Congenital myasthenic syndromes (CMS) a rare cause of uncommon fatigue
DOI:
https://doi.org/10.12775/JEHS.2023.13.02.004Keywords
congenital myasthenic syndromes, neuromuscular disease, weakness, inheritanceAbstract
Introduction and purpose:
Muscle weakness in newborns, infants and young children can be caused by disorders of the neuromuscular junction (NMJ). Congenital myasthenic syndromes (CMS) are a group of rare genetic diseases whose symptoms resemble the clinical picture of autoimmune myasthenia gravis. There are many mutations that can disrupt the neuromuscular transmission leading to pathology. The diagnosis of CMS is based on genetic testing. The aim of this study is to draw clinicians' attention to the symptoms and present current forms of CMS diagnosis and management.
State of knowledge:
An increasing number of genetic changes are associated with CMS pathology. They are divided, depending on the location in the NMJ of the encoded protein, into presynaptic, synaptic and postsynaptic. The most common disorder is the mutation of CHRNE, which is responsible for the expression of one of the subunits in the structure of the acetylcholine receptor. Regardless of the type of disease, the characteristic symptom is uncommon fatigue of skeletal muscles. It may present as ptosis of one or both eyelids or gait disturbance. The interview, laboratory tests and EMG are helpful in the diagnosis, but genetic tests play a key role. They can target specific mutations or cover the entire genome comprehensively. Currently used drugs alleviate the course of CMS by increasing the release of acetylcholine or increasing the concentration of acetylcholine in the synaptic cleft.
Conclusion:
Because of its rarity and variability, many CMS patients may be misdiagnosed. It is important to implement extensive genetic diagnostics and early implementation of treatment. There is a need for long-term studies of CMS cases and implementation of therapies targeted at specific mutations.
References
Rodríguez Cruz, P. M., Palace, J., & Beeson, D. (2018). The Neuromuscular Junction and Wide Heterogeneity of Congenital Myasthenic Syndromes. International journal of molecular sciences, 19(6), 1677. https://doi.org/10.3390/ijms19061677
Troha Gergeli, A., Neubauer, D., Golli, T., Butenko, T., Loboda, T., Maver, A., & Osredkar, D. (2020). Prevalence and genetic subtypes of congenital myasthenic syndromes in the pediatric population of Slovenia. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 26, 34–38. https://doi.org/10.1016/j.ejpn.2020.02.002
Krenn, M., Sener, M., Rath, J., Zulehner, G., Keritam, O., Wagner, M., Laccone, F., Iglseder, S., Marte, S., Baumgartner, M., Eisenkölbl, A., Liechtenstein, C., Rudnik, S., Quasthoff, S., Grinzinger, S., Spenger, J., Wortmann, S. B., Löscher, W. N., Zimprich, F., Kellersmann, A., … Cetin, H. (2022). The clinical and molecular landscape of congenital myasthenic syndromes in Austria: a nationwide study. Journal of neurology, 10.1007/s00415-022-11440-0. Advance online publication. https://doi.org/10.1007/s00415-022-11440-0
Della Marina, A., Wibbeler, E., Abicht, A., Kölbel, H., Lochmüller, H., Roos, A., & Schara, U. (2020). Long Term Follow-Up on Pediatric Cases With Congenital Myasthenic Syndromes-A Retrospective Single Centre Cohort Study. Frontiers in human neuroscience, 14, 560860. https://doi.org/10.3389/fnhum.2020.560860
Abicht, A., Müller, J. S., & Lochmüller, H. (2003). Congenital Myasthenic Syndromes Overview. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle.
Vanhaesebrouck, A. E., & Beeson, D. (2019). The congenital myasthenic syndromes: expanding genetic and phenotypic spectrums and refining treatment strategies. Current opinion in neurology, 32(5), 696–703. https://doi.org/10.1097/WCO.0000000000000736
Zhang, Y., Cheng, X., Luo, C., Lei, M., Mao, F., Shi, Z., Cao, W., Zhang, J., & Zhang, Q. (2020). Congenital Myasthenic Syndrome Caused by a Novel Hemizygous CHAT Mutation. Frontiers in pediatrics, 8, 185. https://doi.org/10.3389/fped.2020.00185
English, B. A., Hahn, M. K., Gizer, I. R., Mazei-Robison, M., Steele, A., Kurnik, D. M., Stein, M. A., Waldman, I. D., & Blakely, R. D. (2009). Choline transporter gene variation is associated with attention-deficit hyperactivity disorder. Journal of neurodevelopmental disorders, 1(4), 252–263. https://doi.org/10.1007/s11689-009-9033-8
Finsterer J. (2019). Congenital myasthenic syndromes. Orphanet journal of rare diseases, 14(1), 57. https://doi.org/10.1186/s13023-019-1025-5
Aran, A., Segel, R., Kaneshige, K., Gulsuner, S., Renbaum, P., Oliphant, S., Meirson, T., Weinberg-Shukron, A., Hershkovitz, Y., Zeligson, S., Lee, M. K., Samson, A. O., Parsons, S. M., King, M. C., Levy-Lahad, E., & Walsh, T. (2017). Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome. Neurology, 88(11), 1021–1028. https://doi.org/10.1212/WNL.0000000000003720
Shen, X. M., Selcen, D., Brengman, J., & Engel, A. G. (2014). Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology, 83(24), 2247–2255. https://doi.org/10.1212/WNL.0000000000001079
Salpietro, V., Lin, W., Delle Vedove, A., Storbeck, M., Liu, Y., Efthymiou, S., Manole, A., Wiethoff, S., Ye, Q., Saggar, A., McElreavey, K., Krishnakumar, S. S., SYNAPS Study Group, Pitt, M., Bello, O. D., Rothman, J. E., Basel-Vanagaite, L., Hubshman, M. W., Aharoni, S., Manzur, A. Y., … Houlden, H. (2017). Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Annals of neurology, 81(4), 597–603. https://doi.org/10.1002/ana.24905
Shen, X. M., Scola, R. H., Lorenzoni, P. J., Kay, C. S., Werneck, L. C., Brengman, J., Selcen, D., & Engel, A. G. (2017). Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome. Annals of clinical and translational neurology, 4(2), 130–138. https://doi.org/10.1002/acn3.387
Fionda, L., Turon-Sans, J., Fuentes Prior, P., Bernal Noguera, S., Cortés-Vicente, E., López-Pérez, M. A., Gallardo, E., & Rojas-García, R. (2021). A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?. Journal of the peripheral nervous system : JPNS, 26(1), 113–117. https://doi.org/10.1111/jns.12425
Engel, A. G., Selcen, D., Shen, X. M., Milone, M., & Harper, C. M. (2016). Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurology. Genetics, 2(5), e105. https://doi.org/10.1212/NXG.0000000000000105
Régal, L., Shen, X. M., Selcen, D., Verhille, C., Meulemans, S., Creemers, J. W., & Engel, A. G. (2014). PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology, 82(14), 1254–1260. https://doi.org/10.1212/WNL.0000000000000295
Krejci, E., Thomine, S., Boschetti, N., Legay, C., Sketelj, J., & Massoulié, J. (1997). The mammalian gene of acetylcholinesterase-associated collagen. The Journal of biological chemistry, 272(36), 22840–22847. https://doi.org/10.1074/jbc.272.36.22840
Ito, M., & Ohno, K. (2018). Protein-anchoring therapy to target extracellular matrix proteins to their physiological destinations. Matrix biology : journal of the International Society for Matrix Biology, 68-69, 628–636. https://doi.org/10.1016/j.matbio.2018.02.014
Ohno, K., Brengman, J., Tsujino, A., & Engel, A. G. (1998). Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme. Proceedings of the National Academy of Sciences of the United States of America, 95(16), 9654–9659. https://doi.org/10.1073/pnas.95.16.9654
Legay C. (2018). Congenital myasthenic syndromes with acetylcholinesterase deficiency, the pathophysiological mechanisms. Annals of the New York Academy of Sciences, 1413(1), 104–110. https://doi.org/10.1111/nyas.13595
Maselli, R. A., Arredondo, J., Vázquez, J., Chong, J. X., Bamshad, M. J., Nickerson, D. A., Lara, M., Ng, F., Lo, V. L., Pytel, P., & McDonald, C. M. (2018). A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5. Annals of the New York Academy of Sciences, 1413(1), 119–125. https://doi.org/10.1111/nyas.13585
Maselli, R. A., Ng, J. J., Anderson, J. A., Cagney, O., Arredondo, J., Williams, C., Wessel, H. B., Abdel-Hamid, H., & Wollmann, R. L. (2009). Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. Journal of medical genetics, 46(3), 203–208. https://doi.org/10.1136/jmg.2008.063693
Logan, C. V., Cossins, J., Rodríguez Cruz, P. M., Parry, D. A., Maxwell, S., Martínez-Martínez, P., Riepsaame, J., Abdelhamed, Z. A., Lake, A. V., Moran, M., Robb, S., Chow, G., Sewry, C., Hopkins, P. M., Sheridan, E., Jayawant, S., Palace, J., Johnson, C. A., & Beeson, D. (2015). Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain. American journal of human genetics, 97(6), 878–885. https://doi.org/10.1016/j.ajhg.2015.10.017
Lorenzoni, P. J., Scola, R. H., Kay, C. S., & Werneck, L. C. (2012). Congenital myasthenic syndrome: a brief review. Pediatric neurology, 46(3), 141–148. https://doi.org/10.1016/j.pediatrneurol.2011.12.001
Gómez-García de la Banda, M., Simental-Aldaba, E., Fahmy, N., Sternberg, D., Blondy, P., Quijano-Roy, S., & Malfatti, E. (2022). Case Report: A Novel AChR Epsilon Variant Causing a Clinically Discordant Salbutamol Responsive Congenital Myasthenic Syndrome in Two Egyptian Siblings. Frontiers in neurology, 13, 909715. https://doi.org/10.3389/fneur.2022.909715
Engel A. G. (2018). Genetic basis and phenotypic features of congenital myasthenic syndromes. Handbook of clinical neurology, 148, 565–589. https://doi.org/10.1016/B978-0-444-64076-5.00037-5
Estephan, E. P., Zambon, A. A., Marchiori, P. E., da Silva, A. M. S., Caldas, V. M., Moreno, C. A. M., Reed, U. C., Horvath, R., Töpf, A., Lochmüller, H., & Zanoteli, E. (2018). Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil. Neuromuscular disorders : NMD, 28(11), 961–964. https://doi.org/10.1016/j.nmd.2018.08.007
Oury, J., Zhang, W., Leloup, N., Koide, A., Corrado, A. D., Ketavarapu, G., Hattori, T., Koide, S., & Burden, S. J. (2021). Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia. Nature, 595(7867), 404–408. https://doi.org/10.1038/s41586-021-03672-3
Engel, A. G., Shen, X. M., Selcen, D., & Sine, S. (2012). New horizons for congenital myasthenic syndromes. Annals of the New York Academy of Sciences, 1275(1), 54–62. https://doi.org/10.1111/j.1749-6632.2012.06803.x
Jacquier, A., Risson, V., Simonet, T., Roussange, F., Lacoste, N., Ribault, S., Carras, J., Theuriet, J., Girard, E., Grosjean, I., Le Goff, L., Kröger, S., Meltoranta, J., Bauché, S., Sternberg, D., Fournier, E., Kostera-Pruszczyk, A., O'Connor, E., Eymard, B., Lochmüller, H., … Schaeffer, L. (2022). Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons. Acta neuropathologica, 144(4), 707–731. https://doi.org/10.1007/s00401-022-02475-8
Heckmann, J. M., Europa, T. A., Soni, A. J., & Nel, M. (2022). The Epidemiology and Phenotypes of Ocular Manifestations in Childhood and Juvenile Myasthenia Gravis: A Review. Frontiers in neurology, 13, 834212. https://doi.org/10.3389/fneur.2022.834212
Angelini, C., Giaretta, L., & Marozzo, R. (2018). An update on diagnostic options and considerations in limb-girdle dystrophies. Expert review of neurotherapeutics, 18(9), 693–703. https://doi.org/10.1080/14737175.2018.1508997
Kondo, H., Tsuji, Y., Lee, T., Saito, Y., & Nishino, I. (2022). Severe congenital myasthenic syndrome with novel variants in the CHRND gene. Pediatrics international : official journal of the Japan Pediatric Society, 64(1), e15342. https://doi.org/10.1111/ped.15342
Rodríguez Cruz, P. M., Cossins, J., Estephan, E. P., Munell, F., Selby, K., Hirano, M., Maroofin, R., Mehrjardi, M. Y. V., Chow, G., Carr, A., Manzur, A., Robb, S., Munot, P., Wei Liu, W., Banka, S., Fraser, H., De Goede, C., Zanoteli, E., Conti Reed, U., Sage, A., … Beeson, D. (2019). The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations. Brain : a journal of neurology, 142(6), 1547–1560. https://doi.org/10.1093/brain/awz107
Cimpoca-Raptis, B. A., Ciobanu, A. M., Gica, N., Peltecu, G., Mitrea, D., & Panaitescu, A. M. (2021). Fetal Surveillance in Pregnancies with Myasthenia Gravis. Medicina (Kaunas, Lithuania), 57(11), 1277. https://doi.org/10.3390/medicina57111277
Qashqari, H., McNiven, V., Gonorazky, H., Mendoza-Londono, R., Hassan, A., Kulkarni, T., Amburgey, K., & Dowling, J. J. (2022). PURA syndrome: neuromuscular junction manifestations with potential therapeutic implications. Neuromuscular disorders : NMD, 32(10), 842–844. https://doi.org/10.1016/j.nmd.2022.09.007
Engel, A. G., Shen, X. M., & Selcen, D. (2018). The unfolding landscape of the congenital myasthenic syndromes. Annals of the New York Academy of Sciences, 1413(1), 25–34. https://doi.org/10.1111/nyas.13539
Caldas, V. M., Heise, C. O., Kouyoumdjian, J. A., Zambon, A. A., Silva, A. M. S., Estephan, E. P., & Zanoteli, E. (2020). Electrophysiological study of neuromuscular junction in congenital myasthenic syndromes, congenital myopathies, and chronic progressive external ophthalmoplegia. Neuromuscular disorders : NMD, 30(11), 897–903. https://doi.org/10.1016/j.nmd.2020.10.002
Engel, A. G., Shen, X. M., Selcen, D., & Sine, S. M. (2015). Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. The Lancet. Neurology, 14(5), 461. https://doi.org/10.1016/S1474-4422(15)00010-1
Huang, K., Luo, Y. B., Bi, F. F., & Yang, H. (2021). Pharmacological Strategy for Congenital Myasthenic Syndrome with CHRNE Mutations: A Meta-Analysis of Case Reports. Current neuropharmacology, 19(5), 718–729. https://doi.org/10.2174/1570159X18666200729092332
Kao, J. C., Milone, M., Selcen, D., Shen, X. M., Engel, A. G., & Liewluck, T. (2018). Congenital myasthenic syndromes in adult neurology clinic: A long road to diagnosis and therapy. Neurology, 91(19), e1770–e1777. https://doi.org/10.1212/WNL.0000000000006478
Lee, M., Beeson, D., & Palace, J. (2018). Therapeutic strategies for congenital myasthenic syndromes. Annals of the New York Academy of Sciences, 1412(1), 129–136. https://doi.org/10.1111/nyas.13538
McMacken, G. M., Spendiff, S., Whittaker, R. G., O'Connor, E., Howarth, R. M., Boczonadi, V., Horvath, R., Slater, C. R., & Lochmüller, H. (2019). Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome. Human molecular genetics, 28(14), 2339–2351. https://doi.org/10.1093/hmg/ddz059
Bestue-Cardiel, M., Sáenz de Cabezón-Alvarez, A., Capablo-Liesa, J. L., López-Pisón, J., Peña-Segura, J. L., Martin-Martinez, J., & Engel, A. G. (2005). Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology, 65(1), 144–146. https://doi.org/10.1212/01.wnl.0000167132.35865.31
Lee, M., Beeson, D., & Palace, J. (2018). Therapeutic strategies for congenital myasthenic syndromes. Annals of the New York Academy of Sciences, 1412(1), 129–136. https://doi.org/10.1111/nyas.13538
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2022 Jan Lejman, Kinga Panuciak, Emilia Nowicka, Angelika Mastalerczyk, Karolina Makowska, Michał Obel, Kamila Czyżak, Wiktor Wiśniewski
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 721
Number of citations: 0
