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Objectives: To study the prevalence of tumor marker (TM) carcinoembryonic antigen (CEA), cancer antigen 125 (CA 125), and cancer antigen 15-3 (CA 15-3) levels in the Saudi population, based on gender, age, and demographic region, and whether the patients were referred by a hospital or self-referred., Methods: Retrospective analysis was carried out on 7,019 samples gathered from the Western, Northern, Central, Southern, and Eastern regions of Saudi Arabia between 2021-2022. The TMs were categorized into normal and abnormal levels, according to the reference ranges. Statistical analysis was carried out to assess the relations between variants (age groups, gender, and demographic regions) using the Chi-square test, and their correlations were assessed using Spearman's test., Results: Among all patients, CEA, CA 125, and CA 15-3 levels were found to be significantly correlated with age ( p =0.0001). The CEA and CA 15-3 levels increased in both males and females with age. The CA 125 was shown to have an abnormally increased level in males with age., Conclusion: Increased levels of CEA, CA 125, and CA 15-3 TMs in the study population were significantly correlated with age. The CEA and CA 15-3 levels were within the normal range, while CA 125 levels were above the normal range in the older male population. These results suggest that the utilization of such TMs is age dependent and would have validity if applied with other parameters., (Copyright: © Saudi Medical Journal.)

Background: This study aims to explore the association between the quality of life (QoL) in children with Down syndrome (DS) and its relationship with demographic characteristics of both parents and children. The investigation encompasses five domains: physical and psychological well-being, autonomy and parental relationship, social well-being, and peers, as well as school and the learning environment., Method: An online questionnaire, the KIDSCREEN-27, was used to measure the QoL of 112 families with DS in Saudi Arabia, referred to as "Parent-Reported Measures." Descriptive statistics were analyzed using the Statistical Package for Social Sciences., Results: The study found that the QoL of children with DS showed high scores in the psychological well-being, autonomy, parental relations, school, and learning environment domains. However, the physical and social well-being and peer domains had lower scores, although still considered "good scores." Family income had a positively significant influence on all QoL domains. Specifically, higher family income was associated with better QoL outcomes, except for social well-being. Parental age was found to influence psychological well-being, while parental education and the relationship between the parent and child influenced social well-being. Lastly, the child's gender was found to have an impact on the school and learning environment domain., Conclusion: The study highlights the importance of understanding the impact of the demographic variability of children with DS and their parents on the QoL of their children. It emphasizes the need to address the needs of families with lower incomes and the importance of parental education and relationships with their children in improving social well-being. The findings could aid policymakers and healthcare providers in improving the QoL for families with children who have DS., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: One of the complications of diabetes mellitus (DM) is diabetic nephropathy (DN), which plays a significant role in the progression of end-stage renal disease. Oxidative stress is implicated in DN pathogenesis, and genetic variations in antioxidant enzymes such as superoxide dismutase 2 (SOD2) and catalase (CAT) may contribute to the susceptibility. This study aimed to investigate the potential association between single nucleotide polymorphisms (SNPs) in antioxidant enzymes, specifically SOD2 rs4880 and CAT rs769217, and the risk of T2D and susceptibility to DN within the Saudi population., Methods: This case-control study included 150 participants, comprising 50 patients with T2D without DN (group 1), 50 patients with T2D with DN (group 2), and 50 healthy participants (group 3). The samples were genotyped using real-time PCR for SOD2 rs4880 and CAT rs769217 SNPs. Sanger sequencing was used for validation. Statistical analyses were performed to explore associations between these SNPs and T2D with or without DN., Results: No significant difference was observed in CAT rs769217 expression between the groups. However, a significant difference was observed in SOD2 rs4880 expression between the healthy controls and patients with T2D with DN (p = .028). Furthermore, SOD2 rs4880 was associated with approximately threefold increased risk of DN in patients with T2D compared to that in healthy participants (odds ratio [OR] = 2.99 [1.31-6.83]). Validation through Sanger sequencing further confirmed these findings., Conclusions: The findings of this study provide evidence that SOD2 rs4880 SNP may contribute to inadequate defence by the antioxidant enzyme, SOD2, against DM-induced oxidative stress and thus cause DN in Saudi patients with T2D. Therefore, SOD2 rs4880 may serve as a predictive marker to prevent the development and progression of DN in patients with T2D., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Foreign body insertion inside the nose is not uncommon in pediatric age groups. It can pass unnoticed by parents, sometimes underdiagnosed or incompletely removed by a clinician. In another scenario, it may be incidentally discovered by imaging during dental workups commonly. This foreign body acts like a nidus for a rhinolith, as it gets calcified over years and becomes like a stone, causing unilateral nasal symptoms. Herein, we present a case of a young female with a rhinolith mistaken for fungal mud. We aim to emphasize this rare clinical condition that, if left unperceived, may lead to complications including, but not limited to, sinusitis, pressure necrosis to the surrounding structure causing septal perforation, or naso-palatal fistula., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alrayes et al.)

Studies assessing the clinical and radiographic success of LSTR in terms of the presence of pain, mobility, swelling, fistula/sinus tract, interradicular radiolucency, and root resorption have not been performed. We therefore performed a systematic review with the aim of evaluating the effectiveness of lesion sterilization and tissue repair (LSTR), using three antibacterial mixtures (3Mix), in treating primary teeth. Well-defined search strategies developed for four electronic databases, Web of Science, OVID, PubMed, and Scopus, were used in this study. Two independent reviewers selected relevant articles from 3,232 studies by screening titles and abstracts. Based on the inclusion criteria, 25 articles were selected. Eight analyses of clinical and radiographic results were conducted based on 6, 12, 18, and 24-month follow-up intervals. Data extraction and quality appraisal were performed by three independent reviewers. The composition of antibiotic mixtures used for LSTR varied substantially, with inconsistent radiographic and clinical success rates across the included studies. A quantitative grouping of the studies showed no significant differences between 3Mix and the control medicaments regarding radiographical and clinical success ( p -value > 0.05). The available evidence on different LSTR using 3Mix is scarce, and the study findings were inconsistent. Therefore, additional clinical trials on 3Mix with different compositions are needed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background Approximately 50 million people globally suffer from epilepsy. The prevalence of epilepsy in Saudi Arabia has been reported at 6.5 per 1,000 persons, affecting nearly 1% of the entire population. However, limited data is available in the country regarding the sociodemographic factors affecting epilepsy and its associated postictal symptoms, which may lead to stigmatization and negatively impact patients. Methods A cross-sectional study was conducted at King Abdulaziz University Hospital (KAUH) in a survey format. Ethical approval was obtained from the Research Ethics Committee of the Faculty of Medicine at King Abdulaziz University. The study population included patients with epilepsy who visited King Abdulaziz University Hospital's outpatient neurology clinics from October 2021 to March 2022. Results The study participants' average age at the time of the first seizure was 16.5 years, with patients experiencing seizures as early as within the first year of life and as late as 70 years of age. Patients who had had their first seizure during the first year of life did not have any schooling (p<0.0001) and had learning difficulties (p<0.00001). Focal onset impaired awareness seizures were significantly associated with motor weakness (p=0.023) and mood alterations (p=0.014), while postictal fear, anxiety or panic, and sleep disruption were statistically significant for focal onset aware seizures (p=0.015 and p=0.050). Conclusion This study highlights the sociodemographic differences between patients in Saudi Arabia and in other areas. It may also point to novel findings regarding the postictal symptoms associated with the various seizure types., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alyoubi et al.)

Background: Inflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD., Method: The whole exome sequences (WESs) of three consanguineous Saudi families having many siblings with IBD were analyzed to discover the causal genetic defect. Then, we used a combination of artificial intelligence approaches, such as functional enrichment analysis using immune pathways and a set of computational functional validation tools for gene expression, immune cell expression analyses, phenotype aggregation, and the system biology of innate immunity, to highlight potential IBD genes that play an important role in its pathobiology., Results: Our findings have shown a causal group of extremely rare variants in the LILRB1 (Q53L, Y99N, W351G, D365A, and Q376H) and PRSS3 (F4L and V25I) genes in IBD-affected siblings. Findings from amino acids in conserved domains, tertiary-level structural deviations, and stability analysis have confirmed that these variants have a negative impact on structural features in the corresponding proteins. Intensive computational structural analysis shows that both genes have very high expression in the gastrointestinal tract and immune organs and are involved in a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune functional impairment contributing to IBD., Conclusion: The present study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jan, Al-Numan, Al-Twaty, Alrayes, Alsufyani, Alaifan, Alhussaini, Shaik, Awan, Qari, Saadah, Banaganapalli, Mosli and Elango.)

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., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Tetralogy of Fallot (TOF) is a rare, complex congenital heart defect caused by genetic and environmental interactions that results in abnormal heart development during the early stages of pregnancy. Genetic basis of TOF in Saudi populations is not yet studied. Therefore, the objective of this study is to screen for the molecular defects causing TOF in Saudi patients., Methods: A family with non-syndromic TOF was recruited from the Western region of Saudi Arabia. Whole exome sequencing (WES) was performed on the proband and her parents. The identified candidate variant was verified by sanger sequencing. Also, different computational biology tools were used to figure out how candidate variants affect the structure and function of candidate protein involved in TOF., Results: A novel heterozygous de novo mutation in LRP1 (p. G3311D) gene was identified in the index case. Also, this variant was absent in the in-house exome sequencing data of 80 healthy Saudi individuals. This variant was predicted to be likely pathogenic, as it negatively affects the biophysical chemical properties and stability of the protein. Furthermore, functional biology data from knock out mouse models confirms that molecular defects in LRP1 gene leads to cardiac defects and lethality. This variant was not previously reported in both Arab and global population genetic databases., Conclusion: The findings in this study postulate that the LRP1 variant has a role in TOF pathogenesis and facilitate accurate diagnosis as well as the understanding of underlying molecular mechanisms and pathophysiology of the disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a multifactorial progressive airflow obstruction in the lungs, accounting for high morbidity and mortality across the world. This study aims to identify potential COPD blood-based biomarkers by analyzing the dysregulated gene expression patterns in blood and lung tissues with the help of robust computational approaches. The microarray gene expression datasets from blood (136 COPD and 6 controls) and lung tissues (16 COPD and 19 controls) were analyzed to detect shared differentially expressed genes (DEGs). Then these DEGs were used to construct COPD protein network-clusters and functionally enrich them against gene ontology annotation terms. The hub genes in the COPD network clusters were then queried in GWAS catalog and in several cancer expression databases to explore their pathogenic roles in lung cancers. The comparison of blood and lung tissue datasets revealed 63 shared DEGs. Of these DEGs, 12 COPD hub gene-network clusters (SREK1, TMEM67, IRAK2, MECOM, ASB4, C1QTNF2, CDC42BPA, DPF3, DET1, CCDC74B, KHK, and DDX3Y) connected to dysregulations of protein degradation, inflammatory cytokine production, airway remodeling, and immune cell activity were prioritized with the help of protein interactome and functional enrichment analysis. Interestingly, IRAK2 and MECOM hub genes from these COPD network clusters are known for their involvement in different pulmonary diseases. Additional COPD hub genes like SREK1, TMEM67, CDC42BPA, DPF3, and ASB4 were identified as prognostic markers in lung cancer, which is reported in 1% of COPD patients. This study identified 12 gene network- clusters as potential blood based genetic biomarkers for COPD diagnosis and prognosis., Competing Interests: The authors have declared that no competing interests exist.

Familial hypercholesterolemia (FH) is a monogenic lipid disorder which promotes atherosclerosis and cardiovascular diseases. Owing to the lack of sufficient published information, this study aims to identify the potential genetic biomarkers for FH by studying the global gene expression profile of blood cells. The microarray expression data of FH patients and controls was analyzed by different computational biology methods like differential expression analysis, protein network mapping, hub gene identification, functional enrichment of biological pathways, and immune cell restriction analysis. Our results showed the dysregulated expression of 115 genes connected to lipid homeostasis, immune responses, cell adhesion molecules, canonical Wnt signaling, mucin type O-glycan biosynthesis pathways in FH patients. The findings from expanded protein interaction network construction with known FH genes and subsequent Gene Ontology (GO) annotations have also supported the above findings, in addition to identifying the involvement of dysregulated thyroid hormone and ErbB signaling pathways in FH patients. The genes like CSNK1A1, JAK3, PLCG2, RALA, and ZEB2 were found to be enriched under all GO annotation categories. The subsequent phenotype ontology results have revealed JAK3I , PLCG2, and ZEB2 as key hub genes contributing to the inflammation underlying cardiovascular and immune response related phenotypes. Immune cell restriction findings show that above three genes are highly expressed by T-follicular helper CD4 + T cells, naïve B cells, and monocytes, respectively. These findings not only provide a theoretical basis to understand the role of immune dysregulations underlying the atherosclerosis among FH patients but may also pave the way to develop genomic medicine for cardiovascular diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Objective: With this cross-sectional study, we aimed to evaluate factors associated with moderate and high risk of periodontal disease (PD) progression in the Saudi population., Methods: We reviewed 281 patients' clinical charts from predoctoral periodontal clinics at the dental teaching hospital in the College of Dentistry (COD) at Imam Abdulrahman Bin Faisal University (IAU) in Dammam, Saudi Arabia. After obtaining ethical approval, we determined the Periodontal Risk Assessment (PRA) of the included patients based on the modified criteria developed by Lang and Tonetti (2003). We used logistic regression on stratified data and divided the results into two categories (low-moderate and high risk) to assess the effect modifier for potential risk factors. We used SPSS version 22 for data analysis, and considered a P-value ≤ 0.05 to be statistically significant., Results: Out of the 281 patients, 104 (37.0%) were male and 177 (63.0%) were female, with a mean age of 39.9 ± 14.0 years; 78.1% were Saudi nationals, 77% were married, and 44.6% were in the age group of 30 to 49. The PRA revealed 86 (30.5%) to represent high risk, 108 (38.3%) denoted moderate risk, and 88 (31.2%) signaled low risk for periodontitis. Logistic regression analysis showed that males were three times more likely to have high PRA (OR = 3.24) and to be married (OR = 2.77), as well as to be active smokers (OR = 8.87). The highest predictive factors of high PRA were 8 or more pockets ≥ 5 mm (OR = 29.0), those with active diabetes mellitus (DM; OR = 10.2), and those with 8 or more missing teeth (OR = 9.15)., Conclusion: Saudi males who are married and have residual periodontal pockets, are actively diabetic, and with missing teeth are at high risk of PD. Further research is needed with a larger sample size comparing the general population with and without PD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

The incidence of periodontal diseases is associated with multiple comorbidities that influence a patient's treatment planning. This study evaluates the relation between periodontal disease and multiple comorbidities reported in the Saudi population from the Eastern province. This study was conducted on 190 patients, who visited the periodontology clinics at Imam Abdulrahman Bin Faisal University, Saudi Arabia. Demographic data, smoking habits, past medical and dental histories, blood pressure, random blood glucose, and recent haemoglobin A1c were recorded. A comprehensive periodontal examination included the number of missing teeth, pocket depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and mobility of all teeth except third molars. Radiographic bone loss was measured on standardized full-mouth periapical radiographs. Multivariable regression models were calculated aiming to see the association between different comorbidities and alveolar bone loss with confounders controlled. Out of 190 periodontitis patients, 56 (29.5%) were males and 134 (70.5%) were females. More than half of the patients (60%) were between 26 and 50 years, 30% of them had diabetes, and 18% were smokers. The risk of alveolar bone loss was higher in persons who had diabetes and those who had both diabetes and coronary heart disease than those who did not, although the association was not statistically significant ( B = 1.26, 95%CI = -0.30, 2.82, and B = 2.86, 95%CI = -1.25, 6.96, respectively). The risk of alveolar bone loss was significantly higher among persons with diabetes and hypertension ( B = 2.82 and 95%CI = 0.89, 4.75). Collectively, the risk of alveolar bone loss in periodontitis patients increases with diabetes in the presence of other comorbidities regardless of smoking or gender., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Marwa Madi et al.)

Objective: To evaluate the quality of life (QOL) of dental professionals in the Eastern Province of Saudi Arabia., Methods: This cross-sectional study recruited dental professionals (general dentists, specialists, and consultants) from public and private sectors in the Eastern Province of Saudi Arabia. The World Health Organization's QOL Assessment-BREF (WHOQOL-BREF) questionnaire was administered among study participants. The questionnaire addresses four domains of QOL which are physical, psychological, social relationships, and environment., Results: There were 313 dental professionals in the study with a mean age of 35.72 (8.58) years. The mean score of QOL in the sample was 63 (13.9) on a 0-100 scale. 75% of the participants rated their QOL as good or very good. Of four domains, the social relationship domain had the highest mean score of QOL (67.04 SD: 23.52) and the physical domain had the lowest score (59.66 SD: 14.69). There were significant differences in the QOL of consultants (66.46 SD: 12.55), specialists (65.42 SD: 12.91), and general dentists (61.06 SD: 14.18) ( P  0.010). The participants with medical illness had significantly lower QOL (56.91 SD: 12.83) than those without medical illness (63.67 SD: 13.92) ( P  0.01). There were significant differences in the QOL of participants with 0-10 years since graduation (61.97 SD: 14.71), 11-20 years (61.92 SD: 13.56), and more than 20 years (68.53 SD: 10.71) ( P  0.009)., Conclusion: The qualifications, medical illness, and years since graduation were important determinants of QOL among dental professionals. Measures should be taken to improve QOL of dental professionals which can enhance the quality of patient care., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Nabras Alrayes et al.)

Background: Syndactyly is a clinical feature of split-hand foot malformation (SHFM), ectodermal-dysplasia-syndactyly (EDSS1) and Cenani-Lenz syndactyly syndromes (CLSS). In EDSS1, only cutaneous syndactyly is observed, with sparse hair, abnormal nails and dentition. In SHFM, bony syndactyly may vary from hypoplasia of one phalanx to aplasia of central digits, extending to complete fusion of all fingers and toes in CLSS. Several genes have been assigned to these syndromes. Performing a single step molecular diagnostics becomes a challenge when a phenotype has overlaps with several syndromes or when some of the clinical features are not fully expressed in patients., Methods: Whole exome sequencing (WES) analysis on one sample derived from a consanguineous family was performed. A causative variant in WES data was prioritized via standard bioinformatics tools. The selected variant was Sanger sequenced in all the available family members for autosomal recessive segregation., Results: A novel missense variant (c.1151A>G; p.Tyr384Cys) was identified in the LRP4 gene. Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant. The variant is neither reported in 1000 human genomes, nor in 60 706 exomes databases, and is predicted as "pathogenic" by SIFT, Polyphen-2 and MutationTaster software., Conclusions: The present study broadens the pathogenic spectrum of the LRP4 gene in syndactyly syndromes. WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in syndactyly and related phenotypes., (© 2019 John Wiley & Sons, Ltd.)

Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.

Autosomal recessive primary microcephaly (MCPH) refers to a genetically heterogeneous group of neurodevelopmental disorders in which patients exhibit a marked decrease in occipitofrontal head circumference at birth and a variable degree of intellectual disability. To date, 18 genes have been reported for MCPH worldwide. We enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. Whole exome sequencing (WES) with 100× coverage was performed on two affected siblings after defining common regions of homozygosity through genome-wide single nucleotide polymorphism (SNP) microarray genotyping. WES data analysis, confirmed by subsequent Sanger sequence validation, identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene on chromosome 7p21.2. Population screening of 178 ethnically matched control chromosomes and consultation of the Exome Aggregation Consortium database, containing 60,706 individuals' exomes worldwide, confirmed that this mutation was not present outside the family. To the best of our knowledge, this is the first evidence of an AGMO mutation underlying primary microcephaly and intellectual disability in humans. Our findings further expand the genetic heterogeneity of MCPH in familial cases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum., Results: A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP-12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity., Conclusion: This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

Perrault syndrome (PRLTS) is a clinically and genetically heterogeneous disorder. Both male and female patients suffer from sensory neuronal hearing loss in early childhood, and female patients are characterized by premature ovarian failure and infertility after puberty. Clinical diagnosis may not be possible in early life, because key features of PRLTS, for example infertility and premature ovarian failure, do not appear before puberty. Limb spasticity, muscle weakness, and intellectual disability have also been observed in PRLTS patients. Mutations in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. We discovered a consanguineous Saudi family with the PRLTS3 phenotype showing an autosomal recessive mode of inheritance. The patients had developed profound hearing loss, brain atrophy, and lower limb spasticity in early childhood. For molecular diagnosis, we complimented genome-wide homozygosity mapping with whole exome sequencing analyses and identified a novel homozygous mutation in exon 6 of CLPP at chromosome 19p13.3. To our knowledge, early onset with regression is a unique feature of these PRLTS patients that has not been reported so far. This study broadens the clinical spectrum of PRLTS3., (Copyright © 2015 Elsevier B.V. All rights reserved.)