Myasthenia gravis with antibodies to muscle-specific kinase

133 Pages·2012·5.45 MB·English

Cover Page

The handle http://hdl.handle.net/1887/20412 holds various files of this Leiden University
dissertation.

Author: Niks, E.H.
Title: Myasthenia gravis with antibodies to muscle-specific kinase : clinical
characteristics, epidemiology, and immunological aspects
Issue Date: 2013-01-17
Myasthenia gravis with antibodies
to muscle-specific kinase
Clinical characteristics, epidemiology, and immunological aspects
Erik H. Niks
ISBN: 978-94-6108-377-7
Lay-out and printing by Gildeprint Drukkerijen - Enschede, the Netherlands
Cover image: parasternal intercostal muscle biopsy from a MuSK MG patient, showing
increased branching of intramuscular nerves compatible with nerve sprouting.
Part of this material is reproduced with permission from Elsevier Ltd., BMJ Publishing
Group Ltd., John Wiley and Sons, and Wolters Kluwer Health.
This research project was supported by a grant of the Prinses Beatrix Fonds (project number
MAR02-0110)
Myasthenia gravis with antibodies
to muscle-specific kinase
Clinical characteristics, epidemiology, and immunological aspects
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof. mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties
te verdedigen op donderdag 17 januari 2013 klokke 15:00 uur
door
Erik Harmen Niks
geboren te Veenendaal
in 1972
Promotiecommissie
Promotor: Prof. dr. J.J.G.M. Verschuuren
Co-promotor: Dr. M.J.D. van Tol
Overige leden: Prof. dr. J.B.M. Kuks, Universitair Medisch Centrum Groningen
Prof. dr. J.G. van Dijk
Em. prof. dr. A.R. Wintzen
Contents
Chapter I General introduction 7
Chapter II Epidemiology of myasthenia gravis with anti-muscle-specific 19
kinase antibodies in the Netherlands
Chapter III Clinical comparison of myasthenia gravis subtypes reveals 27
predominant limb-girdle and extraocular muscle weakness in
seronegative patients
Chapter IV Strong association of MuSK antibody-positive myasthenia gravis 45
and HLA-DR14-DQ5
Chapter V Clinical fluctuations in MuSK myasthenia gravis are related to 51
antigen-specific IgG4 instead of IgG1
Chapter VI No auto-antibodies against synaptic ErbB in seronegative 65
myasthenia gravis
Chapter VII A transient neonatal myasthenic syndrome with anti-MuSK 77
antibodies
Chapter VIII Pre- and postsynaptic neuromuscular junction abnormalities in 83
MuSK myasthenia
Chapter IX Summary, discussion and future perspectives 95
Nederlandstalige samenvatting 103
Chapter X Appendices

- List of abbreviations 109
- List of publications 111
- Curriculum Vitae 115
- Dankwoord 117
- References 119

I
General introduction
Chapter I
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General introduction
Introduction to myasthenia gravis R1
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Myasthenia gravis (MG) is one of the best characterised neuromuscular or autoimmune R3
disorders. The Greek words myos (muscle) and asthenos (weakness) refer to the presence of R4
pure motor weakness that can affect extraocular, bulbar, axial and limb muscles. Myasthenic R5
weakness is characterised by its fluctuating nature and fatigability. When symptoms are R6
restricted to ophthalmoparesis and ptosis, MG is classified as ocular MG (OMG). Weakness R7
in other muscles is termed generalised MG (GMG). Thomas Willis was probably the first to R8
describe a myasthenic patient in his book “De Anima Brutorum” from 1672. He described a R9
“prudent and honest woman” suffering from fluctuating weakness in the arms and legs, but R10
also from compromised articulation. 1 R11
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“For some time she can speak freely and readily enough, but after long, hasty or R13
laborious speaking she is not able to speak a word, but becomes mute as a fish and R14
does not recover till after an hour or two” R15
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It cannot be proven, nor ruled out, that this was in fact the first patient described with R17
autoantibodies to muscle-specific kinase (MuSK), one of the key elements in neuromuscular R18
signal transmission, as will be highlighted in this thesis. By the end of the 19th century, R19
Wilhelm Erb and Samuel Goldflam provided a detailed description of the disease in which R20
ptosis and ophthalmoparesis frequently occur as first symptoms, followed by weakness of R21
chewing, swallowing and speaking, with a further spread towards neck and limb muscles. R22
The clinical hallmark of MG is the fluctuating character of the weakness, becoming worse R23
upon sustained movement and by the end of the day. 2,3 In 1934, Mary Walker reported a R24
temporary improvement of facial weakness in an MG patient after subcutaneous injections R25
of physostigmine. By then, it was known that physostigmine inhibited the breakdown of R26
the neurotransmitter acetylcholine (ACh). Together with the discovery of the role of ACh in R27
neuromuscular signal transmission by Dale and Feldberg in that same year, the pathology R28
of MG was thought to be a curare-like poisoning of the “motor end-organs or myoneural R29
junctions”. 4,5 The first description of histological malformation of the neuromuscular R30
junction (NMJ) in MG patients was made by Coërs and Desmedt in 1959. 6 In 1960, after R31
having studied 440 MG cases, the Scottish neurologist Simpson postulated the still current R32
autoimmune hypothesis of the mechanism of MG, based on observations including thymic R33
hyperplasia and occasional transfer of the disease from a mother to her newborn child during R34
the first weeks of life. He also acknowledged a genetic susceptibility for immunological R35
disorders such as systemic lupus erythematosus in patients and thyroid disease in their R36
relatives. 7 In 1976, the biochemist Lindstrom induced antibodies as a coincidental side-effect R37
of his studies in rabbits injected with the postsynaptic acetylcholinereceptor (AChR) derived R38
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