Browsing by Author "Heckmann, J M"

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    Open Access
    Incidence of seropositive myasthenia gravis in Cape Town and South Africa
    (2007) Bateman, K J; Heckmann, J M; Little, F; Schinkel, M
    Background. Myasthenia gravis (MG) is a treatable autoimmune disease characterised by fatiguable weakness of skeletal muscles. More than 85% of MG patients have antibodies to the acetylcholine receptor (AChR) at the neuromuscular junction or are seropositive for MG (SPMG). In the developed world the incidence of MG has increased, particularly among older individuals, but no epidemiological studies have been done on SPMG in Africa. Objectives. To determine the annual incidence rate (IR) of SPMG in the Cape Town (CT) municipality, and the crude annual IR of SPMG for the whole of South Africa (SA). Methods. Positive AChR antibody tests were identified between 1 January 2003 and 1 January 2005 for patients living in CT, and the age- and sex-specific incidences were calculated. To determine the national crude annual IR over the same period, positive assays were identified from the laboratories that process AChR assays for SA. National Census 2001 population statistics formed the denominators. Results. There were 65 positive assays in CT, and 230 nationwide. Based on these figures the annual IR for CT was 11.2 per million per year (95% confidence interval (CI) 8.7 - 14.3), and for South Africa 2.6 per million / year (95% CI 2.2 - 2.9). After a questionnaire response from CT neurologists regarding the routine use of the AChR antibody assay, the annual IR for CT was adjusted to 12.6 per million (95% CI 9.9 - 15.9) to incorporate those presumed to have SPMG without a confirmatory test. In CT, the IR in females was 15.3 per million / year (95% CI 11.2 - 20.4), and in males, 6.8 per million / year (95% CI 4.1 - 10.7). The CT IRs for blacks, coloureds and whites were not statistically different after adjusting for age and gender. The IR of SPMG in CT was 6 times greater in those presenting after the age of 50 years than in those with earlier disease onset (95% CI 3.7 - 9.7). Conclusions. The annual IR of SPMG in CT is much the same as rates recorded recently in other developed countries, but the rest of SA has a much lower IR. A preponderance of MG starting after the age of 50 years reflects a worldwide trend, although the CT data showed a relatively lower-than-expected incidence for older males. IRs for SPMG vary widely in different regions in SA; this is likely to be related to differences in regional health care delivery, and underdiagnosis.
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    Investigating the functionality of candidate susceptibility genes in ophthalmoplegic myasthenia gravis using patient-derived material
    (2019) Moyakhe, Lihle Bayavuya; Heckmann, J M; Nel, M; Prince, Sharon
    Ophthalmoplegic myasthenia gravis (OP-MG) is a subphenotype of an autoimmune disease, myasthenia gravis (MG). This subphenotype described by our group is characterised by extraocular muscle (EOM) weakness which does not respond to standard immunosuppressive therapy whilst the non-ocular muscles do respond to treatment. OP-MG predominantly affects patients of African genetic ancestry and most commonly those with juvenile-onset. The cause of OP-MG is unknown. Previously, in efforts to understand the pathophysiology of this subphenotype, whole-exome sequencing was undertaken which identified amongst others a putatively functional multi-allelic deletion in the 5’ untranslated regulatory region of the ST8SIA1 gene. The most frequent deletion was c.-477_475 delCCC. The first aim of this thesis was to assess the functionality of this variant. To this end, in vitro promoter-reporter assays were performed after the delCCC deletion (MT) was created by site-directed mutagenesis of the wild-type (WT) promoter. Transient transfection assays showed that basal promoter activity of the MT promoter was lower than the WT promoter in the human fibroblast cell line (HT1080, p=0.031) but not in a mouse myoblast cell line (C2C12, p=0.33). Next, gene expression analysis was performed in opportunistically sampled orbital fibroblasts (n=5 controls, n= 2 OP-MG) and the endogenous expression levels of ST8SIA1 was determined under basal conditions and following treatment with homologous MG sera to mimic MG conditions. Although there was no significant difference in the basal ST8SIA1 expression levels in OP-MG ocular fibroblasts when compared to the control ocular fibroblasts (p=0.091), there were significantly lower ST8SIA1 expression levels in OPMG ocular fibroblasts in response to MG sera (p=0.024). Previous work by others also identified two other African specific gene variants in IL6R and TGFB1 which associated with OP-MG and in which luciferase reporter work showed functional implications. This thesis conducted the first examination of the endogenous expression levels of these genes in patientderived ocular fibroblasts. There was no difference in TGFB1 expression levels between OP- MG and control ocular fibroblasts under basal conditions or following treatment with MG sera (p>0.3). However, IL6R expression showed a similar trend to the luciferase reporter assays results in HT1080 cells. Both the OP-MG ocular fibroblasts tested harboured the 3’UTR IL6R c.*3043T>C variant, which was predicted to alter a putative miRNA binding site and showed a trend towards repression of IL6R expression in response to MG sera (p=0.083). In conclusion, although faced with the scarcity of sample tissue, we were able to use patient-derived ocular fibroblasts to validate previous genetic association studies and in vitro assays. Although the ocular fibroblasts are not EOM, they are both specialised tissue existing in the same microenvironment. Since MG sera modulate the expression of ST8SIA1 and IL6R differently between OP-MG and controls, our findings suggest that these genes may play a role in the OP-MG pathogenesis. Larger sample sizes are required for a more accurate representation of endogenous gene expression within these cell lines as the sample size is a factor when determining the significance of data. This is, however, a challenge due to the scarcity and unavailability of EOM for cell culture.
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    Neuropsychiatric symptoms in patients with thymoma-associated and non-thymoma myasthenia gravis
    (2014) Freeman, C; Lewis, I G S; Heckmann, J M
    Background. Around 10 - 15% of patients with myasthenia gravis (MG) have a thymoma, and non-motor symptoms are more frequent in these patients. We hypothesised that neuropsychiatric symptoms would also be more frequent. Methods. A cross-sectional study of 30 consecutive MG patients attending a clinic at Groote Schuur Hospital, Cape Town, South Africa, was done over a 6-month period in 2010. Each patient underwent a series of single-blinded neuropsychiatric assessments, including the 16-item, self-reported Flanagan Quality of Life (QOL) scale, the Beck Depression Inventory second version, the Young Mania Rating Scale, the Hamilton Anxiety Rating Scale and the Brief Psychiatric Rating Scale (BPRS). Results. The frequency and nature of neuropsychiatric symptoms were similar between thymoma (n=9) and non-thymoma (n=21) MG patients. Symptoms of moderate or severe depression and anxiety were present in around 30%. The severity of depression symptoms correlated with MG severity. Prednisone dosing was not associated with neuropsychiatric symptoms or QOL scores. Those with longer duration of MG were more likely to have higher scores on the BPRS and anxiety scales. Those with younger-onset MG had higher BPRS scores and a tendency to suicidal behaviour. Conclusion. Although no association with thyoma was found, this study shows that neuropsychiatric conditions may be underdiagnosed in patients with MG. Systematic depression screening should be done at outpatient clinics, particularly for those who developed symptoms at a young age, those with severe disease and those with a long duration of illness.