Myasthenia gravis in South Africans: Racial differences in clinical manifestations

Heckmann, Jeannine M; Owen, Elizabeth; Little, Francesca

doi:10.1016/j.nmd.2007.07.002

Cited by 63 publications

(89 citation statements)

References 26 publications

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“…39 Thus, the effect of the c.-198C4G SNP on DAF regulation during the autoimmune response in a compartment such as the EOM may occur at both complement and T-cell modulation levels. Reviewing the clinical data on our cases developing the severe ocular phenotype, 17 it was evident that persistent non-fatigable EOM pareses often only developed months into the MG disease process, suggesting that it was dependent on a critical factor(s) additional to the autoantibody-mediated immune response.…”

Section: Discussionmentioning

confidence: 89%

“…At diagnosis, most MG patients had paresis of at least one EOM that, in the majority, subsequently resolved on immunosuppressive therapy. 17 However, during the MG disease course and on immunotherapy, patients of African ancestry were more likely to develop dysfunction of at least one EOM (26.5%; 95% CI: 18.6, 35.7) compared with Whites (15.2%; 95% CI: 5.8, 30.4), with an even greater racial disproportion when those with pareses of five or more EOMs are categorized (20.6 vs 9.1%, respectively) ( Table 1). Of the 30 subjects with more than one EOM paresis, only 1 had ocular MG (complete ophthalmoplegia previously described 17 ), 3 were seronegative (and MuSK negative) and 1 had concomitant thyroid disease (excluded from analysis).…”

Section: Clinical Datamentioning

confidence: 99%

“…Those with complete ophthalmoplegia also had bilateral ptosis at rest. 17 Supplementary Figure 1 shows the distribution of EOM dysfunction in those with African ancestry compared with those without; all the subjects with pareses of X5 EOMs had at least unilateral ptosis at rest and those with pareses of X9 EOMs also had bilateral ptosis.…”

Section: Clinical Datamentioning

confidence: 99%

“…17 Observational data were collected at each clinic visit. Owing to a high proportion of EOM dysfunction noted in our patients, a grading system for scoring limitation of EOMs was introduced to quantify the number of EOMs showing limitation of movement; 17 Supplementary Figure S1 denotes the number of individuals with EOM paresis at rest (excluding those whose EOM show fatigability). EOM paresis scoring was carried out before and independent of genotyping.…”

Section: Patientsmentioning

confidence: 99%

“…2,15 From clinical observations, a larger proportion of South African (SA) subjects with African genetic ancestry (either indigenous Black African (Black) or mixed ancestry (M/A)) were noted to develop severe myasthenic extraocular muscle (EOM) dysfunction (including levator palpebrae muscles); almost half of these patients only developed this ocular phenotype while receiving standard immunosuppressive therapy, with the remaining MG signs responding appropriately to therapy. 17 DAF provides substantial complement protection for eye tissues, 18 and as the expression of DAF in the EOMs of mice is substantially lower than other skeletal muscle allotypes, 14,19 we reasoned that MG patients developing severe EOM damage may have lower background or inducible DAF expression.…”

Section: Introductionmentioning

confidence: 99%

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A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C4G SNP (odds ratio ¼ 8.6; P ¼ 0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5 0 -flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C4G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.

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Section: Discussionmentioning

confidence: 89%

Section: Clinical Datamentioning

confidence: 99%

Section: Clinical Datamentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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Racial differences in myasthenia gravis in Alabama

Morgan

Liang

et al. 2009

Muscle and Nerve

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Demographic, clinical, and laboratory features were compared in 235 white and African-American (AA) patients with myasthenia gravis (MG) at the University of Alabama at Birmingham Neuromuscular Disease Clinic from May 2003 to January 2008. Seventy nine percent of patients were white. Acetylcholine receptor antibody was positive in 71% of white patients and in 59% of AA. In patients with seronegative generalized MG, the rate of positive muscle-specific tyrosine kinase antibody (MuSK-Ab) was significantly higher in AA than it was in whites (50% in AA vs. 17% in whites). Ocular MG was seronegative in 75% of AA patients. In AA, MG occurred earlier and more frequently in females, whereas, in whites, disease onset was later and more common in males. Another significant difference was a higher percentage of abnormality on repetitive nerve stimulation in AA. There was also a tendency for more severe forms of MG in AA. There are racial differences in MG between whites and AA in Alabama. These racial differences highlight the need to study biological factors in the pathogenesis of MG and to assess different approaches in diagnosis and treatment.

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Incidence of acetylcholine receptor‐antibody‐positive myasthenia gravis in South Africa

Busisiwe

Lesosky

Liebenberg³

et al. 2015

Muscle and Nerve

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Myasthenia gravis in South Africans: Racial differences in clinical manifestations

Cited by 63 publications

References 26 publications

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Racial differences in myasthenia gravis in Alabama

Incidence of acetylcholine receptor‐antibody‐positive myasthenia gravis in South Africa

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