Cohort Of South African Patients Research Articles

Exploring the anatomical configurations of the cerebral arteries in a cohort of South African patients

The cerebral arteries, specifically the anterior cerebral artery (ACA) and posterior cerebral artery (PCA), work together with the smaller calibre arteries to provide effective communication between the anterior and posterior circuits of the brain via the circle of Willis (CoW). Morphologic variations of the cerebral arteries and the CoW may alter blood flow to the brain, resulting in intracranial vascular disorders associated with stroke, and aneurysms. This study aimed to document the morphology of the cerebral arteries and the CoW in the South African population. Two hundred and thirty-nine computed tomography angiography scans were assessed. Cerebral arteries and CoW normal morphology and variations were classified as complete, absent, or hypoplastic. The ACA A1 was absent in 4.91%, hypoplastic in 30.40%, fenestrated in 1.06%, and typical in 63.6%. The ACA A2 was absent in 0.42%, hypoplastic in 26.28%, and typical in 69.44%. We found triple ACA A2 in 2.98%, azygos in 1.28% and fenestrated in 1.28%. The middle cerebral artery (MCA) was hypoplastic in 7.35% and typical in 92.64%. The PCA was hypoplastic in 28.74% and typical in 71.25%. Knowledge of the configuration of the CoW plays a significant role in guiding therapeutic decision-making in treating various neurovascular pathologies.

Mutation profiling in South African patients with Cornelia de Lange syndrome phenotype.

Cornelia de Lange Syndrome (CdLS) presents with a variable multi-systemic phenotype and pathogenic variants have been identified in five main genes. This condition has been understudied in African populations with little phenotypic and molecular information available. We present a cohort of 14 patients with clinical features suggestive of CdLS. Clinical phenotyping was carried out and cases were classified according to the international consensus criteria. According to this criteria, nine patients had classical CdLS, one had non-classical CdLS and four presented with a phenotype that suggested molecular testing for CdLS. Each patient underwent mutation profiling using a targeted next generation sequencing panel of 18 genes comprising known and suspected CdLS causal genes. Of the 14 patients tested, pathogenic and likely pathogenic variants were identified in nine: eight variants in the NIPBL gene and one in the STAG1 gene. We present the first molecular data for a cohort of South African patients with CdLS. Eight of the nine variants identified were in the NIPBL gene, the most commonly involved gene in cases of CdLS. This is also the first report of a patient of African ancestry presenting with STAG1-related CdLS.

Modeling the impact of universal tuberculosis molecular testing and timing of tuberculosis preventive treatment during antiretroviral therapy initiation in South Africa.

Targeted universal tuberculosis (TB) testing can improve TB detection among people with HIV. This approach is being scaled up in South Africa through Xpert MTB/RIF Ultra testing for individuals starting antiretroviral therapy and annually thereafter. Clarity is needed on how Universal Xpert testing may affect TB preventive treatment (TPT) provision, and on whether TPT should be delayed until TB is ruled out. State-transition microsimulation. We simulated a cohort of South African patients being screened for TB while entering HIV care. We compared clinical and cost outcomes between four TB screening algorithms: symptom-based, C-reactive protein-based, and Universal Xpert testing with either simultaneous or delayed TPT initiation. Prompt TB treatment initiation among simulated patients with TB increased from 26% (24-28%) under symptom screening to 53% (50-56%) with Universal Xpert testing. Universal Xpert testing led to increased TPT uptake when TPT initiation was simultaneous, but to approximately 50% lower TPT uptake if TPT was delayed. Universal Xpert with simultaneous TPT prevented incident TB compared to either symptom screening (median 17 cases averted per 5000 patients) or Universal Xpert with delayed TPT (median 23 averted). Universal Xpert with Simultaneous TPT cost approximately $39 per incremental TPT course compared to Universal Xpert with delayed TPT. Universal Xpert testing can promote timely treatment for newly diagnosed people with HIV who have active TB. Pairing universal testing with immediate TPT will improve the promptness, uptake, and preventive effects of TPT. Simultaneous improvements to TB care cascades are needed to maximize impact.

The prognostic impact of monocyte fluorescence, immunosuppressive monocytes and peripheral blood immune cell numbers in HIV-associated Diffuse Large B-cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a high grade non-Hodgkin lymphoma which is common among immunodeficient people. Derangements of peripheral blood immune cells have been described to have a prognostic impact in DLBCL in high income countries, including a monocytosis, the ratios of lymphocytes to both monocytes (L:M) and neutrophils (N:L), as well as the numbers of regulatory T-cells (Tregs) and immunosuppressive monocytes (HLA-DRlow monos). To date, the impact of these variables has not been assessed in the setting of HIV-associated DLBCL (HIV-DLBCL), which is among the most common malignancies seen in people living with HIV. In this study, we assessed these factors in a cohort of South African patients with DLBCL and a high HIV-seropositivity-rate. In addition, we evaluated the prognostic value of monocyte activation (as reflected by monocyte fluorescence (MO-Y) on a Sysmex haematology analyser). This parameter has to date not been assessed in the setting of DLBCL. A full blood count and differential count as well as flow cytometry for HLA-DRlow monocyte and Treg enumeration were performed in patients with incident DLBCL referred to the Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa between November 2019 and May 2022. Additional clinical and laboratory data were recorded from the patient charts and laboratory information system. Seventy-six patients were included, of whom 81.3% were people living with HIV with a median CD4 count of 148 cells/ul. Most patients had advanced stage disease (74.8%) and were predominantly treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy (without Rituximab). At a median follow-up period of 19 months, the median survival time was 3.5 months, with a 12-month survival rate of 27.0%. All of the immune-cell-related variables (with the exception of the CD4 count) were similar between the people living with HIV and the HIV-negative individuals. In contrast to previous studies, a high monocyte count, the L:M and increased numbers of HLA-DRlow monocytes were not significantly associated with survival in HIV-DLBCL, while a neutrophilia (>8 x 109/L), the N:L (>6:1), high numbers of Tregs (≥5.17% of CD4s) and lymphopenia (<1.3 x 109/L) were. In addition, increased monocyte fluorescence (MO-Y >115.5) was associated with superior outcomes, which we speculate to reflect a more robust antitumour immune response among individuals with high levels of monocyte activation. On Cox Proportional hazard analysis, immune-cell factors independently associated with survival included a CD4 count <150 cells/ul and a neutrophilia. The monocyte count, L:M and the number of HLA-DRlow monos are not strong prognostic indicators in HIV-DLBCL, while a low CD4 count and neutrophilia are. Elevation of the MO-Y shows some promise as a potential biomarker of antitumour immunity; further study in this regard would be of interest.

Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis

BackgroundThis retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline.MethodsData were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months’ bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome.ResultsData were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment.ConclusionData from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk–benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.

Anterior Synostotic Plagiocephaly: A Quantitative Analysis of Craniofacial Features Using Computed Tomography.

The premature fusion of one coronal suture causes anterior synostotic plagiocephaly (ASP), which results in overt craniofacial dysmorphology that could be challenging to correct. This study aimed to document and compare the morphometry of the anterior cranial fossa (ACF), orbit, and ear on the ipsilateral (synostotic) and contralateral (nonsynostotic) sides in a select cohort of South African patients with ASP, using computed tomography (CT) scans. The dimensions of the ACF, orbit and the position of the ear on the ipsilateral and contralateral sides were measured using a set of anatomical landmarks on 2-dimensional CT scans of 18 consecutive patients diagnosed with nonsyndromic ASP. The differences between the ipsilateral and contralateral sides were calculated and expressed as a percentage of the contralateral side. All ACF parameters decreased significantly on the ipsilateral side when compared to the contralateral side, resulting in the volume of the ACF being the most affected (-27.7%). In terms of the orbit, on the ipsilateral side, the length-infraorbital rim, height, and surface area parameters increased significantly, with the height being the most affected (24.6%). The remaining orbital parameters (length-supraorbital rim, breadth and volume) decreased significantly, with the length-supraorbital rim parameter being the most affected (-10.8%). The ipsilateral ear was found to be displaced anteriorly (9.33mm) and caudally (5.87mm) from the contralateral ear. These measures may be useful to surgeons during corrective surgery by indicating the degree of the asymmetry on each side, making it easier to plan the technique and extent of surgical correction of the affected structures.

Intestinal fatty acid binding protein (I-FABP) and CXC3L1 evaluation as biomarkers for patients at high-risk for coeliac disease in Johannesburg, South Africa

Coeliac disease (CD) is an autoimmune disorder and one of the few gastroenteropathies with accurate serological testing. CD serology has decreased accuracy for patients on a gluten-free diet and for monitoring mucosal healing. New ancillary tests would, therefore, be useful. Intestinal Fatty Acid Binding Protein (I-FABP) and CX3CL1 (Fractalkine) are two promising biomarkers for CD but haven’t been examined in patients who are at a high-risk for CD such as patients with type one diabetes (TID). This study, therefore, aimed to investigate serum levels of I-FABP and CX3CL1 in a cohort of South African patients with TID at a high-risk of developing CD. The serum I-FABP levels were significantly higher in CD-positive patients compared to CD-negative individuals (p = 0.03). No significant differences in the serum CX3CL1 levels were detected although this may reflect the impact of the comorbid autoimmune diseases had on the serum CX3CL1 levels. In conclusion, this study is the first to assess the levels of these biomarkers in a multiethnic population with comorbid autoimmune disease and determined I-FABP to be the more promising biomarker in such clinical contexts. Future research should focus on a diverse biomarker panel and longitudinal follow-up of patients at a high-risk for CD.

Prevalence and Predictors of Abdominal Aorta Calcification in Patients With Psoriasis-A Case Control Study.

BackgroundPsoriasis is associated with a high prevalence of cardiovascular disease in Caucasians, but only a few studies from sub-Saharan Africa have investigated the prevalence of cardiovascular disease in patients with psoriasis. Abdominal aortic calcification (AAC) is a strong predictor of future cardiovascular events and all-cause mortality in the general population. We investigated the prevalence and risk factors for AAC in a predominantly non-Caucasian cohort of South African patients with psoriasis.MethodsA cross-sectional case-control study of adult psoriasis patients (n = 69) and controls (n = 80), matched for gender, ethnicity and body mass index, attending tertiary Dermatology and Rheumatology clinics in Johannesburg, South Africa. Demographic, anthropometric, clinical and biochemical data were recorded. All participants underwent non-contrast abdominal CT scans. Images were assessed for AAC at the supra-coeliac aorta, supra-mesenteric aorta and aortic bifurcation using Horos DICOM viewer software.ResultsAbdominal aortic calcification at any site was more prevalent in the psoriasis than control group (47.8% vs 22.5%, p < 0.005). The aortic bifurcation was the commonest site for AAC in both groups, but more prevalent in the psoriasis group (42.0% vs 21.3%, p < 0.005). The psoriasis group was also more likely to smoke, have hypertension and type 2 diabetes (56.5% vs 25.0%, p < 0.005; 72.0% vs 55.0%, p < 0.005; 24.6% vs 3.80%, p < 0.0005, respectively). Multivariable logistic regression analysis demonstrated that age, smoking and type 2 (T2DM) diabetes were independently associated with AAC (odds ratio (95% CIs): 1.16 (1.07, 1.20), 4.30 (2.15, 8.61) and 3.45 (1.09, 15.7) respectively), but psoriasis was not. Forward regression analysis demonstrated that smoking attenuated the association of psoriasis with AAC.ConclusionOur findings show AAC to be more common in psoriasis patients compared to controls. Age, T2DM and smoking were independent predictors of AAC. Smoking cessation is essential in psoriatic patients to reduce the risk of cardiovascular events. The clinical utility of AAC detection by CT imaging to risk stratify for hard cardiovascular outcomes needs to be explored.

TBIO-01. Mutation Profiling of Paediatric Solid Tumours in a Cohort of South African Patients

BACKGROUND: The incidence of childhood cancer incidence is increasing gradually in low-middle income countries, such as South Africa. Globally, there is an extensive range of familial- and hereditary-cancer syndromes, where underlying germline variants increase the likelihood of developing cancer in childhood. Next-Generation Sequencing (NGS) technologies have been key in determining the occurrence and genetic contribution of germline variants to paediatric cancer development. We aimed to design and evaluate a candidate gene panel, specific to inherited cancer-predisposing genes to provide a comprehensive insight into the contribution of germline variants to childhood cancer. METHODS: 32 paediatric patients (aged 0-18 years) diagnosed with a malignant tumour were recruited and biological samples were obtained. After quality control, DNA was sequenced using an ion Ampliseq 50 candidate gene panel design and Ion Torrent S5 technologies. Sequencing variants were called using Ion Torrent Suite software and were subsequently annotated using Ion Reporter and Ensembl's VEP. High priority variants were manually analysed using tools such as MutationTaster, SIFT-INDEL and VarSome. Putative identified candidates were validated via Sanger Sequencing. RESULTS: The patients studied had a variety of cancers, the most common being nephroblastoma (13), followed by osteosarcoma (4) and astrocytoma (3). We identified 10 pathogenic / likely pathogenic variants in 10 patients, most of which were novel. CONCLUSIONS: According to literature, we expected ~10% of our patient population to harbour pathogenic or likely pathogenic germline variants, however we reported about 3 times (~30%) more than we expected. Majority of the identified variants are novel; this may be because this is the first study of its kind in an understudied South African population

Undiagnosed disease program in South Africa: Results from first 100 exomes.

The Undiagnosed Disease Program in South Africa (UDP) sought to prospectively evaluate the clinical utility of exome sequencing (ES) in a phenotypically diverse, multi-ethnic cohort of South African patients with suspected rare genetic disorders. ES was undertaken in 100 sequential patients (93 singletons, 3 duos, and 4 trios) recruited to the UDP at Stellenbosch University. The data were analyzed through two separate bioinformatics pipelines (EVIDENCE from 3 billion and our in-house pipeline). A definitive diagnosis could be reached in 51% (51/100) patients, with 46% (46/100) patients having either pathogenic or likely pathogenic single-nucleotide variants/indels (SNVs/indels), and 5 patients with likely-pathogenic copy number variants (CNVs) (5/100). The CNVs were subsequently confirmed on microarray or MLPA analysis. Detailed phenotyping and HPO terms enabled analysis and variant identification. Twenty-five novel variants in 22 genes are reported here. We provide data from the first year of this UDP and show that even amongst mainly singletons from an understudied, diverse African population, ES is a valuable diagnostic tool, especially if it includes CNV analysis. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery.

A Profile and Three-Year Follow-Up of Patients with Basal Cell Carcinoma in the Western Cape, South Africa.

Background Basal cell carcinoma (BCC) is an important malignancy in sub-Saharan Africa. There is a paucity of data regarding BCC in South Africa. Aims To describe the clinicopathological features of patients presenting with BCC in a cohort of South African patients. Methods This retrospective descriptive study reviewed the medical records of 149 patients with BCC who attended the dermatology clinic at Tygerberg Academic Hospital from September 2015 to August 2016. Demographic and clinical data of those patients with histologically proven BCC were retrieved from clinical records. The data included the assessment for BCC recurrence after three years (September 2016–August 2019). Results Of 390 patients, 155 (39.7%) had histologically confirmed BCCs. Complete medical records were available for 149 of these patients, and most were male (55.7%) and white (85.9%) with a median age of 70 years. Most patients had their BCC lesions for 12 months (43.1%) before diagnosis. BCCs were mostly located on the head and neck area (58.1%). In most patients (72.0%), a diagnostic punch biopsy confirmed BCC. Plastic surgeons subsequently excised the BCC lesions in 74.0% of these patients. The most common histological subtype was nodular BCC (74.0%). The National Comprehensive Cancer Network (NCCN) risk of recurrence was approximately evenly distributed between high- (54.1%) and low-risk groups (45.9%). The major high-risk feature was the location (36.6%). Histologically confirmed BCC recurrence occurred in 9 of the 149 patients (3.7%) over three years. Conclusions BCC represents a high burden of disease in our setting. Compared to existing studies, the BCCs in this study are clinically and histologically similar to international reports.

Nodal disease predicts recurrence whereas other traditional factors affect survival in a cohort of South African patients with differentiated thyroid carcinoma

Background and aimInformation on patients with differentiated thyroid carcinoma in South Africa is limited. The objective of this study was to review demographics and tumour characteristics in a cohort of patients with differentiated thyroid carcinoma, presenting to Groote Schuur Hospital and evaluate risk factors for recurrence and survival.Patients and methodologyRetrospective demographic and clinical data were collected on all patients referred between January 2003 and December 2013. Prognostic factors for recurrence free survival and cancer specific survival were assessed using univariate and multivariate analyses.ResultsThe total number of patients was 231.The median age at presentation was 44 years and 82% were female patients. The pathological sub-types were papillary (60.6%), follicular (38.9%) and poorly differentiated (0.5%). Total thyroidectomy was performed in 191 patients and 30 patients required neck dissections. A total of 171 (74%) patients received 131Iodine. The recurrence free and cause specific survival rates at 10 years were 83 and 91%, respectively. Nodal disease at presentation was the only significant risk factor for recurrence (p < 0.001) on multivariate analysis. Significant risk factors for cause specific mortality were age ≥ 45 years (p = 0.006), follicular pathology (p = 0.004), extra-thyroid extension (p = 0.013) and residual tumour (p = 0.004).ConclusionsConsistent with international trends, patients with differentiated thyroid carcinoma treated at Groote Schuur Hospital had a favourable prognosis. The known risk factors associated with recurrence and survival in this South African cohort were consistent with those reported in developed countries.

The management and outcomes of Staphylococcus aureus bacteraemia at a South African referral hospital: A prospective observational study

ObjectivesData on the management and outcomes of Staphylococcus aureus bacteraemia (SAB) in resource-limited settings are limited. The aim of this study was to describe a cohort of South African patients with SAB, and explore the factors associated with complicated infection and death. MethodsThis was a prospective observational study of patients over the age of 13 years admitted to a South African referral hospital with SAB. ResultsOne hundred SAB infection episodes occurring in 98 patients were included. SAB was healthcare-associated in 68.4%; 24.0% of all cases were caused by methicillin-resistant S. aureus (MRSA). Ninety-day mortality was 47.0%, with 83.3% of deaths attributable to SAB. There was a trend towards increased 90-day mortality with MRSA infection (odds ratio (OR) 1.28, 95% confidence interval (CI) 1.0–15.1) and the presence of comorbidities (OR 4.1, 95% CI 1.0–21.6). The risk of complicated infection was higher with non-optimal definitive antibiotic therapy (OR 8.5, 95% CI 1.8–52.4), female sex (OR 3.8, 95% CI 1.1–16.3), and community-acquired infection (OR 7.4, 95% CI 2.0–33.1). Definitive antibiotic therapy was non-optimal in 22.6% of all cases. ConclusionsSAB-related mortality was high. A large proportion of cases may be preventable, and there is a need for improved antibiotic management.

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

AimsAcute intermittent porphyria (AIP) is a disorder of the haem biosynthetic pathway caused by mutations in the hydroxymethylbilane synthase (HMBS) gene. Knowledge of the spectrum of mutations present in South...

Clinical findings and genetic screening for copy number variation mutations in a cohort of South African patients with Parkinson's disease.

Parkinson's disease (PD), with a prevalence of up to 4% in Western countries, appears to be less common in Africa, possibly in part because of genetic factors. African studies investigating the genetic causation of PD are limited. To describe the clinical and genetic findings in a group of black South African patients with PD. All black African patients with PD from a tertiary hospital neurology clinic were examined. Symptoms were scored according to the Unified Parkinson's Disease Rating Scale (UPDRS), and patients were classified according to motor features. Genomic DNA was extracted and multiplex ligation-dependent probe amplification was used for detection of copy number variation (CNV) mutations in the known PD-causing genes. Sixteen patients were identified (ages 56 - 82 years). Three had a family history of PD. Classification into motor subtypes showed 44% mixed, 31% akinetic-rigid, and 25% tremor-dominant subtypes. UPDRS scores ranged from 7 to 88, with dementia in 20%. No patient had G2019SLRRK2and A30PSNCAmutations, and all except one had no CNV mutations in the known PD-causing genes. A female patient (age of onset 50 years, no family history) had aparkingene heterozygous deletion of exon 4. She had hyperreflexia, bilateral Hoffmann's reflexes, normal plantar responses and no dystonia. This group of black African patients showed similar characteristics to patients in Western studies, possibly with a higher proportion having tremor-dominant disease. Genetic analysis showed oneparkingene mutation. The limited knowledge on PD-causing genes and mutations in black populations warrants further studies involving next-generation sequencing approaches.

Exonic rearrangements in the known Parkinson’s disease-causing genes are a rare cause of the disease in South African patients

Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. To date, a number of PD-causing genes have been found, including SNCA, LRRK2, VPS35, PARK2, PINK1, DJ-1, ATP13A2, and most recently CHCHD2. Mutations in these genes range from point mutations to larger exonic rearrangements including deletions and duplications. This study aimed to detect possible copy number variation (CNV) in the known PD-causing genes in a cohort of South African patients with PD. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed on a total of 210 South African PD patients, and possible CNVs were verified using quantitative real time PCR. No homozygous or compound heterozygous exon rearrangements in the genes analysed were found in the patient group. A heterozygous PARK2 exon 4 deletion was found in a sporadic patient with an age at onset of 51 years. Sanger sequencing did not reveal any additional mutations in PARK2 in this patient. Combining our results with that of previous studies in a South African cohort, the frequency of exonic rearrangements in the known PD-causing genes is only 1.8% (8/439 patients). In conclusion, CNV in the known PD-causing genes are a rare cause of PD in a South African cohort, and there may be as yet unknown genetic causes of PD that are specific to patients of African ethnicity.

Risperidone-associated adverse drug reactions and CYP2D6 polymorphisms in a South African cohort

BackgroundContradictory information exists regarding the influence of CYP2D6 polymorphisms on adverse drug reactions (ADRs) (extrapyramidal symptoms (EPS) and weight gain) related to risperidone treatment. This prompted us to evaluate the influence of CYP2D6 genetic variation in a cohort of South African patients who presented with marked movement disorders and/or weight gain while on risperidone treatment. MethodsPatients who were experiencing marked risperidone ADRs were recruited from Weskoppies Public Psychiatric Hospital. As poor or intermediate metabolism was expected, comprehensive CYP2D6 sequence variations were evaluated using XL-PCR+Sequencing. ResultsNo statistically significant association was found between CYP2D6 poor metabolism and risperidone ADRs. An inverse relationship between EPS and weight gain was however identified. A novel CYP2D6 allele was identified which is unlikely to affect metabolism based on in silico evaluation. ConclusionCYP2D6 variation appeared not to be a good pharmacogenetic marker for predicting risperidone-related ADRs in this naturalistic South African cohort. Evaluation of a larger cohort would be needed to confirm these observations, including an examination of the role of potential intermediaries between the hypothesised genetic and clinical phenotypes.

Discovery of novel candidate urinary protein biomarkers for prostate cancer in a multiethnic cohort of South African patients via label-free mass spectrometry.

Improvement in diagnostic accuracy of prostate cancer (PCa) progression using MS-based methods to analyze biomarkers in our African, Caucasian, and Mixed Ancestry patients can advance early detection and treatment monitoring. MS-based proteomic analysis of pooled (N = 36) and individual samples (N = 45) of PCa, benign prostatic hyperplasia, normal healthy controls, and patients with other uropathies was used to identify differences in proteomics profile. Samples were analyzed for potential biomarkers and proteome coverage in African, Caucasian, and Mixed Ancestry PCa patients. A total of 1102 and 5595 protein groups and nonredundant peptides, respectively, were identified in the pooling experiments (FDR = 0.01). Twenty potential biomarkers in PCa were identified and fold differences ± 2SD were observed in 17 proteins using intensity-based absolute quantification. Analysis of 45 individual samples yielded 1545 and 9991 protein groups and nonredundant peptides, respectively. Seventy-three (73) proteins groups, including existing putative PCa biomarkers, were found to be potential biomarkers of PCa by label-free quantification and demonstrated ethnic trends within our PCa cohort. Urinary proteomics is a promising route to PCa biomarker discovery and may serve as source of ethnic-related biomarkers of PCa.

Clinical and genetic characterization of a founder PKHD1 mutation in Afrikaners with ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) occurs in 1:20,000 live births. Disease expression is widely variable, with approximately 30 % of affected neonates dying perinatally, while others survive to adulthood. Mutations at the PKHD1 locus are responsible for all typical presentations. The objectives of this study were to define the clinical and genetic characteristics in a cohort of South African patients of Afrikaner origin, a population with a high prevalence of ARPKD. DNA from the cohort was analyzed for background haplotypes and the p.M627K mutation previously identified in two unrelated Afrikaner patients. The clinical phenotype of the homozygous group was characterized. Analysis of 36 Afrikaner families revealed that 27 patients, from 24 (67 %) families, were homozygous for the p.M627K substitution, occurring on a common haplotype. The clinical phenotype of the homozygous individuals was variable. Our data provide strong evidence that the p.M627K substitution is a founder mutation in the Afrikaner population and can be used for streamlined diagnostic testing for at-risk pregnancies. The observed clinical variability suggests that disease expression is modulated by other genetic loci or by gene-environment interactions.

P-0143 - Gastrointestinal Stromal Tumours in a Cohort of South African Patients

Introduction: Gastrointestinal stromal tumours (GISTs) have not been extensively studied in African populations, which are known to possess great genetic diversity. As mutational status has been linked with clinical response to imatinib and altered mutational profiles may affect disease characteristics, it is important to document the disease profile in African patients. The aim of this study was to review a cohort of South African patients and assess patient and tumour characteristics and treatment outcome.