Organic acidurias in Egyptian children: The urge for high-risk screening.

BACKGROUND: Organic acidurias are a group of inborn errors of metabolism. They present a significant diagnostic challenge and are associated with serious morbidity and mortality. They are considered the most frequent inborn errors of metabolism among high-risk children. Gas chromatography-mass spectrometry is a reliable diagnostic technique for organic acidurias. This hospital-based study aimed to quantify the frequency of organic acidurias among a group of high-risk Egyptian pediatric patients and to highlight the importance of high-risk screening for such disorders. METHODS: One hundred and fifty high-risk children who presented to the inherited metabolic disease unit and the pediatric intensive care units of Cairo University Children Hospital were tested for urine organic acids using gas chromatography-mass spectrometry. RESULTS: Thirty percent (45/150) of the patients were confirmed as having an altered organic acids profile. Neurological manifestations were the most common presentation. Glutaric aciduria type I and maple-syrup urine disease were the most common disorders encountered among the group that was studied. CONCLUSION: Organic acid detection by gas chromatography-mass spectrometry is key to the diagnosis of many metabolic disorders. Until a national expanded newborn screening program is established, high-risk screening is strongly encouraged for the early detection of, and proper intervention for such disorders among Egyptian children.

Eight-year outcomes of 'the Cairo Kidney Centre sequential protocol'.

OBJECTIVES: To describe the long-term results of a previously developed a sirolimus-based sequential immunosuppression protocol for kidney transplant comprising 2 phases: sirolimus + cyclosporine + prednisolone for 3 months followed by sirolimus + prednisolone + mycophenolate mofetil with steroid minimization the first year. Two-year outcomes of patients on this protocol (group A) showed equivalent patient and graft survival, yet with significantly better function, compared with those on cyclosporine + mycophenolate mofetil + prednisolone (group B). MATERIALS AND METHODS: We report the 8-year outcomes in the same cohort (76 patients in group A and 37 in group B). RESULTS: 42% switched from group A to B versus 43% switching from B to A. Intent-to-treat patient survivals at 5 and 8 years were 88% and 85.5% for group A, and 78% and 73% for group B. Death-censored graft survivals were 93% for group A and 95% for group B. Graft function was significantly better at 8 years, with 91% of group A patients compared with 50% in group B having estimated glomerular filtration rates > 45 mL/min/1.73 m2, and a significantly lower incidence of chronic allograft nephropathy in the former. Secondary parameters including blood pressure control, new onset diabetes mellitus, proteinuria and other drug-related adverse events showed no significant differences between the groups. CONCLUSIONS: The sirolimus-based sequential immunosuppression protocol was well tolerated in 58% of patients. The intent-to-treat and patients-ontherapy analyses revealed that it was equivalent to the widely used cyclosporine + mycophenolate mofetil + prednisolone protocol regarding patient and graft survival. It is associated with better graft function and lower incidence of chronic allograft nephropathy in 8 years' follow-up. The incidence of drug-related adverse reactions was not statistically different from those in the comparator.

Triple test screening for Down syndrome: an Egyptian-tailored study.

BACKGROUND: The incidence of Down syndrome (DS) in Egypt varies between 1:555 and 1:770 and its screening by triple test is becoming increasingly popular nowadays. Results, however, seem inaccurate due to the lack of Egyptian-specific information needed for risk calculation and a clear policy for programme implementation. Our study aimed at calculation and validation of the triple marker medians used in screening Egyptian females as well as to recommend programme conventions to unify screening in this country. METHODS: The study was conducted on 668 Egyptian women, in weeks 15-20 of pregnancy as proven by sonar. Chorionic gonadotropin (CG), α-fetoprotein (AFP) and unconjugated oestriol (uE3) were measured on Siemens Immulite analyzer. Medians of the three parameters were calculated, regressed against gestational age (GA) and weighted by the number of participants/week. Equations were derived to adjust each parameter to the maternal weight and were centered on the median Egyptian weight. Prisca software was fed with the above data, multiples-of-median (MoM) and DS risks were calculated and the screening performance was evaluated at a mid-trimester risk cutoff of 1:270. RESULTS: Log-linear [AFP/uE3 = 10(A+B*GA)] and exponential equations [CG = A*e (B*GA)] were derived and the regressed medians were found to follow similar patterns to other Asian and Western medians. Oestriol was always lowest (even halved) while CG and AFP were intermediate. A linear reciprocal model best fitted weight distribution among Egyptians and successfully adjusted each parameter to a weight of 78.2 kg. Epidemiological monitoring of these recommendations revealed satisfactory performance in terms of 6.7% initial positive rate and 1.00 grand MoM. CONCLUSIONS: Adoption of the above recommendations is hoped to pave the way to a successful DS screening programme tailored to Egyptian peculiarities.

Validation of a proposed warfarin dosing algorithm based on the genetic make-up of Egyptian patients.

BACKGROUND: Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms. OBJECTIVE: The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP) 2C9 single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients. METHODS: Eighty-four patients, 41 males and 43 females, with a median (25th-75th percentiles) age of 39 (31-48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2-3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of CYP2C9 (1075A>C) and VKORC1 (1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender, CYP2C9 and VKORC1 SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2-3. The new warfarin dosing algorithm was examined in a second cohort of patients (n=34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at http://www.warfarindosing.org. RESULTS: In the study cohort, warfarin dose/week in VKORC1 TT subjects was statistically significantly lower than in VKORC1 CC/CT subjects (p=0.032), while there was no statistically significant difference in warfarin dose/week between CYP2C9*1*1 and *1*3 (p=0.925). A multivariate stepwise linear regression analysis revealed that age and VKORC1 had independent and significant contributions to the overall variability in warfarin dose with a p-value=0.013 and 0.042, respectively. Maintenance dose (mg/week)=65.226-0.422×(age) - 9.474×(VKORC1). The estimated regression equation was able to account for 20.5% of the overall variability in warfarin maintenance dose. A significant positive correlation, with sufficient strength, was observed between the predicted warfarin dose and the actual prescribed dose (r=0.453, p=0.001). In the validation cohort, after application of the dosing algorithm, correlation between predicted and actual dose was statistically significant (p=0.023). The equation was particularly successful among patients with a dose≥35 mg/week. The correlation coefficient between the actual and predicted doses for IWPC and Gage were 0.304 and 0.276, respectively. When compared with our algorithm (r=0.279), the difference was non-significant: p=0.903 and 0.990, respectively. CONCLUSION: VKORC1 (1173C>T) contributes to the warfarin dose variability. Patients' age and genetic variants of VKORC1 account for nearly 20.5% of the variability in warfarin dose required to achieve an INR of 2-3. The success of a prediction equation based on these variables was proved in a different cohort: the predicted dose correlated significantly with the maintenance dose and the equation was more successful among patients with a dose≥35 mg/week. The results of the warfarin algorithm we developed were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (VKORC1 1173C>T) only. This represents an economic advantage in our community. Replication of this study in a larger cohort of patients is necessary before translation of this knowledge into clinical guidelines for warfarin prescription.