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.

Elevated serum tumour necrosis factor-like weak inducer of apoptosis in alopecia areata: a possible marker of disease severity.

BACKGROUND: Alopecia areata (AA) is, an organ-specific autoimmune disease, characterized by an aberrant expression of cytokines of the T helper 1 type. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifactorial cytokine that exerts a role in the pathogenesis of inflammatory and autoimmune diseases, especially in cutaneous diseases. AIM: To estimate the serum level of TWEAK in AA and to correlate it with different parameters. METHODS: This case-control study enrolled 40 patients with AA and 50 clinically healthy volunteers matched for age and sex. A blood sample (5 mL) was extracted from each participant for analysis of serum TWEAK levels by ELISA. RESULTS: Levels of TWEAK were significantly higher in patients with AA (mean ± SD 213.7 ± 59.2 pg/mL, range 109.1-341.6 pg/mL) than in controls (95.97 ± 13.28 pg/mL, range 80.1-152.3 pg/mL) (P < 0.001). A significant positive correlation was found between serum TWEAK level and the Severity of Alopecia Tool (SALT) score (r = 0.56, P < 0.001). CONCLUSION: To our knowledge, this study highlights for the first time a possible link between higher serum TWEAK level and AA. Serum TWEAK level appears to reflect AA disease severity.

Serum miR-210 and miR-155 expression levels as novel biomarkers for rheumatoid arthritis diagnosis.

BACKGROUND: MicroRNAs play a crucial role in the regulation of immune response. We hypothesised roles for serum miR-210 and miR-155 in the diagnosis of rheumatoid arthritis (RA) and relationships with the clinical and laboratory variables including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, tumour necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß). METHODS: MiR-210 and miR-155 levels were identified by real-time polymerase chain reaction (PCR). TNF-α and IL-1ß were measured by enzyme-linked immunosorbent assay and routine markers by standard techniques in 100 patients with RA and 100 individuals as healthy controls. Disease activity in the patients was assessed by DA-S28. RESULTS: MiR-210 was lower in RA compared to controls [median/IQR 0.96 (0.8-1.24) vs. 4 (1.28-3.93), p < 0.001]. miR-210 correlated inversely with clinical and laboratory variables including TNF-α and IL-1ß (both r = -0.96, p < 0.001). MiR-155 expression was increased in RA compared to controls [median/IQR 6 (3.5-8.1) vs. 1.0 (0.95-1.6), p < 0.001] and correlated with TNF-α and IL-1ß (both r = 0.94, p < 0.001). In multivariate analysis, miR-210 and miR-155 were both independent diagnostic markers for RA, and both were associated with RA disease activity. CONCLUSION: Serum miR-210 and miR-155 levels are independent diagnostic markers for RA, out-performing several routine indices and reflect disease activity. Thus, miR-210 and miR-155 might serve as non-invasive biomarkers for the diagnosis of RA.

Risk of Colorectal Carcinoma May Predispose to the Genetic Variants of the GST, CYP450, and TP53 Genes Among Nonsmokers in the Saudi Community.

PURPOSE: Colorectal carcinoma (CRC) represents a considerable public health burden in Saudi Arabia. Several candidate genes and genetic variants have been associated with morbidity and mortality among patients with CRC. We explored whether allelic variants of the GSTM1, GSTT1, CYP450 (rs4646903 and rs1048943), and TP53 (rs1042522) genes predisposed nonsmoking Saudi individuals to increased risk for CRC. PATIENTS AND METHODS: DNA from buccal cells of 158 participants (80 with CRC and 78 healthy controls) were analyzed for five SNPs using conventional PCR and TaqMan genotyping assays. The SNPStats software was utilized to choose the best interactive inheritance mode for selected SNPs (https://www.snpstats.net). RESULTS: The mean age of diagnosis was 62.4±13.5 years (range, 40-83 years), with those aged 71-80 years and those aged 40-50 years accounting for the most diagnoses (35.7% and 28.6% of diagnosis, respectively). The GSTM1 and TP53 rs1042522 SNPs were associated with CRC (OR= 3.7; P< 0.0001, and OR= 1.6; P= 0.033, respectively). A plausible contribution to CRC was observed for the GSTM1 and TP53 rs1042522 SNPs (x 2 Yates= 14.7; P= 0.00013, and x 2 Yates= 11.2; P= 0.0008, respectively), while the GSTT1 null variant did not affect risk. Heterozygosity in the CYP450 (rs4646903 and rs1048943 SNPs) was associated with a significant risk for CRC. The GSTM1/GSTT1 and CYP450 rs4646903/rs1048943 SNP pairs were in linkage disequilibrium, and the associations were statistically significant (P= 0.01 and P= 4.6x10‒7, respectively). CONCLUSION: The GSTM1 and TP53 rs1042522 variants can increase the development of CRC in Saudi nonsmokers. Even the presence of one copy of a variant allele in the CYP1A1 gene can predispose CRC risk. Additional studies should also examine other SNP combinations with lifestyle factors that may help prevent, rather than facilitate, colorectal tumorigenesis.

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.

Correction to: Ultrasonographic features of acute Charcot neuroarthropathy of the foot: a pilot study.

The authors of the original version of the above article requested the following corrections be noted in Patients and methods, Ultrasonographic examination and Fig. 1 and 2 (legend).

Ultrasonographic features of acute Charcot neuroarthropathy of the foot: a pilot study.

OBJECTIVES: Our aim was to characterize the ultrasonographic features of patients with acute Charcot neuroarthropathy (CN) of the foot. METHODS: In this prospective study, 26 patients with CN of the foot proved by MRI were enrolled. All patients were in early stage of CN with normal radiography (grade 0 modified Eichenholtz classification system). Ultrasonographic examination of mid-tarsal and ankle joints was performed with a 7-15 MHz linear probe. RESULTS: Ages of our patients ranged from 38 to 67 years (57.3 ± 6.4). About 96.2% of our patients (25 patients) had diabetes mellitus. Ultrasonographic findings were as follows: effusion/synovitis (100%) with high Doppler activity (92.3%) in the mid-tarsal joints, and effusion/synovitis (92.3%) and high Doppler activity (84.6%) in the ankle joints. Bone erosions were present in the distal fibula in 23 patients (79.3%), while in distal tibia in 9 patients (34.6%). Tendonitis was found in tibialis posterior tendons in 23 patients (88.4%), and in peroneal tendons in 22 patients (84.6%). A combination of active synovitis (in mid-tarsal joints and ankle joints), active tendonitis (of tibialis posterior and peroneal tendons), and erosions in the distal end of fibula was present in 21 patients (80.8%). CONCLUSIONS: Ultrasonography is able to detect soft tissue inflammation and pre-radiographic bony changes in early stages of CN. Key Points •Ultrasound is a useful diagnostic tool for pre-radiographic stages of Charcot joint. •High-grade synovitis, high-grade tenosynovitis, and bony erosions are highly suggestive of Charcot arthropathy.

Genotypic characterization of Pseudomonas aeruginosa isolated from human and animal sources in Egypt.

Two different techniques for the molecular typing of Pseudomonas aeruginosa were used to study the epidemiology of P. aeruginosa strains. Colonization with P. aeruginosa was studied by taking samples of human origin collected from urine, sputum samples of patients suffering from lung manifestations and patients exposed to third-degree burns. In addition, samples of animal origin were collected from mastitic milk and lung tissues of slaughtered calves and from the internal organs of diseased chickens. Typing of 18 isolates was performed by random amplified polymorphic DNA analysis and amplified fragment length polymorphism analysis. Computer-aided cluster analysis indicated that similar groups of related isolates were obtained by each method.