Browsing by Author "Moremi, Kelebogile E."

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    Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing
    (Elsevier, 2019-06) Van Rensburg, Susan J.; Peeters, Armand V.; Van Toorn, Ronald; Schoeman, Johan; Moremi, Kelebogile E.; Van Heerden, Carel J.; Kotze, Maritha J.
    Background: Multiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron. Methods: Whole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers. Results: WES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients. Conclusion: Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria.
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    Pathology-supported genetic testing presents opportunities for improved disability outcomes in multiple sclerosis
    (2023-05-17) Johannes, Clint; Moremi, Kelebogile E.; Kemp, Merlisa C.; Whati, Lindiwe; Engel- Hills, Penelope; Kidd, Martin; van Toorn, Ronald; Jaftha, Mariaan; Janse van Rensburg, Susan; Kotze, Maritha J.
    Background: Lipid metabolism may impact disability in people with multiple sclerosis (pwMS). Methods: Fifty-one pwMS entered an ultrasound and MRI study, of whom 19 had followed a pathology- supported genetic testing program for more than 10 years (pwMS-ON). Genetic variation, blood biochemistry, vascular blood flow velocities, diet and exercise were investigated. Results: PwMS-ON had significantly lower (p < 0.01) disability (Expanded Disability Status Scale) than pwMS not on the program (1.91 ± 0.75 vs 3.87 ± 2.32). A genetic variant in the lipid transporter FABP2 gene (rs1799883; 2445G>A, A54T) was significantly associated (p < 0.01) with disability in pwMS not on the program, but not in pwMS-ON (p = 0.88). Vascular blood flow velocities were lower in the presence of the A-allele. Conclusion: Pathology-supported genetic testing may provide guidance for lifestyle interventions with a significant impact on improved disability in pwMS. Plain Language Summary This study investigated the role of a genetic variant that increases saturated fat absorption and may make people with multiple sclerosis (MS) more susceptible to disability progression. Of 51 people with MS, 19 had followed a program which includes normalization of blood test results and daily intake of unsaturated fatty acids for more than 10 years, while the others had not. The latter group had significantly greater disability than the people who had followed the program, suggesting that the unsaturated fatty acids modulated the effect of the genetic variant. Six MS cases are presented as examples, including a marathon athlete (Case 1) and a patient who showed a dramatic decrease in disability from being wheelchair-bound for 15 years to walking freely (Case 2). Executive Summary: • In order to investigate the conundrum of why some people with multiple sclerosis (pwMS) become disabled while others do not, a cross-sectional interdisciplinary study was initiated from 1996 to the present at Stellenbosch University, to record data into a database regarding genetic variations, blood biochemistry, diet and exercise. Pathology-supported genetic testing (PSGT), a practical method to apply personalized medicine, was implemented to elucidate potential modulation of genetic variations through lifestyle interventions toward prevention of disability in pwMS. • The Gknowmix.org database is used to translate information obtained from a comprehensive study into personalized reports containing guidelines for treatment of pwMS by clinicians and supporting healthcare professionals, which enables P4 medicine: participatory (patient), personalized (scientist), predictive (clinician) and preventive (dietitian). • In the present case–control sub-study, 51 pwMS and 25 controls volunteered for an ultrasound and MRI study. Of these pwMS, 19 had followed the PSGT lifestyle program for more than 10 years, which included normalization of blood biochemistry, dietary intervention and exercise, as well as daily intake of specific supplements (the Rapha Regimen) [3], including unsaturated fatty acids (omega-3 and evening primrose oil). • The 19 pwMS who had followed the program had significantly less disability (p < 0.01), as assessed with the Expanded disability status scale (EDSS), than those who had not followed the program (1.91 ± 0.75 vs 3.87 ± 2.32). Furthermore, in the pwMS who had not followed the program, a genetic variant of a lipid transporter which favors increased absorption of saturated fatty acids, FABP2 rs1799883 (2445G>A, A54T), was associated significantly (p < 0.01) with the EDSS, while in the pwMS who had followed the program there was no association (p = 0.88). There was no difference in allele frequency between pwMS and controls. • Ultrasound assessments showed that higher blood flow velocities in the right common carotid arteries and vertebral arteries were significantly associated with improved EDSS, while the FABP2 rs1799883 variant was associated with decreased blood flow. • In the pwMS, homocysteine was significantly inversely associated with folate intake (p < 0.01). In the controls, saturated/trans fat intake was significantly associated with BMI (p < 0.01). • Six MS cases selected randomly are presented to demonstrate how data integration was instrumental in elucidating how dietary unsaturated fat intake may modulate the effect of FABP2 rs1799883 toward prevention of disability in pwMS who followed the PSGT protocol over more than 10 years. Of these, Case 1 is a marathon athlete, and Case 2 showed a dramatic decrease in EDSS from 7.5 to 2.0 over more than 10 years.
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    Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics
    (Frontiers Media S.A, 2021-09) Mampunye, Lwando; Van der Merwe, Nerina C.; Grant, Kathleen A.; Peeters, Armand V.; Torrorey-Sawe, Rispah; French, David J.; Moremi, Kelebogile E.; Kidd, Martin; Van Eeden, Petrus C.; Pienaar, Fredrieka M.; Kotze, Maritha J.
    Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.