Phenotypic variability to medication management: an update on fragile X syndrome.

This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome's variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000-7000 men and 1 in 4000-6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene's promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS's variable expressivity by regulating the pathophysiological mechanisms related to the syndrome's behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

Genetic etiology and clinical challenges of phenylketonuria.

This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120-360 µmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

Public Concerns and Mental Health Changes Related to the COVID-19 Pandemic Lockdown in Saudi Arabia.

BACKGROUND: Public measures to confine the spread of the novel coronavirus disease 2019 (COVID-19) infection involves partial or full lockdown by some countries including Saudi Arabia. Social isolation, and financial insecurity are potential risk factors for mental changes. This study aimed to address public concerns, and assess mental health changes, and the factors associated with mental health burden in response to the COVID-19 outbreak in Saudi Arabia after the full lockdown is widely employed. METHODS: This cross-sectional study was conducted between 30th of April, and 10th of May, 2020 by posting an online survey on social media platforms (WhatsApp, and Twitter) to collect data on participants' demographics, concerns and worries related to the COVID-19 pandemic, and mental health changes using a validated Arabic version of the self-rated Hospital Anxiety and Depression Scale (HADS). RESULTS: A total of 1,921 responded to the questionnaire. Of them, 1,429 (74.5%) were ≤ 45 years old, and 967 (50.3%) were males. Reported public concerns included disturbed lifestyle, getting self or family member infected, loss job or part of income, difficult access to routine health care, and 55.8% reported negative impact on their mental health. Hospital anxiety and depression scale revealed high rates of depression [717 (37.3%)], and anxiety [508 (26.4%)]. Binary logistic regression revealed that female gender, working for the private sector, smokers, and people with chronic diseases were at increased risk of mental illnesses (p < 0.05). CONCLUSIONS: This study addressed serious public concerns, and substantially high rates of depression and anxiety related to the COVID-19 pandemic, and lockdown.

Mortality rate of ICU patients with the Middle East Respiratory Syndrome - Coronavirus infection at King Fahad Hospital, Jeddah, Saudi Arabia.

OBJECTIVE: The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a novel coronavirus circulating in the Arabian Peninsula since September 2012. It leads to significant respiratory disease and among patients with co-morbidities is associated with high mortality. This research studied the mortality rate of MERS-CoV among intensive care unit (ICU) patients and the correlation of mortality with different co-morbidities. METHODS: This was a retrospective observational study conducted at the Intensive Care Unit of the King Fahad Hospital, Jeddah, Saudi Arabia. Data was obtained through patient chart review. RESULTS: The total sample consisted of 52 laboratory-confirmed MERS-CoV infection patients. 39 patients died, with a 75% case-fatality rate. Many patients had underlying co-morbidities, including diabetes mellitus (51.9%), hypertension (46.2%), and chronic renal disease (21.2%). CONCLUSIONS: MERS-CoV ICU mortality remains markedly high due to a combination of factors; the disease process of MERS-CoV leads to multiple organ failure, particularly respiratory and renal failure.

Post COVID-19 Symptoms Among Infected Vaccinated Individuals: A Cross-Sectional Study in Saudi Arabia.

INTRODUCTION: Multiple studies investigated the endurance and occurrence of symptoms three months after SARS-CoV-2 infection. This study examines the possible effects of COVID-19 vaccination on the persistence of post-recovery symptoms. PATIENTS AND METHODS: A cross-sectional survey was conducted in Saudi Arabia to evaluate 14 prevalent long COVID-19 symptoms among vaccinated individuals. Patients self-reported their acute COVID-19 experience, demographic information, chronic conditions, vaccine history, and persistent symptoms. RESULTS: Of the 484 patients, four respondents were excluded from the study as they had not received the vaccine, and 111 (23.1%) were vaccinated but did not get infected and were also excluded. The remaining 369 (76.9%) reported COVID-19 and a vaccination and thus they were included in the study. The occurrence of post-COVID-19 symptoms was reported in 59 (16.1%) for ≤ 3 months, 202 (54.8%) experienced persistent symptoms 3-6 months, and 108 (29.1%) reported symptoms lasting > 6 months. In relation to age group, persistent symptoms 3-6 months after recovery was more common in those > 50 years and symptoms lasting > 6 months were more common in 30-50 years of age (p < 0.001). Persistence of symptoms for 3-6 months was more common in those who were infected prior to vaccination compared to those who were infected after vaccination (P < 0.001). Of the included patients, 323 (87.5%) rated their health as good, 41 (11.1%) considered it fair, and 5 (1.4%) described their well-being as poor or terrible. CONCLUSION: The study provides information of persistent symptoms in vaccinated individuals who had recovered from COVID-19 and highlights the need for targeted interventions to alleviate post-COVID-19 symptoms. The study is limited by its reliance on self-reported data and potential selection bias. Future research is needed to understand the mechanisms underlying persistent symptoms in vaccinated individuals and to identify effective interventions for long COVID.

Sequence Variants in PSMB8/PSMB9 Immunoproteasome Genes and Risk of Urothelial Bladder Carcinoma.

BACKGROUND: The PSMB8 and PSMB9 immunoproteasome genes are essential in cell processes, such as decisions on cell survival or death, the cell cycle, and cellular differentiation. Because recent evidence has demonstrated an immunological role for proteasomes in various malignancies, including urothelial bladder carcinoma (UBC), we evaluated single nucleotide polymorphisms (SNPs) in PSMB9 and PSMB8. We determined any associations between these SNPs and susceptibility to UBC in the Saudi community. METHODS: Samples of genomic DNA were taken from buccal cells of 111 patients with UBC and 78 healthy controls. TaqMan Real-Time PCR was used to determine genotype distributions and allele frequencies for the PSMB9 rs17587 G>A and PSMB8 rs2071543 G>T SNPs. We used SNPStats (https://www.snpstats.net) to choose each SNP's best interactive inheritance model. RESULTS: The PSMB9 rs17587 SNP was associated with the risk of UBC (odds ratio [OR] = 5.21, P < 0.0001). In contrast, the PSMB8 rs2071543 SNP showed no association with UBC risk (OR = 1.13, P = 0.7871). In terms of genotypic distribution, the rs17587 G>A SNP was more frequent in UBC cases than controls in both the dominant (OR = 7.5; 95% confidence interval, 3.7-15.1; P = 0.0051) and recessive (OR = 17.11, 95% confidence interval 5.1-57.4; P = 0.0026) models. Genotypic distribution of the PSMB8 rs2071543 G>T SNP was not significantly different between cases and controls in any interactive inheritance models (P > 0.05). CONCLUSION: These results suggest a potential role for PSMB9 as a biomarker for increased UBC risk. Discovering more genetic variants within immunoproteasome genes related to antigen presentation could help further our understanding of this risk.

Correlation of Occupational Exposure to Carcinogenic Polycyclic Aromatic Hydrocarbons (cPAHs) and Blood Levels of p53 and p21 Proteins.

Carcinogenic polycyclic aromatic hydrocarbons (cPAHs) are considered the most serious cancer risk. This study was conducted to assess the effect of acute exposure to cPAHs on cancer biomarker proteins p53 and p21 in occupational workers during the hajj season in Makkah. One hundred five participants were recruited, including occupational workers and apparently healthy individuals; air samples were collected using personal sample monitors to identify the subjects' exposure to cPAHs. Quantitative analyses of benzo(a)anthracene (BaA), benzo(b)fluoranthene (BbF), benzo(a)pyrene (BaP), dibenzo(a,h)fluronathene (DBA), indeno(1,2,3-c,d)pyrene (IND) and chyresene (CRY) were carried out using the GC/Mass technique. Serum p53 and p21 proteins were analyzed using ELISA. The ambient air samples collected by the occupationally exposed group were more highly polluted by cPAHs, (90.25 ± 14.1) ng/m3, than those of the unexposed control groups, (30.12 ± 5.56) ng/m3. The concentration of distributive cPAHs was markedly more elevated in the air samples of the exposed group than in those taken from the non-exposed group. The study results demonstrated significant links between short-term exposure to cPAHs and serum p53 and p21 levels. Serum p53 and p21 proteins potentially influence biomarkers when exposed to ambient air cPAHs.

Variations in TAP1 and PSMB9 Genes Involved in Antigen Processing and Presentation Increase the Risk of Vitiligo in the Saudi Community.

BACKGROUND: The antigen processing 1 (TAP1) and proteasome 20S subunit beta 9 (PSMB9) genes are associated with strong susceptibility to many autoimmune diseases. Here, we explored whether TAP1/PSMB9 genetic variants, individually or combined, affected susceptibility to the complex, autoimmune-based skin disorder vitiligo. METHODS: Samples of genomic DNA from buccal cells of 172 patients with vitiligo and 129 healthy controls were analyzed using TaqMan™ genotyping assays for the TAP1 rs1135216 (A>G) and PSMB9 rs17587 (A>G) single nucleotide polymorphisms (SNPs). SNPStats software (https://www.snpstats.net) was utilized to choose the best interactive inheritance mode for selected SNPs. RESULTS: The genotype frequencies for the TAP1 rs1135216 and PSMB9 rs17587 SNPs were in Hardy-Weinberg equilibrium for cases (P= 0.11 and P= 0.10, respectively) but not for controls (P< 0.05). The TAP1 rs1135216 (D637G) and PSMB9 rs17587 (R60H) SNPs increased the risk of vitiligo four-fold and two-fold, respectively (odds ratio [OR]= 4.6; 95% confidence interval [CI], 3.2-6.5; P< 0.0001 and OR= 2.2; 95% CI, 1.5-3.1; P< 0.0001). The recessive model (G/G-D/G versus D/D) and the codominant model (R/R versus R/H) were the best models of inheritance for the rs113526 and rs17587 SNPs, respectively (OR= 16.4; 95% CI, 2.0-138; P= 0.0006 and OR= 1.7; 95% CI, 0.3-1.8; P= 0.013). Vulgaris, focal vulgaris, and acryl/acrofacial were the most common vitiligo subtypes in our sample (51%, 21%, and 19%, respectively). Heterozygous rs113526 (637D/G) and rs17587 (60R/H) were the most common genotypes in most vitiligo subtypes. The heterozygous 637D/G genotype and the 637G variant allele were significantly more common in patients with active disease than in patients with stable disease (P= 0.000052 and P= 0.0063, respectively). CONCLUSION: Our findings suggest a crucial role for TAP1 rs1135216 and PSMB9 rs17587 in the risk and progression of vitiligo in the Saudi community. Genomic analyses are needed to identify more candidate genes and more genetic variants associated with vitiligo.

Correlation of COVID-19 Pandemic with Healthcare System Response and Prevention Measures in Saudi Arabia.

BACKGROUND: The Saudi government has taken the decision to prevent the entrance of about 2.5 million international pilgrims seeking to perform hajj in order to protect the world from a catastrophic widespread of disease. Moreover, health systems in Saudi Arabia are offering free testing for residents whether Saudi and non-Saudi. OBJECTIVE: This study aimed to evaluate the spread of COVID-19 associated with preventive measures taken in Saudi Arabia and to develop a detailed COVID-19 prevention strategy as a framework for the Saudi Arabia community. METHODOLOGY: Population size and age distributions among the country of Saudi Arabia were taken from the 2020 World Population Prospects. Contact patterns were measured using the Saudi Arabia Ministry of Health Statistical Annual Report. CONCLUSIONS: Our study demonstrates that performing screening tests as early as possible to facilitate the rapid detection of infected cases, fast treatment, and instant isolation for suspected cases is the most definitive rejoinder for public health. Moreover, our study revealed the significance of performing preventive measures in reducing infection and death rates around Saudi Arabia by 27%, while in other countries, it reduced the death rate ranging from 10-73%. This study provides an achievable strategy for prevention and early detection of COVID-19 spread.