Apparently, I’m Really Old
I was (not greatly but bemused) surprised that some of my health providers didn’t know what my condition was – it’s that rare. 14 – 20 in 100,000 (I had previously been told 1 in 100,000 and just read this).
NIH just published something in 2019, which is good to see.
Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture
“Myasthenia gravis (MG; from Greek: myos = muscle, asthenos = weakness, and Latin: gravis = severe)”
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies’ pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.
1. Clinical Aspects of Myasthenia Gravis
Myasthenia gravis (MG; from Greek: myos = muscle, asthenos = weakness, and Latin: gravis = severe) is an autoimmune disease of the neuromuscular junction (NMJ), and is considered a classic example of an antibody-mediated autoimmune disease. MG is a rare disorder, with an estimated prevalence of 70–163 per million for acetylcholine receptor (AChR) MG, and around 1.9–2.9 per million for muscle specific kinase (MuSK) MG [1,2,3]. Women are more often affected than men, with a female to male ratio of 3:1 for AChR MG and a ratio of 9:1 for MuSK MG . The characterizing symptom is fatigable skeletal muscle weakness. Initial weakness often affects only ocular muscles, manifesting as ptosis (hanging of the eyelid) or diplopia (double vision). Most patients progress to generalized weakness, e.g., of limb muscles, within the first two years after disease onset. Other muscles that can be involved are bulbar muscles, which are necessary for speaking (leading to dysarthria), chewing and swallowing (causing dysphagia). Respiratory muscles can also be affected in up to 20% of cases with AChR MG, leading to a myasthenic crisis where patients need to be ventilated artificially. AChR MG can be further divided into several subgroups (see also Table 1): (1) Early-onset MG (EOMG) defines patients with an age of onset below 50 years, and are predominantly females with an onset in the 2nd and 3rd decade, frequently present with thymic hyperplasia; (2) late-onset MG (LOMG) with a higher fraction of male patients, often with an additional presence of striational antibodies; (3) thymoma-associated MG (TAMG), which affects approximately 10% of AChR MG patients; (4) ocular MG (OMG) with predominantly ocular symptoms; and (5) fetal or neonatal forms in which maternal autoantibodies pass the placenta. The passive transfer of antibodies against the adult AChR towards the fetus leads to a mild form of transient MG that passes weeks after birth. The symptoms include hypotonia, impaired sucking, swallowing, and breathing. Patients go into remission after days to months [5,6,7]. Antibodies against the fetal form of the AChR cause severe developmental defects and are a cause of arthrogryposis multiplex congenita [8,9,10,11].
|MG Subgroup||Clinical Characteristics||Antigen||Thymus Pathology||IgG Subclass|
|Early onset MG (EOMG)||Age of onset <50, sex ratio (F:M) 3:1, genetic association with HLA-B8, A1, and DRw3||AChR||Thymic lymphofollicular hyperplasia||IgG1, IgG|
|Late onset MG (LOMG)||Age of onset >50, sex ratio (F:M) 1:1.5, genetic association with HLA-A3, B7, and DRw2||AChR||Normal thymus (age-related thymus atrophy)||IgG1, IgG3|
|Thymoma associated MG (TAMG)||Paraneoplastic MG, non-pathogenic antibodies against striated muscle, titin, ryanodine receptor||AChR||Thymoma||IgG1, IgG3|
|Ocular MG (OMG)||Restricted to ocular muscles, low AChR titres||AChR||Variable, no lymphoid follicles||IgG1, IgG3|
|MuSK MG||Severe phenotype, respiratory, and bulbar muscle weakness, sex ratio (F:M) up to 9:1, genetic association with HLA-DR14-DQ5||MuSK||Normal thymus||IgG4|
|Lrp4 MG||Mild phenotype, sex ratio (F:M) 2.5:1||Lrp4||Variable (normal, thymoma, thymic lymphofollicular hyperplasia)||IgG1, IgG2|
|Agrin MG||Generalized weakness, often also additional AChR, MuSK, or Lrp4 antibodies, associated with severe weakness||Agrin||No thymoma (few studies)||N/A|
|Transient neonatal MG (TNMG)||Mild symptoms, onset at birth, remission after days to months||AChR, MuSK||maternal IgG|
|Fetal myasthenia gravis||Reduced fetal mobility, arthrogryposis congenital (AMC), very severe, risk of fetal death||Fetal AChR γ subunit||maternal IgG|
A diagnosis of MG is primarily based on the observation of fluctuating skeletal muscle weakness. Initially, the patients often present with ocular muscle weakness with ptosis and diplopia that is not associated with sensory deficits. The diagnosis is then verified by (1) testing the serum for the presence of known myasthenic autoantibodies (discussed in Section 7 in more detail), (2) electrophysiological tests including single-fiber electromyography (SFEMG), and repetitive nerve stimulation (RNS), and (3) inhibition of acetylcholinesterase (AChE) e.g., with pyridostigmine or ice pack test, which usually improves the symptoms [12,13,14,15]. Although this is not a clinical review (excellent reviews focusing on clinical aspects and diagnosis can be found here: [16,17,18,19]), we would like to briefly discuss the electrophysiology of the NMJ in MG and its relevance for disease diagnosis.