Identification of epilepsy concomitant candidate genes recognized in Saudi epileptic patients.

Saudi Genome program is a revolutionary nationwide transformation initiative of Saudi Vision 2030. The program goals are to recognize and reduce the incidence of genetic diseases in the Kingdom of Saudi Arabia (KSA). Accordingly, the program will establish the foundation for personalized and genomic medicine in the KSA. Epilepsy has a high prevalence in KSA reaching around 6.54 of 1000 individuals with a subsequent massive financial burden. One of the main risk factors for this high prevalence and associated with increased risk of epilepsy development is consanguinity marriage, which is traditional in KSA. In this review, we executed a comprehensive state-of-art literature review regarding epilepsy genetics to offer a perception into the genes associated with epilepsy recognized in Saudi epileptic patients. Several genes' mutations were incorporated in this review including AFG3L2, ASPM, ATN1, ATP1A2, BMP5, CCDC88A, C12orf57, DNAJA1, EML1, ERLIN2, FRRS1L, GABRG3, NRXN3, MDH1, KCNJ10, KCNMA1, KCNT1, KIAA0226, OPHN1, PCCA, PCCB, PEX, PGAP2, PI4K2A, PODXL, PRICKLE1, PNKP, RELN, SCN2A, SCN1B, SLC2A1, SLC19A3, SLC25, SIAH1, SYNJ1, SZT2, TBCK, TMX2, TSC1, TSC2, TSEN, WDR45B, WWOX, UBR, UGDH, and YIF1B. For each of these genes, we tried to explain a little about the gene associated proteins and their roles in epilepsy development.

TREC and KREC profiling as a representative of thymus and bone marrow output in patients with various inborn errors of immunity.

Primary immune deficiency (PID) disorders are clinically and molecularly heterogeneous diseases. T cell receptor excision circles (TRECs) and κ (kappa)-deleting excision circles (KRECs) are markers of T and B cell development, respectively. They are useful tools to assess T and B cell function and immune reconstitution and have been used for newborn screening for severe combined immunodeficiency disease (SCID) and agammaglobulinemia, respectively. Their profiles in several genetically confirmed PIDs are still lacking. The objective of this study was to determine TREC and KREC genomic profiling among various molecularly confirmed PIDs. We used real-time-quantitative polymerase chain reaction (RT-qPCR)-based triplex analysis of TRECs, KRECs and ß-actin (ACTB) in whole blood genomic DNA isolated from 108 patients with molecularly confirmed PIDs. All agammaglobulinemia patients had low KREC counts. All SCIDs and Omenn syndrome patients secondary to mutations in RAG1, RAG2, DCLRE1C and NHEJ1 had low TREC and KREC counts. JAK3-deficient patients had normal KREC and the TREC count was influenced by the type of mutation. Early-onset ADA patients had low TREC and KREC counts. Four patients with zeta-chain-associated protein kinase 70 (ZAP70) had low TREC. All purine nucleoside phosphorylase (PNP) patients had low TREC. Combined immunodeficiency (CID) patients secondary to AK2, PTPRC, CD247, DCLREC1 and STAT1 had normal TREC and KREC counts. Most patients with ataxia-telangiectasia (AT) patients had low TREC and KREC, while most DOCK8-deficient patients had low TRECs only. Two of five patients with Wiskott-Aldrich syndrome (WAS) had low TREC counts as well as one patient each with bare lymphocyte syndrome (BLS) and chronic granulomatous disease. All patients with Griscelli disease, Chediak-Higashi syndrome, hyper-immunoglobulin (Ig)M syndrome and IFNGR2 had normal TREC and KREC counts. These data suggest that, in addition to classical SCID and agammaglobulinemia, TREC/KREC assay may identify ZAP70 patients and secondary target PIDs, including dedicator of cytokinesis 8 (DOCK8) deficiency, AT and some individuals with WAS and BLS.

Hematopoietic stem cell transplantation in children with Griscelli syndrome type 2: a single-center report on 35 patients.

In 2010, we reported the outcome of hematopoietic stem cell transplantation (HSCT) in 11 children with Griscelli syndrome type 2 (GS2). We report here the update on this cohort to include 35 patients. Twenty-seven (77%) patients received conditioning regimen including busulfan, cyclophosphamide with etoposide. Eight (23%) were given busulfan, fludarabine. Thiotepa was added to busulfan and fludarabine regimen in two patients; one received haploidentical marrow and one unrelated cord blood. Posttransplant clinical events included veno-occlusive disease (n = 7), acute (n = 8), or chronic (n = 1) graft-versus-host disease II-IV. With a mortality rate of 37.1% (n = 13) and a median follow-up of 87.7 months of the survivors, 5-year cumulative probability of overall survival (OS) for our cohort of patients was 62.7% (±8.2%). Cumulative probability of 5-year OS was significantly better in those who did not have hemophagocytic lymphohistiocytosis (HLH) prior to HSCT (100% vs. 53.3 ± 9.5%, P value: 0.042). Of the 16 patients with neurologic involvement before HSCT, 8 survived and 3 presented sequelae. OS at 5-year was 50 ± 12.5% and 73.3 ± 10.2% (P value: 0.320) in patients with and without CNS involvement, respectively. In conclusion, HSCT in patients with GS2 is potentially curative with long-term disease-free survival. Early HSCT before the development of the accelerated phase is associated with a better outcome.

Haematopoietic stem cell transplant for hyper-IgM syndrome due to CD40 defects: a single-centre experience.

Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare disease with only a few reported cases of haematopoietic stem cell transplantation (HSCT). In retrospective study, we reviewed all patients with HIGM3 who underwent HSCT at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between 2008 and 2013. Six patients were identified. Three male and three female patients from three families. The median age of diagnosis was 13 months (range, 1-28 months). All lacked CD40 expression on B cells by flow cytometry. The median time from diagnosis to transplantation was 8.5 months (range, 1-17 months). For all patients, the donors were HLA-identical siblings, with the exception of one patient for whom the donor was a sibling with one antigen mismatch. The conditioning regimen was busulfan and cyclophosphamide in five patients and busulfan, cyclophosphamide and antithymocyte globulin in one patient. For GVHD prophylaxis, cyclosporine and methotrexate was used. All patients engrafted. The survival rate was 100%, with a median follow-up of 54 months (range, 30-116 months). One patient developed acute GVHD. All patients showed complete immune recovery with positive CD40 expression on B cells and discontinued IVIG replacement. Our study shows that HSCT is potentially effective at curing the disease.

Surveillance of dialysis events: 12-month experience at five outpatient adult hemodialysis centers in Kuwait.

BACKGROUND: Embedding dialysis surveillance scheme is associated with reductions in blood stream infection and antimicrobial consumption .The aim of this study was to establish baseline dialysis events (DE) rates; hospitalization, intravenous (IV) antibiotics start or a positive blood culture stratified by vascular access category and comparisons to published National Healthcare Safety Network (NHSN) rates. METHODS: A retrospective review of DE was done between January to December 2012, in five outpatient adult hemodialysis center. RESULTS: The pooled mean rates of hospitalization among patients with fistulas, grafts, permanent and temporary catheters were 2.8, 5.7, 5.1, and 10.6 per 100 patient-months, respectively. For positive blood culture the pooled mean rates were 0.2, 1.0, 1.9 and 2.7 per 100 patient-months in these groups. The IV antibiotics starts event pooled mean rates were 5.9, 9.0, 11.8, and 11.2 per 100 patient-months. DE were significantly more common in patients with permanent and temporary catheters when compared with patients with fistulas and graft (p<0.001). CONCLUSION: Surveillance of DE rates in Kuwait revealed significantly lower mean rate of hospitalization and positive blood culture while IV antimicrobial start shows significantly higher mean rate when compared to published NHSN data.

Hematopoietic SCT in children with Griscelli syndrome: a single-center experience.

In total, 11 consecutive pediatric patients with Griscelli syndrome (GS) type 2, who received allogeneic hematopoietic SCT (aHSCT) at our center between 1993 and 2007, were reviewed. The median age at transplantation was 8.2 months (range, 4-36.3 months) and the median time from diagnosis to transplantation was 3.7 months (range, 1.4-19.5 months). Seven patients developed an accelerated phase and were treated with chemotherapy before transplantation. At the time of transplantation, all patients were in clinical remission. The source of grafts was matched-related marrows in eight patients and partially mismatched unrelated cords in three patients. All patients were engrafted at a median time of 15 days (range, 12-36 days). Grade I-II acute GVHD and veno-occlusive disease occurred in three and one patient, respectively. A total of 10 patients are now alive and disease free at a median of 4.8 years post-HSCT. The post transplant course was complicated by CMV infection in four patients. One patient died in remission from septic shock, 6 months after transplantation. Chimerism studies at the last contact are available for nine patients: six patients have complete donor chimerism and three have stable mixed chimerism. Early aHSCT from matched-related donors or unrelated cord blood for children with GS is feasible.

Unrelated cord blood transplantation in pediatric patients: a report from Saudi Arabia.

In unrelated cord blood (UCB) transplantation, survival has been shown to correlate with the degree of HLA matching. Thus, to extend transplant access to different ethnic backgrounds, many western UCB transplantation banks now encourage donation from non-Caucasians. Until recently, Saudi Arabia did not have a national UCB bank. In this study we report our experience in UCB transplantation in children using units procured from western cord blood banks. A total of 97 children underwent unrelated UCB transplantation at King Faisal Specialist Hospital and Research Center (KFSHRC), of which 95 were of Arab ethnicity. A total of 30 patients had malignant disorders, 25 patients had non-malignant hematological disorders and 42 patients had inborn errors. Conditioning was according to disease, with six patients receiving reduced-intensity regimens. In all, 46 patients received one-Ag-mismatched units and 51 received two-Ag-mismatched units. Engraftment occurred in 93% of patients, the 100-TRM was 15%, acute GVHD developed in 20% of patients and chronic GVHD occurred in 9% of patients. The 5-year OS and EFS estimates were 52 and 43%, respectively. The search for UCB transplantation units for Saudi patients in western banks yielded reasonably compatible units for our patients; the results are consistent with published data. Our data are encouraging for UCB transplant programs in countries in which there are no national UCB transplantation banks.

A novel mutation in purine nucleoside phosphorylase in a child with normal uric acid levels.

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is an autosomal recessive disease in which affected children present with recurrent infection and may present with failure to thrive, neurological impairment, autoimmunity, or malignancy. The diagnosis of PNP is usually suggested by a reduced level of serum uric acid. We report here a novel mutation in the nucleoside phosphorylase gene (NP gene) in a patient with primary immunodeficiency and neurological impairment but with normal uric acid levels. The diagnosis was confirmed biochemically and showed a reduced PNP activity, and also by molecular gene analysis. METHODS: A case report and a complete NP gene DNA analysis. RESULT: The sequencing analysis showed a novel homozygous missense mutation, c.487T>C in the NP gene, resulting in a substitution of serine by proline at residue 163 (S163P) in the mature NP protein. CONCLUSION: This NP missense mutation reported here is associated with recurrent infection, developmental delay, and primary immunodeficiency combined with normal uric acid levels in the affected child most likely due to a residual PNP enzyme activity. PNP deficiency causing primary immunodeficiency is still possible, even with normal uric acid levels.