treatment resistant ophthalmoplegia in myasthenia gravis
TRANSCRIPT
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Treatment–resistant Ophthalmoplegia in Myasthenia Gravis
Jeannine HeckmannNeurology DivisionUniversity of Cape TownSouth Africa
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Mathilda Karel Spak (1901 – 2005)
Founder of MGFC
Mother had MG symptoms x 20 yrs
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Phenotype of OP-MG
Histology
"Genotype"
Dynamic studies
Hypothesis of OP-MG pathogenesis
Treatment-resistant ophthalmoplegia in MG (OP-MG)
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Ave annual incidence rate by age at symptom onset 2011-2012 overall ~9 /million/year
men
women
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Subgroup of AChR ab+ MG patients
• Treatment resistant ophthalmoplegia• Juvenile onset MG• African genetic ancestry
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Postulate: Gene variant(s) have no consequence without MG –
however, MG triggers dysregulation in vulnerable EOMs
African Genetic ancestry in South Africa – racial categories in census
Indigenous black SA
Cape mixed African
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Black Africans: colour-coded ancestral gene clusters
West African East African SA
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SA hunter gatherer genomes most diverse-oldest known lineage of modern humans
genome diversity - KhoiSan octogenarians
>13,000 novel amino acid variants
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Cape mixed-African: 400 yrs – mainly Khoisan
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Delayed onset: EOMs initially responded to therapy and then a critical event triggered OP-MG
Immediate onset: EOMs treatment-resistant from diagnosis while remaining muscles respond
AAO-3 MGFA 2A
MGFA 3A MGFA 5 MGFA 5
MGFA 3BMGFA 4B
AAO-12AAO-2 AAO-16
AAO-17 AAO-28
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Every clinic visit: Ophthalmoplegia + MG composite score
Important to document the ophthalmoplegia objectively
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How frequently do we see OP-MG in the clinic?
• Defined as treatment-resistant ophthalmoplegia > 2 yrs• Self categorized by race
African genetic ancestry are younger
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2007-2017
13 OMG; 74 GMG• Observational• BL weak EOMs• 1st 12 months Rx
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Earlier and “aggressive” immune therapies associated with resolution of ophthalmoparesis
<12 mo symptoms + immune therapy/pred. 2x > chance of resolutionMedian resolution early rx group – 4 mo.
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MGFA gr3b : Bilat. ophthalmoparesis x 3 yrs
Control: Stabbed & blind/sensory squint x 3yr
Paralysed medial rectus MG vs control
Z line streamingSubsarcolemmal mitoch.Abnormal mitoch.
OP-MG
OP-MG Control
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Neurogenic changesAtrophy of type IIMitochondrial stress
Poor muscle force & contractility
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PCA plot –2 subpopulations segregate but not OP-MG vs control MG
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P< 1x10-5
P< 1x10-3
Manhatten plot of GW single gene variant association OP-MG vs control MG
Subthreshold analysis: Top 2 ranked regulatory variants in gene promoters - expressed in muscle3x more frequent in Africans > Europeans
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• Unbiased
• Gene-based association analysis of collective putative functional variant burden in genes in OP-MG vs cntrl MG p< 0.015
• Ranked according to GTEx expression level in skeletal muscle
+ Muscle atrophy
+ integrity Myosin HC
Transcripts per million in skeletal muscle
- Satellite cell act.
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MyoDadenovirus
48 hrs
Primary dermal fibroblasts
AdMyoD-myocytes
Figure adapted from C.F. Bentzinger et al. Cold Spring Harb Perspect Biol 2012
Gene expression? Patient-derived myoblast cultures
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homologous 5% MG sera x 24 hrs
OP-MG (10) vs control MG (6)
Gene pair expression levels correlate in nodes (r>0.9; FDR <0.01)
Gene expression array
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Surrogate OP-MG muscle model: dysregulated ‘myocyte’ gene expression
suggests functional relationship
• 50% OP-MG genes correlated with 40% MG/EAMG genes • IGF1/AKT pathway –atrophy [EOMs]
• pathway not previously considered relevant in MG correlate with MG/EAMG pathways• Myogenesis & satellite cell activation
• Gangliosphingolipid & glycoprotein synthesis• Integrity of muscle endplate
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Mitochondrial stress
EAMG muscles
Histopathology in MG
MGS induced mito. metabgenes in muscle model
vs Non-paralytic strabismus
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* p<0.01 **p<0.001
Metabolic assay: Oc-fibro cultures: 2 OP-MG vs 5 controls
Similar basal OCR and response to “stressor mix”
MG sera induced > energetic phenotype in OP-MG (3x)
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Glucose & Glycolysis
*
*
Pathogenesis
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Genetic studiesOP-MG vs cntrl MG*
Dynamic studiesMG sera
Gene expression
MG muscleModel*
Ocular Fibro **
Orbic. Oc**
Gene CD55, TGFB1 -/✓ ?
WGS Muscle atrophy ✓ ?
Mitochondrial metab ✓ ✓ ?
Muscle regeneration ✓ ?
2 ‘muscle’ genes? ?
** vs strabismus cntrl
Histology suggests poor contractility critical in EOMs
SUMMARY
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• Melissa Nel
• Tarin Europa
• Mariba Lebeko
• Robyn Rautenbach
• Lihle Moyakhe
• Sharon Prince
• Nicola Mulder
• Mpopi Lenake (ophthalmologist)
• Tony Murray (ophthalmologist)