The Increasing Genetic and Phenotypical Diversity of Congenital Myasthenic Syndromes

Grace McMacken; Angela Abicht; Teresinha Evangelista; Sally Spendiff; Hanns Lochmüller

doi:10.1055/s-0037-1602832

Neuropediatrics, Inhaltsverzeichnis

Neuropediatrics 2017; 48(04): 294-308
DOI: 10.1055/s-0037-1602832

Review Article

Georg Thieme Verlag KG Stuttgart · New York

The Increasing Genetic and Phenotypical Diversity of Congenital Myasthenic Syndromes

Grace McMacken

¹The John Walton Muscular Dystrophy Centre, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

,

Angela Abicht

²Medizinisch-Genetisches Zentrum, Munich, Germany

,

Teresinha Evangelista

¹The John Walton Muscular Dystrophy Centre, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

,

Sally Spendiff

¹The John Walton Muscular Dystrophy Centre, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

,

Hanns Lochmüller

¹The John Walton Muscular Dystrophy Centre, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom

› Institutsangaben

Abstract

The congenital myasthenic syndromes (CMS) are a diverse group of diseases, which result in an increasing range of phenotypes, but which are all due to inherited defects at the neuromuscular junction (NMJ). Although some patients remain genetically undiagnosed, our ability to identify the causative genes has shed new light on the role of previous uncharacterized proteins at the NMJ. Securing the genetic diagnosis can be challenging, but it is of critical importance to allow rational therapeutic intervention. In this review, we summarize the key clinical and pathologic features of the CMS subtypes, outline diagnostic clues, and challenges, and describe the recent advances that have highlighted the overlap between CMS and the muscular dystrophies and peripheral neuropathies.

Keywords

congenital myasthenic syndromes - neuromuscular junction - genetic diagnosis - neurophysiology

Volltext

Referenzen

References
1 Müller JS, Mihaylova V, Abicht A, Lochmüller H. Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev Mol Med 2007; 9 (22) 1-20
2 Engel AG, Shen X-M, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 2015; 14 (04) 420-434
3 Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog Neurobiol 2001; 64 (04) 393-429
4 Arredondo J, Lara M, Ng F. , et al. COOH-terminal collagen Q (COLQ) mutants causing human deficiency of endplate acetylcholinesterase impair the interaction of ColQ with proteins of the basal lamina. Hum Genet 2014; 133 (05) 599-616
5 Slater CR. Reliability of neuromuscular transmission and how it is maintained. Handb Clin Neurol 2008; 91: 27-101
6 McMahan UJ. The agrin hypothesis. Cold Spring Harb Symp Quant Biol 1990; 55: 407-418
7 Weatherbee SD, Anderson KV, Niswander LA. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 2006; 133 (24) 4993-5000
8 Hopf C, Hoch W. Dimerization of the muscle-specific kinase induces tyrosine phosphorylation of acetylcholine receptors and their aggregation on the surface of myotubes. J Biol Chem 1998; 273 (11) 6467-6473
9 Sanes JR, Lichtman JW. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2001; 2 (11) 791-805
10 Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci 2004; 27: 509-547
11 Parsons SM, Bahr BA, Gracz LM. , et al. Acetylcholine transport: fundamental properties and effects of pharmacologic agents. Ann N Y Acad Sci 1987; 493: 220-233
12 Varoqui H, Meunier FM, Meunier FA. , et al. Expression of the vesicular acetylcholine transporter in mammalian cells. Prog Brain Res 1996; 109: 83-95
13 Bazalakova MH, Blakely RD. The high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice. Handb Exp Pharmacol 2006; (175) 525-544
14 Tintignac LA, Brenner H-R, Rüegg MA. Mechanisms regulating neuromuscular junction development and function and causes of muscle wasting. Physiol Rev 2015; 95 (03) 809-852
15 Evangelista T, Hanna M, Lochmüller H. Congenital myasthenic syndromes with predominant limb girdle weakness. J Neuromuscul Dis 2015; 2 (Suppl. 02) S21-S29
16 Engel AG, Lambert EH, Mulder DM. , et al. A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 1982; 11 (06) 553-569
17 Rodríguez Cruz PM, Belaya K, Basiri K. , et al. Clinical features of the myasthenic syndrome arising from mutations in GMPPB. J Neurol Neurosurg Psychiatry 2016; 87 (08) 802-809
18 Finlayson S, Morrow JM, Rodriguez Cruz PM. , et al. Muscle magnetic resonance imaging in congenital myasthenic syndromes. Muscle Nerve 2016; 54 (02) 211-219
19 Selcen D, Milone M, Shen XM. , et al. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol 2008; 64 (01) 71-87
20 Hutchinson DO, Walls TJ, Nakano S. , et al. Congenital endplate acetylcholinesterase deficiency. Brain 1993; 116 (Pt 3): 633-653
21 Belaya K, Finlayson S, Slater CR. , et al. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet 2012; 91 (01) 193-201
22 Guergueltcheva V, Müller JS, Dusl M. , et al. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. J Neurol 2012; 259 (05) 838-850
23 Whittaker RG. Testing the neuromuscular junction: what neurophysiology can offer the neurologist. Pract Neurol 2011; 11 (05) 303-307
24 Whittaker RG, Herrmann DN, Bansagi B. , et al. Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome. Neurology 2015; 85 (22) 1964-1971
25 Engel AG, Selcen D, Shen XM, Milone M, Harper CM. Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurol Genet 2016; 2 (05) e105
26 Shen XM, Scola RH, Lorenzoni PJ. , et al. Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome. Ann Clin Transl Neurol 2017; 4 (02) 130-138
27 Eaton LM, Lambert EH. Electromyography and electric stimulation of nerves in diseases of motor unit; observations on myasthenic syndrome associated with malignant tumors. J Am Med Assoc 1957; 163 (13) 1117-1124
28 Byring RF, Pihko H, Tsujino A. , et al. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscul Disord 2002; 12 (06) 548-553
29 Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology 1987; 37 (02) 206-214
30 van Dijk JG, Lammers GJ, Wintzen AR, Molenaar PC. Repetitive CMAPs: mechanisms of neural and synaptic genesis. Muscle Nerve 1996; 19 (09) 1127-1133
31 Bromberg MB, Scott DM. ; AD HOC Committee of the AAEM Single Fiber Special Interest Group. Single fiber EMG reference values: reformatted in tabular form. Muscle Nerve 1994; 17 (07) 820-821
32 Oda Y. Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system. Pathol Int 1999; 49 (11) 921-937
33 O'Connor E, Töpf A, Müller JS. , et al. Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome. Brain 2016; 139 (Pt 8): 2143-2153
34 Herrmann DN, Horvath R, Sowden JE. , et al. Synaptotagmin 2 mutations cause an autosomal-dominant form of Lambert-Eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet 2014; 95 (03) 332-339
35 Chen X, Tomchick DR, Kovrigin E. , et al. Three-dimensional structure of the complexin/SNARE complex. Neuron 2002; 33 (03) 397-409
36 Shen X-M, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology 2014; 83 (24) 2247-2255
37 Betz A, Ashery U, Rickmann M. , et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron 1998; 21 (01) 123-136
38 Augustin I, Rosenmund C, Südhof TC, Brose N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 1999; 400 (6743): 457-461
39 Siksou L, Varoqueaux F, Pascual O, Triller A, Brose N, Marty S. A common molecular basis for membrane docking and functional priming of synaptic vesicles. Eur J Neurosci 2009; 30 (01) 49-56
40 Adams DJ, Arthur CP, Stowell MHB. Architecture of the synaptophysin/synaptobrevin complex: structural evidence for an entropic clustering function at the synapse. Sci Rep 2015; 5: 13659
41 Mihaylova V, Müller JS, Vilchez JJ. , et al. Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain 2008; 131 (Pt 3): 747-759
42 Shapira YA, Sadeh ME, Bergtraum MP. , et al. Three novel COLQ mutations and variation of phenotypic expressivity due to G240X. Neurology 2002; 58 (04) 603-609
43 Noakes PG, Gautam M, Mudd J, Sanes JR, Merlie JP. Aberrant differentiation of neuromuscular junctions in mice lacking s-laminin/laminin beta 2. Nature 1995; 374 (6519): 258-262
44 Zenker M, Aigner T, Wendler O. , et al. Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet 2004; 13 (21) 2625-2632
45 Maselli RA, Fernandez JM, Arredondo J. , et al. LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. Hum Genet 2012; 131 (07) 1123-1135
46 Huzé C, Bauché S, Richard P. , et al. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet 2009; 85 (02) 155-167
47 Nicole S, Chaouch A, Torbergsen T. , et al. Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain 2014; 137 (Pt 9): 2429-2443
48 Latvanlehto A, Fox MA, Sormunen R. , et al. Muscle-derived collagen XIII regulates maturation of the skeletal neuromuscular junction. J Neurosci 2010; 30 (37) 12230-12241
49 Logan CV, Cossins J, Rodríguez Cruz PM. , et al. Congenital myasthenic syndrome type 19 is caused by mutations in COL13A1, encoding the atypical non-fibrillar collagen type XIII α1 chain. Am J Hum Genet 2015; 97 (06) 878-885
50 Gomez CM, Maselli RA, Vohra BP. , et al. Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms. Ann Neurol 2002; 51 (01) 102-112
51 Shen X-M, Okuno T, Milone M. , et al. Mutations causing slow-channel myasthenia reveal that a valine ring in the channel pore of muscle AChR is optimized for stabilizing channel gating. Hum Mutat 2016; 37 (10) 1051-1059
52 Gautam M, Noakes PG, Mudd J. , et al. Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 1995; 377 (6546): 232-236
53 Burke G, Cossins J, Maxwell S. , et al. Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes. Neurology 2003; 61 (06) 826-828
54 Ohno K, Wang HL, Milone M. , et al. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit. Neuron 1996; 17 (01) 157-170
55 Webster R, Liu W-W, Chaouch A, Lochmüller H, Beeson D. Fast-channel congenital myasthenic syndrome with a novel acetylcholine receptor mutation at the α-ε subunit interface. Neuromuscul Disord 2014; 24 (02) 143-147
56 Habbout K, Poulin H, Rivier F. , et al. A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis. Neurology 2016; 86 (02) 161-169
57 Arnold WD, Feldman DH, Ramirez S. , et al. Defective fast inactivation recovery of Nav 1.4 in congenital myasthenic syndrome. Ann Neurol 2015; 77 (05) 840-850
58 Tsujino A, Maertens C, Ohno K. , et al. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A 2003; 100 (12) 7377-7382
59 Yamanashi Y, Higuch O, Beeson D. Dok-7/MuSK signaling and a congenital myasthenic syndrome. Acta Myol 2008; 27: 25-29
60 Mihaylova V, Salih MA, Mukhtar MM. , et al. Refinement of the clinical phenotype in musk-related congenital myasthenic syndromes. Neurology 2009; 73 (22) 1926-1928
61 Maselli RA, Arredondo J, Cagney O. , et al. Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Hum Mol Genet 2010; 19 (12) 2370-2379
62 Kim N, Stiegler AL, Cameron TO. , et al. Lrp4 is a receptor for agrin and forms a complex with MuSK. Cell 2008; 135 (02) 334-342
63 Li Y, Pawlik B, Elcioglu N. , et al. LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. Am J Hum Genet 2010; 86 (05) 696-706
64 Leupin O, Piters E, Halleux C. , et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 2011; 286 (22) 19489-19500
65 Styrkarsdottir U, Halldorsson BV, Gretarsdottir S. , et al. New sequence variants associated with bone mineral density. Nat Genet 2009; 41 (01) 15-17
66 Selcen D, Shen X, Ohkawara B. , et al. Congenital myasthenic syndrome (CMS) caused by novel mutation in LRP4. Phenotypic heterogeneity and defects in neuromuscular transmission (NMT) identified in a second kinship (P2.021). Neurology 2015; 84 (14) P2.021
67 Ohkawara B, Cabrera-Serrano M, Nakata T. , et al. LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. Hum Mol Genet 2014; 23 (07) 1856-1868
68 Maselli RA, Arredondo J, Cagney O. , et al. Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. Clin Genet 2011; 80 (05) 444-451
69 Forrest K, Mellerio JE, Robb S. , et al. Congenital muscular dystrophy, myasthenic symptoms and epidermolysis bullosa simplex (EBS) associated with mutations in the PLEC1 gene encoding plectin. Neuromuscul Disord 2010; 20 (11) 709-711
70 Raphael AR, Couthouis J, Sakamuri S. , et al. Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations. Brain Res 2014; 1575: 66-71
71 Edvardson S, Porcelli V, Jalas C. , et al. Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J Med Genet 2013; 50 (04) 240-245
72 Chaouch A, Porcelli V, Cox D. , et al. Mutations in the mitochondrial citrate carrier SLC25A1 are associated with impaired neuromuscular transmission. J Neuromuscul Dis 2014; 1 (01) 75-90
73 Régal L, Shen XM, Selcen D. , et al. PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology 2014; 82 (14) 1254-1260
74 Parvari R, Brodyansky I, Elpeleg O, Moses S, Landau D, Hershkovitz E. A recessive contiguous gene deletion of chromosome 2p16 associated with cystinuria and a mitochondrial disease. Am J Hum Genet 2001; 69 (04) 869-875
75 Arredondo J, Lara M, Gospe Jr SM. , et al. Choline acetyltransferase mutations causing congenital myasthenic syndrome: molecular findings and genotype-phenotype correlations. Hum Mutat 2015; 36 (09) 881-893
76 Shen X-M, Crawford TO, Brengman J. , et al. Functional consequences and structural interpretation of mutations of human choline acetyltransferase. Hum Mutat 2011; 32 (11) 1259-1267
77 Schara U, Christen HJ, Durmus H. , et al. Long-term follow-up in patients with congenital myasthenic syndrome due to CHAT mutations. Eur J Paediatr Neurol 2010; 14 (04) 326-333
78 Ohno K, Tsujino A, Brengman JM. , et al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci U S A 2001; 98 (04) 2017-2022
79 Barwick KES, Wright J, Al-Turki S. , et al. Defective presynaptic choline transport underlies hereditary motor neuropathy. Am J Hum Genet 2012; 91 (06) 1103-1107
80 Bauché S, O'Regan S, Azuma Y. , et al. Impaired presynaptic high-affinity choline transporter causes a congenital myasthenic syndrome with episodic apnea. Am J Hum Genet 2016; 99 (03) 753-761
81 Ohno K, Brengman J, Tsujino A, Engel AG. Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme. Proc Natl Acad Sci U S A 1998; 95 (16) 9654-9659
82 Abicht A, Stucka R, Karcagi V. , et al. A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology 1999; 53 (07) 1564-1569
83 Morar B, Gresham D, Angelicheva D. , et al. Mutation history of the Roma/gypsies. Am J Hum Genet 2004; 75 (04) 596-609
84 Müller JS, Baumeister SK, Schara U. , et al. CHRND mutation causes a congenital myasthenic syndrome by impairing co-clustering of the acetylcholine receptor with rapsyn. Brain 2006; 129 (Pt 10): 2784-2793
85 Hoffmann K, Muller JS, Stricker S. , et al. Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal γ subunit. Am J Hum Genet 2006; 79 (02) 303-312
86 Natera-de Benito D, Bestué M, Vilchez JJ. , et al. Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations. Neuromuscul Disord 2016; 26 (02) 153-159
87 Müller JS, Mildner G, Müller-Felber W. , et al. Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology 2003; 60 (11) 1805-1810
88 Müller JS, Abicht A, Burke G. , et al. The congenital myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo-European founder. J Med Genet 2004; 41 (08) e104
89 Sine SM. End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease. Physiol Rev 2012; 92 (03) 1189-1234
90 Schara U, Lochmüller H. Therapeutic strategies in congenital myasthenic syndromes. Neurotherapeutics 2008; 5 (04) 542-547
91 Chaouch A, Müller JS, Guergueltcheva V. , et al. A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome. J Neurol 2012; 259 (03) 474-481
92 Cossins J, Liu WW, Belaya K. , et al. The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. Hum Mol Genet 2012; 21 (17) 3765-3775
93 Krištić J, Lauc G. Ubiquitous importance of protein glycosylation. Methods Mol Biol 2017; 1503: 1-12
94 Senderek J, Müller JS, Dusl M. , et al. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 2011; 88 (02) 162-172
95 Carss KJ, Stevens E, Foley AR. , et al; UK10K Consortium. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan. Am J Hum Genet 2013; 93 (01) 29-41
96 Belaya K, Rodríguez Cruz PM, Liu WW. , et al. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain 2015; 138 (Pt 9): 2493-2504
97 Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol 2016; 263 (04) 826-834
98 Kirsch GE, Narahashi T. 3,4-diaminopyridine. A potent new potassium channel blocker. Biophys J 1978; 22 (03) 507-512
99 Lindquist S, Stangel M. Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine. Neuropsychiatr Dis Treat 2011; 7: 341-349
100 Edgeworth H. The effect of ephedrine in the treatment of myasthenia gravis: second report. J Am Med Assoc 1933; 100: 1401-1401
101 Edgeworth H. A report of progress on the use of ephedrine in a case of myasthenia gravis. J Am Med Assoc 1930; 94: 1136
102 Slater CR, Fawcett PR, Walls TJ. , et al. Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with ‘limb-girdle myasthenia’. Brain 2006; 129 (Pt 8): 2061-2076
103 Gallenmüller C, Müller-Felber W, Dusl M. , et al. Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in MUSK. Neuromuscul Disord 2014; 24 (01) 31-35
104 Salih M. , et al. Salbutamol benefits children with congenital myasthenic syndrome due to ALG2 mutation. J Neurol Sci 2015; 357: e72
105 Fukudome T, Ohno K, Brengman JM, Engel AG. Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor. Neuroreport 1998; 9 (08) 1907-1911
106 Harper CM, Fukodome T, Engel AG. Treatment of slow-channel congenital myasthenic syndrome with fluoxetine. Neurology 2003; 60 (10) 1710-1713
107 Engel AG. The therapy of congenital myasthenic syndromes. Neurotherapeutics 2007; 4 (02) 252-257
108 Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol 1998; 43 (04) 480-484