Shifting spatial, temporal and demographic patterns of dengue incidence and associated meteorological factors in Jazan Region of Saudi Arabia from 2015-2020.

BACKGROUND: Dengue poses a considerable public health threat in Saudi Arabia, with escalating outbreaks in Jazan, where seasonal rains create ideal mosquito breeding conditions. Elucidating local epidemiological dynamics is imperative to strengthen evidence-based prevention policies. This study analyzed the spatiotemporal, demographic, and meteorological patterns of dengue in Jazan from 2015-2020. METHODS: This retrospective cross-sectional study utilized surveillance records for 3427 confirmed dengue cases. Descriptive analyses characterized geographic, seasonal, age, sex, and nationality distributions. Forecasting models project expected epidemics through 2025. Regression analysis identified climate factors associated with monthly case counts. RESULTS: Dengue exhibited shifting seasonal peaks, transitioning into year-round transmission by 2019, indicating endemic establishment. Cases clustered in different high-burden sectors annually, requiring localized vector control. The majority of affected individuals were young male adults, with gender gaps narrowing over time. Saudi nationals had an escalating incidence, but non-citizens showed a higher risk, signaling importation threats. Seasonal outbreaks were associated with temperature, wind speed, and direction. CONCLUSION: Enhanced surveillance, outbreak forecasting, targeted control activities, and integrated prevention policies grounded in continuous evidence assessment can effectively address endemic dengue transmission in Jazan. This study provides key insights to optimize data-driven decision-making for dengue control in Saudi Arabia.

Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy.

CLCN4-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated. CLCN4 encodes the vesicular 2Cl-/H+ exchanger ClC-4, and CLCN4 pathogenic variants frequently result in altered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, together with ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewed our research database for patients with CLCN4 variants and epilepsy, and performed thorough phenotyping. We examined the functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry, and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified, with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI, while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstem hypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4's heterodimerization capability with ClC-3 and suppressed anion currents. The p.(Ile549Leu) variant of patient #2 and p.(Asp89Asn) variant of patient #3 both shift the voltage dependency of transport activation by 20 mV to more hyperpolarizing potentials, relative to the wild-type, with p.(Asp89Asn) favouring higher transport activity. We concluded that p.(Gly342Arg) carried by patient #1 and the p.(Ile549Leu) expressed by patient #2 impair ClC-4 transport function, while the p.(Asp89Asn) variant results in a gain-of-transport function; all three variants result in epilepsy and global developmental impairment, but with differences in epilepsy presentation, growth parameters, and presence or absence of brain malformations.

Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals.

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Potential Biomarkers for Parkinson Disease from Functional Enrichment and Bioinformatic Analysis of Global Gene Expression Patterns of Blood and Substantia Nigra Tissues.

The Parkinson disease (PD) is the second most common neurodegenerative disorder affecting the central nervous system and motor functions. The biological complexity of PD is yet to reveal potential targets for intervention or to slow the disease severity. Therefore, this study aimed to compare the fidelity of blood to substantia nigra (SN) tissue gene expression from PD patients to provide a systematic approach to predict role of the key genes of PD pathobiology. Differentially expressed genes (DEGs) from multiple microarray data sets of PD blood and SN tissue from GEO database are identified. Using the theoretical network approach and variety of bioinformatic tools, we prioritized the key genes from DEGs. A total of 540 and 1024 DEGs were identified in blood and SN tissue samples, respectively. Functional pathways closely related to PD such as ERK1 and ERK2 cascades, mitogen-activated protein kinase (MAPK) signaling, Wnt, nuclear factor-κB (NF-κB), and PI3K-Akt signaling were observed by enrichment analysis. Expression patterns of 13 DEGs were similar in both blood and SN tissues. Comprehensive network topological analysis and gene regulatory networks identified additional 10 DEGs functionally connected with molecular mechanisms of PD through the mammalian target of rapamycin (mTOR), autophagy, and AMP-activated protein kinase (AMPK) signaling pathways. Potential drug molecules were identified by chemical-protein network and drug prediction analysis. These potential candidates can be further validated in vitro/in vivo to be used as biomarkers and/or novel drug targets for the PD pathology and/or to arrest or delay the neurodegeneration over the years, respectively.

The epileptology of Wiedemann-Steiner syndrome: Electroclinical findings in five patients with KMT2A pathogenic variants.

BACKGROUND: Wiedemann-Steiner Syndrome (WSTS) is a rare chromatinopathy caused by pathogenic variants in KMT2A. WSTS is characterized by neurodevelopmental disorders and distinct dysmorphic features. Epilepsy has been reported in only 33 individuals with WSTS, with only limited clinical details described. METHODS: We identified patients with pathogenic KMT2A variants and epilepsy, and performed thorough phenotyping. RESULTS: Five patients were identified, all of whom presented with developmental and epileptic encephalopathy (DEE). Epilepsy syndromes observed included Lennox-Gastaut syndrome [2], infantile epileptic spasms syndrome, and DEE with spike-wave activation in sleep. Seizure types observed included absence, generalized tonic-clonic, myoclonic, tonic, atonic, epileptic spasms, and focal seizures. CONCLUSIONS: The spectrum of epilepsy phenotypes in patients with WSTS can be broad, but presentation is typically severe, usually involving a form of DEE.

Epilepsy surgery outcomes in patients with GATOR1 gene complex variants: Report of new cases and review of literature.

AIM: To report seizure outcomes in children with GATOR1 gene complex disorders who underwent epilepsy surgery and perform a systematic literature search to study the available evidence. METHODS: The records of children with pathogenic/likely pathogenic variants in GATOR1 gene complex who underwent epilepsy surgery were reviewed. Clinical, radiological, neurophysiological, and histological data were extracted/summarized. The systematic review included all case series/reports and observational studies reporting on children or adults with genetic (germline or somatic) variants in the GATOR1 complex genes (DEPDC5, NPRL2, NPRL3) with focal epilepsy with/without focal cortical dysplasia who underwent epilepsy surgery; seizure outcomes were analyzed. RESULTS: Eight children with pathogenic/likely pathogenic variants in GATOR1 complex genes were included. All had drug-resistant epilepsy. Six children had significant neurodevelopmental delay. Epilepsy surgery was performed in all; clinical seizure freedom was noted in 4 children (50%). Systematic literature search identified 17 eligible articles; additional 30 cases with patient-level data were studied. Lesional MRI brain was seen in 80% cases. The pooled rate of seizure freedom following surgery was 60%; FCD IIa was the most encountered pathology. INTERPRETATION: Epilepsy surgery may be effective in some children with GATOR1 complex gene variants. Seizure outcomes may be compromised by extensive epileptogenic zones.

SUDEP risk and autonomic dysfunction in genetic epilepsies.

The underlying pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains unclear. This phenomenon is likely multifactorial, and there is considerable evidence that genetic factors play a role. There are certain genetic causes of epilepsy in which the risk of SUDEP appears to be increased relative to epilepsy overall. For individuals with pathogenic variants in genes including SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1 and DEPDC5, there are varying degrees of evidence to suggest an increased risk for sudden death. Why the risk for sudden death is higher is not completely clear; however, in many cases pathogenic variants in these genes are also associated with autonomic dysfunction, which is hypothesized as a contributing factor to SUDEP. We review the evidence for increased SUDEP risk for patients with epilepsy due to pathogenic variants in these genes, and also discuss what is known about autonomic dysfunction in these contexts.

Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families.

Background: Alström syndrome (AS) is a very rare childhood disorder characterized by cardiomyopathy, progressive hearing loss and blindness. Inherited genetic variants of ALMS1 gene are the known molecular cause of this disease. The objective of this study was to characterize the genetic basis and understand the genotype-phenotype relationship in Saudi AS patients. Methods: Clinical phenotyping and whole-exome sequencing (WES) analysis were performed on six AS patients belonging to two unrelated consanguineous Saudi families. Sanger sequencing was performed to determine the mode of inheritance of ALMS1 variant in first-degree family relatives and also to ensure its rare prevalence in 100 healthy population controls. Results: We identified that Alström patients from both the families were sharing a very rare ALMS1, 3'-splice site acceptor (c.11873-2 A>T) variant, which skips entire exon-19 and shortens the protein by 80 amino acids. This disease variant was inherited by AS patients in autosomal recessive mode and is not yet reported in any population-specific genetic databases. AS patients carrying this mutation showed heterogeneity in clinical presentations. Computational analysis of the mutant centroid structure of ALMS1 mRNA revealed that exon-19 skipping enlarges the hairpin loop and decreases the free energy, eventually affecting its folding pattern, stability, and function. Hence, we propose c.11873-2A as an AS causative potential founder mutation in Saudi Arabia because it is found in two families lacking a common lineage. Conclusions: We conclude that WES analysis potentially helps in clinical phenotyping, early diagnosis, and better clinical management of Alström patients showing variable clinical expressivity.

Molecular differential analysis of uterine leiomyomas and leiomyosarcomas through weighted gene network and pathway tracing approaches.

Uterine smooth muscular neoplastic growths like benign leiomyomas (UL) and metastatic leiomyosarcomas (ULMS) share similar clinical symptoms, radiological and histological appearances making their clinical distinction a difficult task. Therefore, the objective of this study is to identify key genes and pathways involved in transformation of UL to ULMS through molecular differential analysis. Global gene expression profiles of 25 ULMS, 25 UL, and 29 myometrium (Myo) tissues generated on Affymetrix U133A 2.0 human genome microarrays were analyzed by deploying robust statistical, molecular interaction network, and pathway enrichment methods. The comparison of expression signals across Myo vs UL, Myo vs ULMS, and UL vs ULMS groups identified 249, 1037, and 716 significantly expressed genes, respectively (p ≤ 0.05). The analysis of 249 DEGs from Myo vs UL confirms multistage dysregulation of various key pathways in extracellular matrix, collagen, cell contact inhibition, and cytokine receptors transform normal myometrial cells to benign leiomyomas (p value ≤ 0.01). The 716 DEGs between UL vs ULMS were found to affect cell cycle, cell division related Rho GTPases and PI3K signaling pathways triggering uncontrolled growth and metastasis of tumor cells (p value ≤ 0.01). Integration of gene networking data, with additional parameters like estimation of mutation burden of tumors and cancer driver gene identification, has led to the finding of 4 hubs (JUN, VCAN, TOP2A, and COL1A1) and 8 bottleneck genes (PIK3R1, MYH11, KDR, ESR1, WT1, CCND1, EZH2, and CDKN2A), which showed a clear distinction in their distribution pattern among leiomyomas and leiomyosarcomas. This study provides vital clues for molecular distinction of UL and ULMS which could further assist in identification of specific diagnostic markers and therapeutic targets.Abbreviations UL: Uterine Leiomyomas; ULMS: Uterine Leiomyosarcoma; Myo: Myometrium; DEGs: Differential Expressed Genes; RMA: Robust Multiarray Average; DC: Degree of Centrality; BC: Betweenness of Centrality; CGC: Cancer Gene Census; FDR: False Discovery Rate; TCGA: Cancer Genome Atlas; BP: Biological Process; CC: Cellular Components; MF: Molecular Function; PPI: Protein-Protein Interaction.

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients.

Alström syndrome (AS, OMIM ID 203800) is a rare childhood multiorgan disorder, which is widely studied in non-Arab ethnic patients. The clinical and molecular basis of AS and the mode of disease inheritance in consanguineous Arab populations is not well investigated. Therefore, to identify the molecular basis of AS in familial forms, the present study performed whole exome sequencing of 5 AS patients belonging to 2 different Bedouin families from Saudi Arabia. The present study identified the AS causative rare biallelic mutations in ALMS gene:T376S in exon 5 and S909* in exon 8 for family A and an R2721* in exon 10 (R2721*) for family B. ALMS1 targeted genetic sequencing of healthy population controls and family members has confirmed its extremely rare frequency and autosomal recessive mode of inheritance. The truncating mutations S909* and R2721* could cause the loss of CC domains and ALMS motif on C-terminal end of the protein and creates unstable protein, which eventually undergoes intracellular degradation. The premature protein truncating mutations described in our study may eventually provide further insight into the functional domains of the ALMS1 protein and contribute to the understanding of the phenotypic spectrum of AS. Whole exome sequencing based molecular diagnosis is expected to rule out ambiguity surrounding clinical diagnosis of suspected AS cases.

Rapid Resolution of Enterovirus 71-Associated Opsoclonus Myoclonus Syndrome on Intravenous Immunoglobulin.

Nonparaneoplastic opsoclonus-myoclonus ataxia syndrome is a rare neuroinflammatory condition featured by opsoclonus, myoclonus, ataxia, and cognitive behavioral disturbance. The authors report an observation of enterovirus 71-associated opsoclonus-myoclonus ataxia syndrome evolving toward full recovery on intravenous intravenous immunoglobulin (IG) treatment. Based on this case report, enterovirus 71 should be added to the list of infectious agents likely involved in opsoclonus-myoclonus ataxia syndrome, including the emerging subgroup of opsoclonus-myoclonus ataxia syndrome recovering without aggressive or prolonged immunosuppressive intervention. Further studies are mandatory to define the precise role, incidence, treatment, and outcome of enterovirus 71 and other infectious agents in benign forms of opsoclonus-myoclonus ataxia syndrome.

Whole exome sequencing of a consanguineous family identifies the possible modifying effect of a globally rare AK5 allelic variant in celiac disease development among Saudi patients.

Celiac disease (CD), a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR) pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family. Sequence validation of 200 chromosomes each of sporadic CD cases and controls, revealed that this extremely rare (EXac MAF 0.000008) mutation is highly penetrant among general Saudi populations (MAF is 0.62). Genotype and allelic distribution analysis have indicated that this AK5 (c.1683_1684insATT) mutation is negatively selected among patient groups and positively selected in the control group, in whom it may modify the risk against CD development [p<0.002]. Our observation gains additional support from computational analysis which predicted that Iso561 insertion shifts the existing H-bonds between 400th and 556th amino acid residues lying near the functional domain of adenylate kinase. This shuffling of amino acids and their H-bond interactions is likely to disturb the secondary structure orientation of the polypeptide and induces the gain-of-function in nucleoside phosphate kinase activity of AK5, which may eventually down-regulates the reactivity potential of CD4+ T-cells against gluten antigens. Our study underlines the need to have population-specific genome databases to avoid false leads and to identify true candidate causal genes for the familial form of celiac disease.

Progress toward malaria elimination in Jazan Province, Kingdom of Saudi Arabia: 2000-2014.

BACKGROUND: The draft Global Technical Strategy for malaria aims to eliminate malaria from at least 10 countries by 2020. Yemen and Saudi Arabia remain the last two countries on the Arabian Peninsula yet to achieve elimination. Over the last 50 years, systematic efforts to control malaria in the Kingdom of Saudi Arabia has successfully reduced malaria cases to a point where malaria is now constrained largely to Jazan Province, the most south-western area along the Red Sea. The progress toward elimination in this province is reviewed between 2000 and 2014. METHODS: Data were obtained from the Ministry of Health case-reporting systems, activity reports, unpublished consultants reports, and relevant scientific published papers. Sub-provincial population data were obtained the national household censuses undertaken in 2004 and 2010. Rainfall data were obtained from the Meteorological Department in Jazan. RESULTS: Between 2000 and 2014 there were 5522 locally acquired cases of malaria and 9936 cases of imported malaria. A significant reduction in locally acquired malaria cases was observed from 2000 to 2014, resulting in an average annual incidence (2010-2014) of 0.3 cases per 10,000 population. Conversely imported cases, since 2000, remain consistent and higher than locally acquired cases, averaging between 250 and 830 cases per year. The incidence of locally acquired cases is heterogeneous across the Province, with only a few health districts contributing the majority of the cases. The overall decline in malaria case incidence can be attributed to coincidental expansion of control efforts and periods of exceptionally low rainfall. CONCLUSIONS: Jazan province is poised to achieve malaria elimination. There is a need to change from a policy of passive case detection to reactively and proactively detecting infectious reservoirs that require new approaches to surveillance. These should be combined with advanced epidemiological tools to improve the definitions of epidemiological receptive and hotspot malaria risk mapping. The single largest threat currently remains the risks posed by imported infections from Yemen.