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.

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.