPG28 patients. We identified nine kinds of phosphatidylinositols that show significant increases in Ddhd1 knockout mice. Of these, four kinds of phosphatidylinositols replicated the highest level in the SPG28 patient serum. All four kinds of phosphatidylinositols contained oleic acid. This observation suggests that the amount of oleic acid-containing PI was affected by loss of function of DDHD1. Our results also propose the possibility of using oleic acid-containing PI as a blood biomarker for SPG28.

Defining the role of the N-terminal helix in the Arf1 nucleotide switch transition using pressure perturbation.

ADP-Ribosylation Factors (Arfs) are small GTPases that act as molecular “switches” for the signaling cascades responsible for membrane organization within eukaryotic cells. Overactivation and mutations of Arfs or their binding partners have been implicated in several genetic neurological diseases and breast cancer. Within the Arf family, Arf1 is one of the most studied. In its inactive conformation, the protein is bound to GDP and requires the reorganization of the N-terminal third of the protein to accommodate the dissociation and subsequent bind of GTP. During this conformational change, the myristoylated N-terminal helix becomes disordered allowing Arf1 to associate with membranes. Previous literature suggests that the position of the N-terminal helix is the determinant of the nucleotide exchange. In the Δ17Arf1 mutant, increased structural dynamics is observed and the protein can undergo a switch transition in absence of a membrane. We hypothesize that the N-terminal helix of Arf1 enhances the stability of the GDP bound state of the protein and the nucleotide exchange occurs under stringent control. We used high-pressure 1H-15N HSQC NMR spectroscopy and high-pressure SAXS to investigate the effect of the N-terminal helix for protein stability and the nucleotide switch transition. Further, analysis of the relaxation rates from CPMG and CEST provide greater insight into the structural dynamics of the switch transition. Our data provides evidence that the stability of Arf1 can be attributed in part to the presence of the N-terminal helix.

Novel Variants in MPV17, PRX, GJB1, and SACS Cause Charcot-Marie-Tooth and Spastic Ataxia of Charlevoix-Saguenay Type Diseases.

Charcot-Marie-Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix-Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in SACS (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in MPV17 and c.4934G>C (p.Arg1645Pro) in SACS. In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS, was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX, which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17, SACS, PRX, and GJB1 causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot-Marie-Tooth disease (CMT) and spastic ataxia of Charlevoix-Saguenay type.

Viral-mediated gene therapy in pediatric neurological disorders.

Due to the broad application of next-generation sequencing, the molecular diagnosis of genetic disorders in pediatric neurology is no longer an unachievable goal. However, treatments for neurological genetic disorders in children remain primarily symptomatic. On the other hand, with the continuous evolution of therapeutic viral vectors, gene therapy is becoming a clinical reality. From this perspective, we wrote this reviewto illustrate the current state regarding viral-mediated gene therapy in childhood neurological disorders. We searched databases, including PubMed and Google Scholar, using the keywords "adenovirus vector," "lentivirus vector," and "AAV" for gene therapy, and "immunoreaction induced by gene therapy vectors," "administration routes of gene therapy vectors," and "gene therapy" with "NCL," "SMA," "DMD," "congenital myopathy," "MPS" "leukodystrophy," or "pediatric metabolic disorders". We also screened the database of ClinicalTrials.gov using the keywords "gene therapy for children" and then filtered the results with the ones aimed at neurological disorders. The time range of the search procedure was from the inception of the databases to the present. We presented the characteristics of commonly used viral vectors for gene therapy for pediatric neurological disorders and summarized their merits and drawbacks, the administration routes of each vector, the research progress, and the clinical application status of viral-mediated gene therapy on pediatric neurological disorders. Viral-mediated gene therapy is on the brink of broad clinical application. Viral-mediated gene therapy will dramatically change the treatment pattern of childhood neurological disorders, and many children with incurable diseases will meet the dawn of a cure. Nevertheless, the vectors must be optimized for better safety and efficacy.

Эпидемиологические особенности распределения наследственных мозжечковых атаксий

Hereditary cerebellar ataxias (HCA) is a heterogeneous group of genetic neurological neurodegenerative diseases with a steadily progressive course. Ataxia is manifested by disturbed equilibrium, speech. Diseases of this group, as a rule, lead to disability of the patient. Advances in the field of molecular genetic research have made it possible to determine the form of HCA in accordance with the type of inheritance, and on this basis a classification of HCA has been formed. Monogenic (autosomal dominant, autosomal recessive, X-linked) and non-traditional types of inheritance of cerebellar ataxias (mitochondrial, expansion of trinucleotide repeats) are distinguished, sporadic forms with an unidentified or unknown type of transmission are also distinguished. Thus, HCA are classified into autosomal dominant spinocerebellar ataxias (SCA), they include 48 forms, some of which are polyglutamine SCA, and autosomal recessive, about 100 nosological entities. In addition, episodic cerebellar ataxia is also classified as an autosomal dominant ataxia. Among autosomal dominant ataxias, SCA3 or Machado-Joseph disease is the most common, followed by SCA2 and SCA6. However, in Russia, the prevalence is different. Among autosomal recessive ataxias, the most common is Friedreich’s ataxia, which also belongs to polyglutamine diseases. It should be taken into account that different methodological approaches lead to great heterogeneity and scattering of results in determining the prevalence of one or another form of hereditary ataxia both within the country and among the countries. The review presents current data on the prevalence of various forms of HCA in different regions of the world and populations. However, there is still a great deal of uncertainty regarding the overall prevalence of certain hereditary forms of cerebellar ataxia.

IDENTIFICATION OF NOVEL DRUG/LEAD MOLECULE FOR SCHIZOPHRENIA TARGETING RGS4 GENE THROUGH IN-SILICO ANALYSIS

Schizophrenia is a neuropsychiatric disorder that is caused by many factors including changes in the chemistry of the brain, structure of the brain, and genetic factors. The neuropathology of the disorder has been identified morphologically and physiologically through a number of parameters from a reduction in brain size and abnormalities in the neurotransmitter network affecting the brain to changes in the molecular composition of specific cell populations in the brain. Over a long period of time, clinicians and researchers have identified schizophrenia as a complex neurological genetic disorder as a result of the functionality of several susceptible genes. Various scientists are of the opinion that there are about 20 candidate genes that cause schizophrenia. Several genes like Dysbindin, Neuregulin, DAAO, G72, PRODH, COMT, and RGS4 have been proven to be the risk factors for schizophrenia disease. RGS4 was identified as a target gene for schizophrenia. Hence the present study was taken up to identify a Novel Drug/Lead Molecule from 12 selected drugs based on a bioinformatics approach for schizophrenia targeting the RGS4 gene. The genomics and proteomics approach of the RGS4 gene was carried out for nucleotide and protein sequences and the protein was modeled using SPDBV with 80% accuracy. The potential active site amino acids were predicted using molecular cavities based on energy and surface area and the protein was targeted using the best active site amino acids. The protein-ligand interactions were also performed using the Argus Lab engine with flexible docking. The data of the present study reveals that ziprasidone is showing maximum inhibition of the RGS4 gene among the 12 drugs selected for screening. It is thus concluded that ziprasidone with the lowest free energy and high affinity is the best inhibitor for the schizophrenia protein and hence it can be suggested for the treatment of schizophrenia.

Detection of Characteristic Phosphatidylcholine Containing Very Long Chain Fatty Acids in Cerebrospinal Fluid from Patients with X-Linked Adrenoleukodystrophy.

X-linked Adrenoleukodystrophy (X-ALD) is a rare genetic neurological disorder caused by a mutation of the ABCD1 gene that encodes a peroxisomal ABC protein ABCD1. ABCD1 has a role in transporting very long chain fatty acid (VLCFA)-CoA into the peroxisome for β-oxidation. ABCD1 dysfunction leads to reduced VLCFA β-oxidation and in turn increased VLCFA levels in the plasma and the cells of all tissues; these increased plasma levels have been used to diagnose X-ALD. It has been reported that plasma VLCFA is not correlated with the severity and disease phenotype of X-ALD. Therefore, we cannot predict the disease progression by the plasma VLCFA level. Cerebrospinal fluid (CSF) is constantly produced by brain, and thus levels of lipids containing VLCFA in CSF might be informative in terms of assessing X-ALD pathology. LC-MS/MS-based analysis showed that phosphatidylcholine (PC) containing VLCFA signals, such as PC 40 : 0(24 : 0/16 : 0), PC 42 : 0(26 : 0/16 : 0), PC 44 : 4(24 : 0/20 : 4) and PC 46 : 4(26 : 0/20 : 4) were characteristically detected only in the CSF from patients with X- ALD. In the present study, we analyzed limited number of patient's CSF samples (2 patients with X-ALD) due to the limitations of the availability for CSF samples from this rare disease. However, our finding would offer helpful information for studying the disease progression biomarkers in X-ALD. To our knowledge, this is the first report of analyzing lipids containing VLCFA in CSF from patients with X-ALD.