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| field = [[Pediatrics]], [[ |
| field = [[Pediatrics]], [[Pediatric neurology]], Pediatric [[pulmonology]], Pediatric [[intensive care medicine]] |
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| symptoms = [[skeletal muscles]] weaknesses and, in rare cases. organ deformities in one or more areas of the body in fetuses and newborns |
| symptoms = [[skeletal muscles]] weaknesses and, in rare cases. organ deformities in one or more areas of the body in fetuses and newborns |
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| complications = Myasthenic crisis, i.e., weakness in the lungs skeletal muscles causing potentially lethal [[respiratory failure]] |
| complications = Myasthenic crisis, i.e., weakness in the lungs skeletal muscles causing potentially lethal [[respiratory failure]] |
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'''Transient neonatal myasthenia gravis''', i.e., '''TNMG''' (also termed neonatal myasthenia gravis<ref name="pmid37101094">{{cite journal | vauthors = Gilhus NE | title = Myasthenia gravis, respiratory function, and respiratory tract disease | journal = Journal of Neurology | volume = 270 | issue = 7 | pages = 3329–3340 | date = July 2023 | pmid = 37101094 | pmc = 10132430 | doi = 10.1007/s00415-023-11733-y | url = }}</ref>), and its more severe form, '''fetal acetylcholine receptor inactivation syndrome''' (i.e., FARIS), is one of the various types of [[myasthenia gravis]] (i.e., MG).<ref name="pmid38398450">{{cite journal | vauthors = Lindroos JL, Bjørk MH, Gilhus NE | title = Transient Neonatal Myasthenia Gravis as a Common Complication of a Rare Disease: A Systematic Review | journal = Journal of Clinical Medicine | volume = 13 | issue = 4 | date = February 2024 | page = 1136 | pmid = 38398450 | pmc = 10889526 | doi = 10.3390/jcm13041136 | doi-access = free | url = }}</ref> MG is an [[autoimmune disease]] in which individuals form [[antibodies]] that circulate in their blood, enter tissues, bind to certain proteins in the [[neuromuscular junction]]s of skeletal muscles, and thereby reduce the number or ability of these skeletal muscles to contract when appropriately stimulated by [[acetylcholine]]. The affected skeletal muscles are easily fatigable, i.e., weakened after relatively little use. There are |
'''Transient neonatal myasthenia gravis''', i.e., '''TNMG''' (also termed neonatal myasthenia gravis<ref name="pmid37101094">{{cite journal | vauthors = Gilhus NE | title = Myasthenia gravis, respiratory function, and respiratory tract disease | journal = Journal of Neurology | volume = 270 | issue = 7 | pages = 3329–3340 | date = July 2023 | pmid = 37101094 | pmc = 10132430 | doi = 10.1007/s00415-023-11733-y | url = }}</ref>), and its more severe form, '''fetal acetylcholine receptor inactivation syndrome''' (i.e., FARIS), is one of the various types of [[myasthenia gravis]] (i.e., MG).<ref name="pmid38398450">{{cite journal | vauthors = Lindroos JL, Bjørk MH, Gilhus NE | title = Transient Neonatal Myasthenia Gravis as a Common Complication of a Rare Disease: A Systematic Review | journal = Journal of Clinical Medicine | volume = 13 | issue = 4 | date = February 2024 | page = 1136 | pmid = 38398450 | pmc = 10889526 | doi = 10.3390/jcm13041136 | doi-access = free | url = }}</ref> MG is an [[autoimmune disease]] in which individuals form [[antibodies]] that circulate in their blood, enter tissues, bind to certain proteins in the [[neuromuscular junction]]s of skeletal muscles, and thereby reduce the number or ability of these skeletal muscles to contract when appropriately stimulated by [[acetylcholine]]. The affected skeletal muscles are easily fatigable, i.e., weakened after relatively little use. There are 3 types of antibodies that are known to cause TNMG/FARIS: antibodies binding to the adult form of the [[nicotinic acetylcholine receptor]], i.e., adult nAChR, are responsible for most cases of TNMG while antibodies binding to two proteins near these nAChRs, i.e., the [[MuSK protein]] and [[low-density lipoprotein receptor-related protein 4]] (i.e., LRP4) are responsible for many of the remaining cases of TNMG.<ref name="pmid30133097">{{cite journal | vauthors = Gilhus NE, Hong Y | title = Maternal myasthenia gravis represents a risk for the child through autoantibody transfer, immunosuppressive therapy and genetic influence | journal = European Journal of Neurology | volume = 25 | issue = 12 | pages = 1402–1409 | date = December 2018 | pmid = 30133097 | doi = 10.1111/ene.13788 | url = }}</ref><ref name="pmid37038596">{{cite journal | vauthors = Nair SS, Jacob S | title = Novel Immunotherapies for Myasthenia Gravis | journal = ImmunoTargets and Therapy | volume = 12 | issue = | pages = 25–45 | date = 2023 | pmid = 37038596 | pmc = 10082579 | doi = 10.2147/ITT.S377056 | doi-access = free | url = }}</ref><ref name="pmid35074870">{{cite journal | vauthors = Chia R, Saez-Atienzar S, Murphy N, Chiò A, Blauwendraat C, Roda RH, Tienari PJ, Kaminski HJ, Ricciardi R, Guida M, De Rosa A, Petrucci L, Evoli A, Provenzano C, Drachman DB, Traynor BJ | title = Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 119 | issue = 5 | pages = | date = February 2022 | pmid = 35074870 | pmc = 8812681 | doi = 10.1073/pnas.2108672119 | doi-access = free | bibcode = 2022PNAS..11908672C | url = }}</ref> Antibodies directed at the fetal form of nAChRs are responsible for all cases of FARIS.<ref name="pmid37101094"/><ref name="pmid37038596">{{cite journal | vauthors = Nair SS, Jacob S | title = Novel Immunotherapies for Myasthenia Gravis | journal = ImmunoTargets and Therapy | volume = 12 | issue = | pages = 25–45 | date = 2023 | pmid = 37038596 | pmc = 10082579 | doi = 10.2147/ITT.S377056 | doi-access = free | url = }}</ref><ref name="pmid35074870">{{cite journal | vauthors = Chia R, Saez-Atienzar S, Murphy N, Chiò A, Blauwendraat C, Roda RH, Tienari PJ, Kaminski HJ, Ricciardi R, Guida M, De Rosa A, Petrucci L, Evoli A, Provenzano C, Drachman DB, Traynor BJ | title = Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 119 | issue = 5 | pages = | date = February 2022 | pmid = 35074870 | pmc = 8812681 | doi = 10.1073/pnas.2108672119 | doi-access = free | bibcode = 2022PNAS..11908672C | url = }}</ref> |
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MG may present as muscle weakness in different areas of the body: '''a)''' [[ocular myasthenia|ocular MG]] is skeletal muscle weakness in the eyes that causes [[Ptosis (eyelid)|ptosis]] (i.e., eyelid drooping), weak eyelid closure, [[strabismus]] (i.e., one eye turned in a direction different from the other eye), [[diplopia]] (i.e., double vision), and/or complex [[Ophthalmoparesis|ophthalmoplegias]] (e.g., weakness or paralysis of one or more [[extraocular muscles]] responsible for [[eye movements]]);<ref name="pmid37507215">{{cite journal | vauthors = Ng JY, Zarook E, Nicholson L, Khanji MY, Chahal CA | title = Eyes and the heart: what a clinician should know | journal = Heart (British Cardiac Society) | volume = 109 | issue = 22 | pages = 1670–1676 | date = October 2023 | pmid = 37507215 | pmc = 10646879 | doi = 10.1136/heartjnl-2022-322081 | url = }}</ref><ref name="pmid31847046">{{cite journal | vauthors = O'Hare M, Doughty C | title = Update on Ocular Myasthenia Gravis | journal = Seminars in Neurology | volume = 39 | issue = 6 | pages = 749–760 | date = December 2019 | pmid = 31847046 | doi = 10.1055/s-0039-1700527 | url = }}</ref><ref name="pmid33458590">{{cite journal | vauthors = Deymeer F | title = Myasthenia gravis: MuSK MG, late-onset MG and ocular MG | journal = Acta Myologica : Myopathies and Cardiomyopathies : Official Journal of the Mediterranean Society of Myology | volume = 39 | issue = 4 | pages = 345–352 | date = December 2020 | pmid = 33458590 | pmc = 7783433 | doi = 10.36185/2532-1900-038 | url = }}</ref> '''b)''' axial MG is skeletal muscle weakness of the arms, legs, trunk, and/or head that causes weak finger extension, [[wrist drop]], foot and hand dorsiflexions (backward bending or contraction of the foot or hand), difficulty in raising the arms above the head, getting up from low seats or toilets, walking long distances, and climbing stairs, and head drop (i.e., relaxing of the neck muscles);<ref name="pmid31794470">{{cite journal | vauthors = Ciafaloni E | title = Myasthenia Gravis and Congenital Myasthenic Syndromes | journal = Continuum (Minneapolis, Minn.) | volume = 25 | issue = 6 | pages = 1767–1784 | date = December 2019 | pmid = 31794470 | doi = 10.1212/CON.0000000000000800 | url = }}</ref><ref name="pmid34064035">{{cite journal | vauthors = Dresser L, Wlodarski R, Rezania K, Soliven B | title = Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations | journal = Journal of Clinical Medicine | volume = 10 | issue = 11 | date = May 2021 | page = 2235 | pmid = 34064035 | pmc = 8196750 | doi = 10.3390/jcm10112235 | doi-access = free | url = }}</ref> and '''c)''' bulbar MG is weakness of the skeletal muscles activated by nerves from the lower part of the [[brain stem]] termed the [[medulla oblongata]] that causes slurred speech, [[dysphagia]] (i.e., difficulty in swallowing), [[dysphonia]] (i.e., hoarse voice), bilateral [[facial nerve]] weakness, jaw weakness, and weaknesses of the respiratory muscles that may lead to a myasthenic crisis, i.e., life-threatening [[respiratory arrest]].<ref name="pmid31794470"/><ref name="pmid37900462">{{cite journal | vauthors = Gosain D, Das T | title = Myasthenia Gravis Presenting as Bulbar Palsy | journal = Cureus | volume = 15 | issue = 9 | pages = e46082 | date = September 2023 | pmid = 37900462 | pmc = 10611170 | doi = 10.7759/cureus.46082 | doi-access = free | url = }}</ref> MG, particularly in long-standing cases, may have two or all three ocular, axial, or bulbar symptoms.<ref name="pmid31794470"/><ref name="pmid34064035"/><ref name="pmid37900462"/> MG has also been separated into only two types: ocular MG and generalized MG, i.e., all other types of MG.<ref name="pmid38790567">{{cite journal | vauthors = Maeda M, Shimomura H, Tokunaga S, Taniguchi N, Lee T, Takeshima Y | title = Clinical Characteristics and Treatment of Juvenile Myasthenia Gravis-A Single-Center Experience | journal = Children (Basel, Switzerland) | volume = 11 | issue = 5 | date = May 2024 | page = 572 | pmid = 38790567 | pmc = 11120409 | doi = 10.3390/children11050572 | doi-access = free | url = }}</ref> |
MG may present as muscle weakness in different areas of the body: '''a)''' [[ocular myasthenia|ocular MG]] is skeletal muscle weakness in the eyes that causes [[Ptosis (eyelid)|ptosis]] (i.e., eyelid drooping), weak eyelid closure, [[strabismus]] (i.e., one eye turned in a direction different from the other eye), [[diplopia]] (i.e., double vision), and/or complex [[Ophthalmoparesis|ophthalmoplegias]] (e.g., weakness or paralysis of one or more [[extraocular muscles]] responsible for [[eye movements]]);<ref name="pmid37507215">{{cite journal | vauthors = Ng JY, Zarook E, Nicholson L, Khanji MY, Chahal CA | title = Eyes and the heart: what a clinician should know | journal = Heart (British Cardiac Society) | volume = 109 | issue = 22 | pages = 1670–1676 | date = October 2023 | pmid = 37507215 | pmc = 10646879 | doi = 10.1136/heartjnl-2022-322081 | url = }}</ref><ref name="pmid31847046">{{cite journal | vauthors = O'Hare M, Doughty C | title = Update on Ocular Myasthenia Gravis | journal = Seminars in Neurology | volume = 39 | issue = 6 | pages = 749–760 | date = December 2019 | pmid = 31847046 | doi = 10.1055/s-0039-1700527 | url = }}</ref><ref name="pmid33458590">{{cite journal | vauthors = Deymeer F | title = Myasthenia gravis: MuSK MG, late-onset MG and ocular MG | journal = Acta Myologica : Myopathies and Cardiomyopathies : Official Journal of the Mediterranean Society of Myology | volume = 39 | issue = 4 | pages = 345–352 | date = December 2020 | pmid = 33458590 | pmc = 7783433 | doi = 10.36185/2532-1900-038 | url = }}</ref> '''b)''' limb/axial MG is skeletal muscle weakness of the arms, legs, trunk, and/or head that causes weak finger extension, [[wrist drop]], foot and hand dorsiflexions (backward bending or contraction of the foot or hand), difficulty in raising the arms above the head, getting up from low seats or toilets, walking long distances, and climbing stairs, and head drop (i.e., relaxing of the neck muscles);<ref name="pmid31794470">{{cite journal | vauthors = Ciafaloni E | title = Myasthenia Gravis and Congenital Myasthenic Syndromes | journal = Continuum (Minneapolis, Minn.) | volume = 25 | issue = 6 | pages = 1767–1784 | date = December 2019 | pmid = 31794470 | doi = 10.1212/CON.0000000000000800 | url = }}</ref><ref name="pmid34064035">{{cite journal | vauthors = Dresser L, Wlodarski R, Rezania K, Soliven B | title = Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations | journal = Journal of Clinical Medicine | volume = 10 | issue = 11 | date = May 2021 | page = 2235 | pmid = 34064035 | pmc = 8196750 | doi = 10.3390/jcm10112235 | doi-access = free | url = }}</ref> and '''c)''' bulbar MG is weakness of the skeletal muscles activated by nerves from the lower part of the [[brain stem]] termed the [[medulla oblongata]] that causes slurred speech, [[dysphagia]] (i.e., difficulty in swallowing), [[dysphonia]] (i.e., hoarse voice), bilateral [[facial nerve]] weakness, jaw weakness, and weaknesses of the respiratory muscles that may lead to a myasthenic crisis, i.e., life-threatening [[respiratory arrest]].<ref name="pmid31794470"/><ref name="pmid37900462">{{cite journal | vauthors = Gosain D, Das T | title = Myasthenia Gravis Presenting as Bulbar Palsy | journal = Cureus | volume = 15 | issue = 9 | pages = e46082 | date = September 2023 | pmid = 37900462 | pmc = 10611170 | doi = 10.7759/cureus.46082 | doi-access = free | url = }}</ref> MG, particularly in long-standing cases, may have two or all three ocular, limb/axial, or bulbar symptoms.<ref name="pmid31794470"/><ref name="pmid34064035"/><ref name="pmid37900462"/> MG has also been separated into only two types: ocular MG and generalized MG, i.e., all other types of MG.<ref name="pmid38790567">{{cite journal | vauthors = Maeda M, Shimomura H, Tokunaga S, Taniguchi N, Lee T, Takeshima Y | title = Clinical Characteristics and Treatment of Juvenile Myasthenia Gravis-A Single-Center Experience | journal = Children (Basel, Switzerland) | volume = 11 | issue = 5 | date = May 2024 | page = 572 | pmid = 38790567 | pmc = 11120409 | doi = 10.3390/children11050572 | doi-access = free | url = }}</ref> MG is caused by antibodies directed at adult nAChR (70-85% of cases), the MUSK protein (1-10 % of cases), or the LRP4, protein (1% to 5% of cases).<ref name="pmid36945795">{{cite journal | vauthors = Li W, Liu P, Cui W, Wang S, Ji Y, Zhang L, He X, Zhou S, Shen T, Zhao X, Lv J, Zhang Y, Zhang J, Fang H, Yang J, Zhang Y, Cui X, Zhang Q, Gao F | title = Clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis in China | journal = Muscle & Nerve | volume = 67 | issue = 6 | pages = 481–488 | date = June 2023 | pmid = 36945795 | doi = 10.1002/mus.27822 | url = }}</ref><ref name="pmid37090043">{{cite journal | vauthors = Li Y, Peng Y, Yang H | title = Serological diagnosis of myasthenia gravis and its clinical significance | journal = Annals of Translational Medicine | volume = 11 | issue = 7 | pages = 290 | date = April 2023 | pmid = 37090043 | pmc = 10116419 | doi = 10.21037/atm-19-363 | doi-access = free | url = }}</ref> Uncommonly, individuals present with the symptoms of MG but test negative for antibodies to the nAChR, MuSK, and LRP4 protein, i.e., they have triple seronegative MG. This may be due to laboratory test inaccuracies, decreased antibody production, [[immunosenescence]], previous immunosuppressive therapies, acquired immunodeficiencies, depletion of the [[antigen]] attacked by the MG-causing antibody, or other diseases that mimic MG.<ref name="pmid37759888">{{cite journal | vauthors = Vinciguerra C, Bevilacqua L, Lupica A, Ginanneschi F, Piscosquito G, Rini N, Rossi A, Barone P, Brighina F, Di Stefano V | title = Diagnosis and Management of Seronegative Myasthenia Gravis: Lights and Shadows | journal = Brain Sciences | volume = 13 | issue = 9 | date = September 2023 | page = 1286 | pmid = 37759888 | pmc = 10526522 | doi = 10.3390/brainsci13091286 | doi-access = free | url = }}</ref> It is also possible that other proteins found to be elevated in some cases of MG (i.e., the [[agrin]] protein) or some as yet unidentified protein will be found to cause MG.<ref name="pmid37090043"/> |
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TNMG is one form of pediatric myasthenia gravis. Pediatric myasthenia gravis has two other forms which should not be confused with TNMG. Juvenile myasthenia gravis (JMG) refers to cases of MG that occur in children before the age of 19. It has been diagnosed in children as young as 8 months of age but, unlike TNMG, has not been diagnosed in fetuses (i.e., 9 weeks or older unborn offspring) or newborns.<ref name="pmid38790567"/> JMG accounts for about 10–15% of all MG cases and appears to be more prevalent in Asian than white populations, i.e., it represents up to 50% of all TNMG in Asians. Unlike TNMG but similar to MG, JMG is caused by the afflicted individuals production of antibodies directed at |
TNMG is one form of pediatric myasthenia gravis. Pediatric myasthenia gravis has two other forms which should not be confused with TNMG. Juvenile myasthenia gravis (i.e., JMG) refers to cases of MG that occur in children before the age of 19. It has been diagnosed in children as young as 8 months of age but, unlike TNMG, has not been diagnosed in fetuses (i.e., 9 weeks or older unborn offspring) or newborns.<ref name="pmid38790567"/> JMG accounts for about 10–15% of all MG cases and appears to be more prevalent in Asian than white populations, i.e., it represents up to 50% of all TNMG in Asians. Unlike TNMG but similar to MG, JMG is caused by the afflicted individuals production of antibodies directed at adult nAChRs, MuSK, or LRP4. (Individuals with JMG have an increased rate of also having [[Hashimoto disease]], [[polymyositis]], and other [[autoimmune diseases]].<ref name="pmid38790567"/><ref name="pmid28941526">{{cite journal | vauthors = Peragallo JH | title = Pediatric Myasthenia Gravis | journal = Seminars in Pediatric Neurology | volume = 24 | issue = 2 | pages = 116–121 | date = May 2017 | pmid = 28941526 | doi = 10.1016/j.spen.2017.04.003 | url = }}</ref>) The other form of pediatric myasthenia gravis is termed the [[congenital myasthenic syndrome]], i.e., CMGS. CMGS is not an autoimmune disease. It is a group of rare hereditary disorders in which the neuromuscular transmission in their skeletal muscles is dysfunctional due to the inheritance of defective genes.<ref name="pmid34749429">{{cite journal | vauthors = Estephan EP, Zambon AA, Thompson R, Polavarapu K, Jomaa D, Töpf A, Helito PV, Heise CO, Moreno CA, Silva AM, Kouyoumdjian JA, Morita MD, Reed UC, Lochmüller H, Zanoteli E | title = Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis | journal = European Journal of Neurology | volume = 29 | issue = 3 | pages = 833–842 | date = March 2022 | pmid = 34749429 | doi = 10.1111/ene.15173 | url = }}</ref> The defective genes code for proteins in the neuromuscular junctions that, due to their defects, reduce the number of nAChRs that are functional.<ref name="pmid35074870"/> One study reviewed the mutations in 32 genes that were responsible for causing CMGS. These genes' protein products function as [[ion-channels]], enzymes, or structural, signaling, sensor, or [[Transport protein|transporter]] proteins in the neuromuscular junctions. The skeletal muscles of individuals with one of these mutations exhibited easy fatigability, [[hypotonia]] (i.e., poor [[muscle tone]]), weakness, and/or delayed development of facial, bulbar, limb, respiratory, head, and/or back skeletal muscles.<ref name="pmid30808424">{{cite journal | vauthors = Finsterer J | title = Congenital myasthenic syndromes | journal = Orphanet Journal of Rare Diseases | volume = 14 | issue = 1 | pages = 57 | date = February 2019 | pmid = 30808424 | pmc = 6390566 | doi = 10.1186/s13023-019-1025-5 | doi-access = free | url = }}</ref> Mutations in the ''[[COLQ]], [[CHRNE]], [[RAPSN]], [[Dok-7]],'' and ''[[Choline acetyltransferase|CHAT]]'' genes were the most common mutations causing CMGS. None of the reported mutations caused pure ocular myasthenia, i.e., skeletal muscles weaknesses in the eye but not other areas.<ref name="pmid30808424"/> |
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== Causes == |
== Causes == |
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=== Transient neonatal myasthenia gravis === |
=== Transient neonatal myasthenia gravis === |
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TNMG is due to antibodies against the adult nAChR (about 85% of cases), the MuSK protein (about 6% of cases), and the LRP4 |
TNMG is due to antibodies against the adult nAChR (about 85% of cases), the MuSK protein (about 6% of cases), and the LRP4 in many of the remaining cases. These antibodies flow from the mother's blood through the [[placenta]] and into the fetus's blood and tissue.<ref name="pmid30133097"/><ref name="pmid32117321">{{cite journal | vauthors = Lazaridis K, Tzartos SJ | title = Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics | journal = Frontiers in Immunology | volume = 11 | issue = | pages = 212 | date = 2020 | pmid = 32117321 | pmc = 7033452 | doi = 10.3389/fimmu.2020.00212 | doi-access = free | url = }}</ref><ref name="pmid17915563">{{cite journal | vauthors = Newsom-Davis J | title = The emerging diversity of neuromuscular junction disorders | journal = Acta Myologica : Myopathies and Cardiomyopathies : Official Journal of the Mediterranean Society of Myology | volume = 26 | issue = 1 | pages = 5–10 | date = July 2007 | pmid = 17915563 | pmc = 2949330 | doi = | url = }}</ref><ref name="pmid37453109">{{cite journal | vauthors = Ristovska S, Stomnaroska O, Dimitrioska R | title = Transient Neonatal Myasthenia Gravis: A Case Report | journal = Prilozi (Makedonska Akademija Na Naukite I Umetnostite. Oddelenie Za Medicinski Nauki) | volume = 44 | issue = 2 | pages = 165–169 | date = July 2023 | pmid = 37453109 | doi = 10.2478/prilozi-2023-0036 | url = }}</ref> TNMG affects about 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis<ref name="pmid17915563"/> and has been reported to occur in the offspring of mothers who have MG that is in [[Remission (medicine)|remission]].<ref name="pmid38186498">{{cite journal | vauthors = Mishra AK, Varma A | title = Myasthenia Gravis: A Systematic Review | journal = Cureus | volume = 15 | issue = 12 | pages = e50017 | date = December 2023 | pmid = 38186498 | pmc = 10767470 | doi = 10.7759/cureus.50017 | doi-access = free | url = }}</ref> |
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=== Fetal acetylcholine receptor inactivation syndrome === |
=== Fetal acetylcholine receptor inactivation syndrome === |
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In rare cases, the FARIS form of TNMG develops in the fetus. It occurs when the mother's antibodies are directed at the fetal form of the nAChR and flow from her circulation through the placenta and into the fetus's circulation and tissues. The fetal and adult nAChR proteins consists of 4 subunit proteins, (α2, β, γ, δ) and (α2, β, ε, δ), respectively, with the fetal form persisting in the fetus until its γ subunit is replaced by the ε subunit to form the adult nAChR; this occurs by about the 33rd week of [[gestation]].<ref name="pmid17915563"/> Some publications have termed the more severe forms of FARIS as arthrogryposis multiplex congenita. i.e., AMC, because |
In rare cases, the FARIS form of TNMG develops in the fetus. It occurs when the mother's antibodies are directed at the fetal form of the nAChR and flow from her circulation through the placenta and into the fetus's circulation and tissues. The fetal and adult nAChR proteins consists of 4 subunit proteins, (α2, β, γ, δ) and (α2, β, ε, δ), respectively, with the fetal form persisting in the fetus until its γ subunit is replaced by the ε subunit to form the adult nAChR; this occurs by about the 33rd week of [[gestation]].<ref name="pmid17915563"/> Some publications have termed the more severe forms of FARIS as arthrogryposis multiplex congenita. i.e., AMC, because its offspring, among other severe abnormalities, have [[arthrogryposis]], i.e., disabling joint [[contractures]].<ref name="pmid37186601">{{cite journal | vauthors = Allen NM, O'Rahelly M, Eymard B, Chouchane M, Hahn A, Kearns G, Kim DS, Byun SY, Nguyen CE, Schara-Schmidt U, Kölbel H, Marina AD, Schneider-Gold C, Roefke K, Thieme A, Van den Bergh P, Avalos G, Álvarez-Velasco R, Natera-de Benito D, Cheng MH, Chan WK, Wan HS, Thomas MA, Borch L, Lauzon J, Kornblum C, Reimann J, Mueller A, Kuntzer T, Norwood F, Ramdas S, Jacobson LW, Jie X, Fernandez-Garcia MA, Wraige E, Lim M, Lin JP, Claeys KG, Aktas S, Oskoui M, Hacohen Y, Masud A, Leite MI, Palace J, De Vivo D, Vincent A, Jungbluth H | title = The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD) | journal = Brain : A Journal of Neurology | volume = 146 | issue = 10 | pages = 4233–4246 | date = October 2023 | pmid = 37186601 | pmc = 10545502 | doi = 10.1093/brain/awad153 | url = }}</ref> |
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== Symptoms == |
== Symptoms == |
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It is very likely and therefore to be anticipated that a fetus/newborn will have TNMG if: '''a)''' one or more of its siblings was previously diagnosed as having TNMG<ref name="pmid38398450"/> or '''b)''' if he/she is the offspring of a mother with MG and exhibits reduced, declining, or absent [[fetal movement |
It is very likely and therefore to be anticipated that a fetus/newborn will have TNMG if: '''a)''' one or more of its siblings was previously diagnosed as having TNMG<ref name="pmid38398450"/> or '''b)''' if he/she is the offspring of a mother with MG and exhibits reduced, rapidly declining, or absent [[fetal movement]]s.<ref name="pmid17915563"/> (Fetal movements are movements caused by the fetus's own muscle activity). Women perceive the first of their offspring's movements between the 16th and 20th weeks of their pregnancy after which the number of these movements may increase to a peak by 29 to 38 week of gestation. A fetus may show a gradual and slight decline in the number of its movements during its [[Pregnancy#Trimesters|third trimester]] due to its improved coordination and/or reduced [[amniotic fluid]] volume coupled with increases in its size. However, sharp declines in its movements are warnings that the fetus has serious abnormalities or difficulties (e.g., inadequate tissue oxygen levels).<ref name="pmid15315592">{{cite journal | vauthors = Olesen AG, Svare JA | title = Decreased fetal movements: background, assessment, and clinical management | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 83 | issue = 9 | pages = 818–26 | date = September 2004 | pmid = 15315592 | doi = 10.1111/j.0001-6349.2004.00603.x | url = }}</ref> |
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=== Transient neonatal myasthenia gravis === |
=== Transient neonatal myasthenia gravis === |
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About 50% of TNMG cases first show symptoms at birth with the remaining showing symptoms 6 to 72 hours or, uncommonly, up to several days after birth.<ref name="pmid33597740">{{cite journal | vauthors = Kochhar PK, Schumacher RE, Sarkar S | title = Transient neonatal myasthenia gravis: refining risk estimate for infants born to women with myasthenia gravis | journal = Journal of Perinatology : Official Journal of the California Perinatal Association | volume = 41 | issue = 9 | pages = 2279–2283 | date = September 2021 | pmid = 33597740 | doi = 10.1038/s41372-021-00970-6 | url = }}</ref> This delay may be due to the [[immunosuppressing]] actions of [[α-fetoprotein]] which is elevated in pregnant women and newborns<ref name="pmid38619448">{{cite journal | vauthors = Yeo YH, Lee YT, Tseng HR, Zhu Y, You S, Agopian VG, Yang JD | title = Alpha-fetoprotein: Past, present, and future | journal = Hepatology Communications | volume = 8 | issue = 5 | pages = | date = May 2024 | pmid = 38619448 | pmc = 11019827 | doi = 10.1097/HC9.0000000000000422 | url = }}</ref> and/or the transfer of [[cholinesterase inhibitor]] medications used during labor from the mother to her newborn.<ref name="pmid31794470"/> The afflicted offspring typically show skeletal muscle [[hypotonia]] (i.e., poor [[muscle tone]]) and weaknesses that are most prominent in head and neck muscles and cause [[diplegia#Facial diplegia|facial diplegia]] (i.e., paralysis or weakness of the skeletal muscles on both sides of the face), reduced control of swallowing; weak crying, sucking, and chewing; the inability to keep the jaw in place; feeding difficulties; and breathing difficulties which, while rare, may require [[mechanical ventilation]]<ref name="pmid38398450"/><ref name="pmid28941526"/><ref name="pmid17915563"/> In a review study only one in 15 newborns with TNMG needed [[intubation]] and mechanical ventilation for its respiratory distress.<ref name="pmid33597740"/> Some infants with TNMG develop [[jaundice]]; this jaundice may be due to inadequate fluid intake rather than direct damage to the liver. In the majority of TNMG |
About 50% of TNMG cases first show symptoms at birth with the remaining showing symptoms 6 to 72 hours or, uncommonly, up to several days after birth.<ref name="pmid33597740">{{cite journal | vauthors = Kochhar PK, Schumacher RE, Sarkar S | title = Transient neonatal myasthenia gravis: refining risk estimate for infants born to women with myasthenia gravis | journal = Journal of Perinatology : Official Journal of the California Perinatal Association | volume = 41 | issue = 9 | pages = 2279–2283 | date = September 2021 | pmid = 33597740 | doi = 10.1038/s41372-021-00970-6 | url = }}</ref> This delay may be due to the [[immunosuppressing]] actions of [[α-fetoprotein]] which is elevated in pregnant women and newborns<ref name="pmid38619448">{{cite journal | vauthors = Yeo YH, Lee YT, Tseng HR, Zhu Y, You S, Agopian VG, Yang JD | title = Alpha-fetoprotein: Past, present, and future | journal = Hepatology Communications | volume = 8 | issue = 5 | pages = | date = May 2024 | pmid = 38619448 | pmc = 11019827 | doi = 10.1097/HC9.0000000000000422 | url = }}</ref> and/or the transfer of [[cholinesterase inhibitor]] medications used during labor from the mother to her newborn.<ref name="pmid31794470"/> The afflicted offspring typically show skeletal muscle [[hypotonia]] (i.e., poor [[muscle tone]]) and weaknesses that are most prominent in head and neck muscles and cause [[diplegia#Facial diplegia|facial diplegia]] (i.e., paralysis or weakness of the skeletal muscles on both sides of the face), reduced control of swallowing; weak crying, sucking, and chewing; the inability to keep the jaw in place; feeding difficulties; and breathing difficulties which, while rare, may require [[mechanical ventilation]]<ref name="pmid38398450"/><ref name="pmid28941526"/><ref name="pmid17915563"/> In a review study only one in 15 newborns with TNMG needed [[intubation]] and mechanical ventilation for its respiratory distress.<ref name="pmid33597740"/> Some infants with TNMG develop [[jaundice]]; this jaundice may be due to inadequate fluid intake rather than direct damage to the liver. In the majority of TNMG newborns, their dysfunctions, including those that are severe or life-threatening, improve and then end within a short time after their maternal TNMG-causing antibodies have dissipated, generally within 3 to 4 months after their birth.<ref name="pmid38398450"/><ref name="pmid28941526"/><ref name="pmid17915563"/> |
||
=== Fetal acetylcholine receptor inactivation syndrome === |
=== Fetal acetylcholine receptor inactivation syndrome === |
||
Fetuses and newborns with FARIS generally have a more severe disease than those with TNMB. FARIS is caused by antibodies blocking the fetal type of nAChRs. This blockage causes disorders that begin during the early phases of fetal development and result in tissue and organ malformations as well as other disorders that are not fully reversible and may last a lifetime.<ref name="pmid38398450"/> In a review of 46 FARIS cases including those that would be classified as the severest form of FARIS (sometimes termed '''fetal acetylcholine receptor antibody-related disorder''', i.e., FARAD): '''a)''' half of the cases occurred in mothers who, while having MG, had not previously been diagnosed as having it; '''b)''' 7 pregnancies were terminated because of serious symptoms and/or organ malformations in the fetus; '''c)''' 4 offspring died after birth due mainly to [[respiratory failure]]; and '''d)''' surviving infants had weaknesses in or [[muscle contracture]]s of the bulbar and respiratory skeletal muscles that caused facial muscle weaknesses, leg/arm muscle weaknesses, [[velopharyngeal insufficiency]] (i.e., speech deficits due to poor movement of the [[soft palate]]), feeding difficulties, hearing losses, weakness of the [[Thoracic diaphragm|diaphragm]], [[pyloric stenosis]] (i.e., narrowing of the opening in the stomach that connects to the beginning of the small intestine), and [[central nervous system]] deficiencies such as [[autism]], [[language disorder]]s (i.e., impaired processing of linguistic information), the [[attention deficit hyperactivity disorder]], and [[intellectual impairment]]s.<ref name="pmid37186601"/> Other studies on the severe form of FARIS reported on cases of fetuses and newborns that suffered [[polyhydramnios]], i.e., excessive [[amniotic fluid]] in the [[amniotic sac]], [[arthrogryposis]], i.e., congenital joint contractures, and [[esophageal atresia]], i.e., the [[esophagus]] ending in a pouch rather than entering the stomach.<ref name="pmid17915563"/><ref name="pmid37186601"/> |
Fetuses and newborns with FARIS generally have a more severe disease than those with TNMB. FARIS is caused by antibodies blocking the fetal type of nAChRs. This blockage causes disorders that begin during the early phases of fetal development and result in tissue and organ malformations as well as other disorders that are not fully reversible and may last a lifetime.<ref name="pmid38398450"/> In a review of 46 FARIS cases including those that would be classified as the severest form of FARIS (sometimes termed '''fetal acetylcholine receptor antibody-related disorder''', i.e., FARAD): '''a)''' half of the cases occurred in mothers who, while having MG, had not previously been diagnosed as having it; '''b)''' 7 pregnancies were terminated because of serious symptoms and/or organ malformations in the fetus; '''c)''' 4 offspring died after birth due mainly to [[respiratory failure]]; and '''d)''' surviving infants had weaknesses in or [[muscle contracture]]s of the bulbar and respiratory skeletal muscles that caused facial muscle weaknesses, leg/arm muscle weaknesses, [[velopharyngeal insufficiency]] (i.e., speech deficits due to poor movement of the [[soft palate]]), feeding difficulties, hearing losses, weakness of the [[Thoracic diaphragm|diaphragm]], [[pyloric stenosis]] (i.e., narrowing of the opening in the stomach that connects to the beginning of the small intestine), and [[central nervous system]] deficiencies such as [[autism]], [[language disorder]]s (i.e., impaired processing of linguistic information), the [[attention deficit hyperactivity disorder]], and [[intellectual impairment]]s. The cause(s) for the cited central nervous system's defects is not understood.<ref name="pmid37186601"/> Other studies on the severe form of FARIS reported on cases of fetuses and newborns that suffered [[polyhydramnios]], i.e., excessive [[amniotic fluid]] in the [[amniotic sac]], [[arthrogryposis]], i.e., congenital joint contractures, and [[esophageal atresia]], i.e., the [[esophagus]] ending in a pouch rather than entering the stomach.<ref name="pmid17915563"/><ref name="pmid37186601"/> |
||
== Diagnosis == |
== Diagnosis == |
||
The congenital myasthenic syndrome (i.e., CMGS) and Juvenile MG (i.e., JMG) must be distinguished from TNMG/FARIS. Individuals with one of the CMGS inherited genetic disease do not have circulating antibodies to the adult nAChR, MuSK |
The congenital myasthenic syndrome (i.e., CMGS) and Juvenile MG (i.e., JMG) must be distinguished from TNMG/FARIS. Individuals with one of the CMGS inherited genetic disease do not have circulating antibodies to the adult nAChR, MuSK, or LRP4 proteins.<ref name="pmid34749429"/> Individuals with JMG do have these circulating antibodies but in no case have they presented with symptoms at ages less than 8 months.<ref name="pmid38790567"/> The presence of classic TNMG symptoms in the offspring of mothers who have MG is regarded as sufficient evidence for the diagnosis of TNMG in their offspring. However, the offspring of about 88% of mothers with MG do not have TNMG,<ref name="pmid33597740"/> and the offspring of TNMG may not have "classic" MG symptoms,<ref name="pmid34749429"/> i.e., may not have clinical abnormalities clear enough to support the diagnosis of TNMG.<ref name="pmid34064035"/><ref name="pmid17915563"/> In these cases, the identification of antibodies to the adult nAChR, MuSK, or LRP4 protein or to the fetal nAChR in the offspring's circulation is the definitive standard for diagnosing TNMG and FARIS, respectively.<ref name="pmid38790567"/><ref name="pmid37090043"/><ref name="pmid28941526"/><ref name="pmid37186601"/> |
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== Treatment == |
== Treatment == |
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=== Transient neonatal myasthenia gravis === |
=== Transient neonatal myasthenia gravis === |
||
A review of 147 cases of TNMG concluded that 4 days of hospital monitoring was sufficient to detect respiratory depression and other serious complications of TNMG such as bulbar MG muscle involvement which is associated with an increased risk of leading to respiratory depression.<ref name="pmid33597740"/> The treatment of TNMG is mainly supportive and dependent on the severity of the newborn's symptoms, i.e., it ranges from small oral feedings to mechanical ventilation but nonetheless is based on knowing that these symptoms will disappear or at least not worsen in most cases after 3 to 4 months.<ref name="pmid38398450"/><ref name="pmid28941526"/> A recent review<ref name="pmid38398450"/> recommended the treatments listed in the following Table for TNMG-afflicted offspring based on the severity of their symptoms. (In this Table: a positive pharmacological challenge test is one showing definite improvement in myasthenic muscle weakness within 10–15 minutes of administering a single intramuscular or subcutaneous injection of neostigmine;<ref name="pmid38398450"/> [[intravenous immunoglobulin]] therapy is the infusion of a mixture of human antibodies that have a wide range of anti-inflammatory and other actions of clinical benefit in treating TNMG;<ref name="pmid35350948">{{cite journal | vauthors = Dalakas MC, Meisel A | title = Immunomodulatory effects and clinical benefits of intravenous immunoglobulin in myasthenia gravis | journal = Expert Review of Neurotherapeutics | volume = 22 | issue = 4 | pages = 313–318 | date = April 2022 | pmid = 35350948 | doi = 10.1080/14737175.2022.2057223 | url = }}</ref> and [[plasmapheresis]] is the removal of plasma from MG patients or exchange of their plasma with normal human plasma to reduce the MG-causing antibody levels and thereby the symptoms of TNMG.<ref name="pmid38306763">{{cite journal | vauthors = Ghimire A, Kunwar B, Aryal B, Gaire A, Bist A, Shah B, Mainali A, Ghimire B, Gajurel BP | title = Assessing the comparative efficacy of plasmapheresis and Intravenous immunoglobulin in myasthenia gravis treatment: A systematic review and meta-analysis | journal = Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia | volume = 121 | issue = | pages = 1–10 | date = March 2024 | pmid = 38306763 | doi = 10.1016/j.jocn.2024.01.025 | url = }}</ref>) Note that newborns undergoing |
A review of 147 cases of TNMG concluded that 4 days of hospital monitoring was sufficient to detect respiratory depression and other serious complications of TNMG such as bulbar MG muscle involvement which is associated with an increased risk of leading to respiratory depression.<ref name="pmid33597740"/> The treatment of TNMG is mainly supportive and dependent on the severity of the newborn's symptoms, i.e., it ranges from small oral feedings to mechanical ventilation but nonetheless is based on knowing that these symptoms will disappear or at least not worsen in most cases after 3 to 4 months.<ref name="pmid38398450"/><ref name="pmid28941526"/> A recent review<ref name="pmid38398450"/> recommended the treatments listed in the following Table for TNMG-afflicted offspring based on the severity of their symptoms. (In this Table: a positive pharmacological challenge test is one showing definite improvement in myasthenic muscle weakness within 10–15 minutes of administering a single intramuscular or subcutaneous injection of [[neostigmine]];<ref name="pmid38398450"/> [[intravenous immunoglobulin]] therapy is the infusion of a mixture of human antibodies that have a wide range of anti-inflammatory and other actions of clinical benefit in treating TNMG;<ref name="pmid35350948">{{cite journal | vauthors = Dalakas MC, Meisel A | title = Immunomodulatory effects and clinical benefits of intravenous immunoglobulin in myasthenia gravis | journal = Expert Review of Neurotherapeutics | volume = 22 | issue = 4 | pages = 313–318 | date = April 2022 | pmid = 35350948 | doi = 10.1080/14737175.2022.2057223 | url = | doi-access = free }}</ref> and [[plasmapheresis]] is the removal of plasma from MG patients or exchange of their plasma with normal human plasma to reduce the MG-causing antibody levels and thereby the symptoms of TNMG.<ref name="pmid38306763">{{cite journal | vauthors = Ghimire A, Kunwar B, Aryal B, Gaire A, Bist A, Shah B, Mainali A, Ghimire B, Gajurel BP | title = Assessing the comparative efficacy of plasmapheresis and Intravenous immunoglobulin in myasthenia gravis treatment: A systematic review and meta-analysis | journal = Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia | volume = 121 | issue = | pages = 1–10 | date = March 2024 | pmid = 38306763 | doi = 10.1016/j.jocn.2024.01.025 | url = }}</ref>) Note that newborns undergoing mechanical ventilation should not receive acetylcholinesterase inhibitors because these inhibitors may increase airway [[mucous]] secretions and thereby impair this ventilation and increase airway infections.<ref name="pmid37101094"/> |
||
mechanical ventilation should not receive acetylcholinesterase inhibitors because these inhibitors may increase airway [[mucous]] secretions and thereby impair this ventilation and increase airway infections.<ref name="pmid37101094"/> |
|||
{| class="wikitable" |
{| class="wikitable" |
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Line 57: | Line 56: | ||
| Very mild || Fluctuating mild hypotonia, oral feeding possible || Close observation and breastfeeding support |
| Very mild || Fluctuating mild hypotonia, oral feeding possible || Close observation and breastfeeding support |
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|- |
|- |
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| Mild || Persistent or intermittent hypotonia, feeding difficulties || Consider low-dose [[acetylcholinesterase inhibitor]] (e.g., neostigmine or pyridostigmine) before feeding if results of a pharmacological challenge test are positive |
| Mild || Persistent or intermittent hypotonia, feeding difficulties || Consider low-dose [[acetylcholinesterase inhibitor]] (e.g., neostigmine or [[pyridostigmine]]) before feeding if results of a pharmacological challenge test are positive |
||
|- |
|- |
||
| Moderate || Inadequate Oral feeding but no respiratory distress || Nasogastric tube feedings, an acetylcholinesterase inhibitor, and consider giving intravenous immunoglobulin |
| Moderate || Inadequate Oral feeding but no respiratory distress || Nasogastric tube feedings, an acetylcholinesterase inhibitor, and consider giving intravenous immunoglobulin |
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|- |
|- |
||
| Severe || Respiratory distress || |
| Severe || Respiratory distress || Support of respiration, acetylcholinesterase inhibitor, and regular intravenous immunoglobulin and/or plasmapheresis |
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|- |
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=== Fetal acetylcholine receptor inactivation syndrome === |
=== Fetal acetylcholine receptor inactivation syndrome === |
||
A male infant born with FARIS had severe symptoms. He required mechanical ventilation from birth to 3 weeks of age and also had profoundly weak trunk, facial, and bulbar skeletal muscles that improved slowly and only partially over several years. At the age of 4.9 years, he had persistent facial diplegia with severe language difficulties, a weak voice, drooling, and substantially reduced stamina all of which showed little or no response to the oral acetylcholinesterase inhibitor |
A male infant born with FARIS had severe symptoms. He required mechanical ventilation from birth to 3 weeks of age and also had profoundly weak trunk, facial, and bulbar skeletal muscles that improved slowly and only partially over several years. At the age of 4.9 years, he had persistent facial diplegia with severe language difficulties, a weak voice, drooling, and substantially reduced stamina all of which showed little or no response to the oral acetylcholinesterase inhibitor, pyridostigmine.<ref name="pmid26791147">{{cite journal | vauthors = Allen NM, Hacohen Y, Palace J, Beeson D, Vincent A, Jungbluth H | title = Salbutamol-responsive fetal acetylcholine receptor inactivation syndrome | journal = Neurology | volume = 86 | issue = 7 | pages = 692–4 | date = February 2016 | pmid = 26791147 | pmc = 4762416 | doi = 10.1212/WNL.0000000000002382 | url = }}</ref> However, treatment with oral [[salbutamol]], a drug that stimulates the [[beta-2 adrenergic receptor]],<ref name="pmid34749429"/> greatly reduced these symptoms within 48 hours.<ref name="pmid26791147"/> In a subsequent study of 16 individuals with FARIS aged less than 4 weeks, 4 full weeks, 10 weeks, and 6 months to 17 years, oral salbutamol caused symptom improvements in 13 (81.3%) with all three who were 10 weeks old or younger showing improvements.<ref name="pmid37186601"/> In further studies, 21 pregnant women that ended up having FARIS-afflicted offspring were administered an immunotherapeutic regimen consisting of intravenous immunoglobulin or plasmapheresis with or without high-dose [[corticosteroid]]s from their first trimester onward. Compared to 65 immunotherapy-untreated women that had FARIS offspring, this treatment was significantly effective in preventing death and other severe FARIS disorders in the offspring. These beneficial effects were less pronounced when the immunotherapies were given to women later in their pregnancies. The two studies concluded that oral salbutamol is a symptomatic treatment option for neonates as well as older individuals with FARIS<ref name="pmid37186601"/><ref name="pmid26791147"/> and suggested that, while further studies are needed, infusions of the cited immunotherapeutic agents into pregnant women who are known or strongly suspected of carrying fetuses that have FARIS may reduce the severity of their fetuses' symptoms and disorders.<ref name="pmid37186601"/> |
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== References == |
== References == |
Revision as of 00:19, 27 June 2024
Transient neonatal myasthenia gravis | |
---|---|
Specialty | Pediatrics, Pediatric neurology, Pediatric pulmonology, Pediatric intensive care medicine |
Symptoms | skeletal muscles weaknesses and, in rare cases. organ deformities in one or more areas of the body in fetuses and newborns |
Complications | Myasthenic crisis, i.e., weakness in the lungs skeletal muscles causing potentially lethal respiratory failure |
Usual onset | During fetal development |
Duration | Most cases remit by 4 months after birth |
Causes | Antibodies against proteins in the neuromuscular junction of skeletal muscles made by a mother with myasthenia gravis and passed from her blood to her fetus's blood |
Diagnostic method | Classic symptoms of transient neonatal myasthenia gravies in the offspring of mothers who have myasthenia gravis |
Differential diagnosis | Juvenile myasthenia gravis, congenital myasthenia gravis |
Frequency | Rare |
Transient neonatal myasthenia gravis, i.e., TNMG (also termed neonatal myasthenia gravis[1]), and its more severe form, fetal acetylcholine receptor inactivation syndrome (i.e., FARIS), is one of the various types of myasthenia gravis (i.e., MG).[2] MG is an autoimmune disease in which individuals form antibodies that circulate in their blood, enter tissues, bind to certain proteins in the neuromuscular junctions of skeletal muscles, and thereby reduce the number or ability of these skeletal muscles to contract when appropriately stimulated by acetylcholine. The affected skeletal muscles are easily fatigable, i.e., weakened after relatively little use. There are 3 types of antibodies that are known to cause TNMG/FARIS: antibodies binding to the adult form of the nicotinic acetylcholine receptor, i.e., adult nAChR, are responsible for most cases of TNMG while antibodies binding to two proteins near these nAChRs, i.e., the MuSK protein and low-density lipoprotein receptor-related protein 4 (i.e., LRP4) are responsible for many of the remaining cases of TNMG.[3][4][5] Antibodies directed at the fetal form of nAChRs are responsible for all cases of FARIS.[1][4][5]
MG may present as muscle weakness in different areas of the body: a) ocular MG is skeletal muscle weakness in the eyes that causes ptosis (i.e., eyelid drooping), weak eyelid closure, strabismus (i.e., one eye turned in a direction different from the other eye), diplopia (i.e., double vision), and/or complex ophthalmoplegias (e.g., weakness or paralysis of one or more extraocular muscles responsible for eye movements);[6][7][8] b) limb/axial MG is skeletal muscle weakness of the arms, legs, trunk, and/or head that causes weak finger extension, wrist drop, foot and hand dorsiflexions (backward bending or contraction of the foot or hand), difficulty in raising the arms above the head, getting up from low seats or toilets, walking long distances, and climbing stairs, and head drop (i.e., relaxing of the neck muscles);[9][10] and c) bulbar MG is weakness of the skeletal muscles activated by nerves from the lower part of the brain stem termed the medulla oblongata that causes slurred speech, dysphagia (i.e., difficulty in swallowing), dysphonia (i.e., hoarse voice), bilateral facial nerve weakness, jaw weakness, and weaknesses of the respiratory muscles that may lead to a myasthenic crisis, i.e., life-threatening respiratory arrest.[9][11] MG, particularly in long-standing cases, may have two or all three ocular, limb/axial, or bulbar symptoms.[9][10][11] MG has also been separated into only two types: ocular MG and generalized MG, i.e., all other types of MG.[12] MG is caused by antibodies directed at adult nAChR (70-85% of cases), the MUSK protein (1-10 % of cases), or the LRP4, protein (1% to 5% of cases).[13][14] Uncommonly, individuals present with the symptoms of MG but test negative for antibodies to the nAChR, MuSK, and LRP4 protein, i.e., they have triple seronegative MG. This may be due to laboratory test inaccuracies, decreased antibody production, immunosenescence, previous immunosuppressive therapies, acquired immunodeficiencies, depletion of the antigen attacked by the MG-causing antibody, or other diseases that mimic MG.[15] It is also possible that other proteins found to be elevated in some cases of MG (i.e., the agrin protein) or some as yet unidentified protein will be found to cause MG.[14]
TNMG is one form of pediatric myasthenia gravis. Pediatric myasthenia gravis has two other forms which should not be confused with TNMG. Juvenile myasthenia gravis (i.e., JMG) refers to cases of MG that occur in children before the age of 19. It has been diagnosed in children as young as 8 months of age but, unlike TNMG, has not been diagnosed in fetuses (i.e., 9 weeks or older unborn offspring) or newborns.[12] JMG accounts for about 10–15% of all MG cases and appears to be more prevalent in Asian than white populations, i.e., it represents up to 50% of all TNMG in Asians. Unlike TNMG but similar to MG, JMG is caused by the afflicted individuals production of antibodies directed at adult nAChRs, MuSK, or LRP4. (Individuals with JMG have an increased rate of also having Hashimoto disease, polymyositis, and other autoimmune diseases.[12][16]) The other form of pediatric myasthenia gravis is termed the congenital myasthenic syndrome, i.e., CMGS. CMGS is not an autoimmune disease. It is a group of rare hereditary disorders in which the neuromuscular transmission in their skeletal muscles is dysfunctional due to the inheritance of defective genes.[17] The defective genes code for proteins in the neuromuscular junctions that, due to their defects, reduce the number of nAChRs that are functional.[5] One study reviewed the mutations in 32 genes that were responsible for causing CMGS. These genes' protein products function as ion-channels, enzymes, or structural, signaling, sensor, or transporter proteins in the neuromuscular junctions. The skeletal muscles of individuals with one of these mutations exhibited easy fatigability, hypotonia (i.e., poor muscle tone), weakness, and/or delayed development of facial, bulbar, limb, respiratory, head, and/or back skeletal muscles.[18] Mutations in the COLQ, CHRNE, RAPSN, Dok-7, and CHAT genes were the most common mutations causing CMGS. None of the reported mutations caused pure ocular myasthenia, i.e., skeletal muscles weaknesses in the eye but not other areas.[18]
Causes
Transient neonatal myasthenia gravis
TNMG is due to antibodies against the adult nAChR (about 85% of cases), the MuSK protein (about 6% of cases), and the LRP4 in many of the remaining cases. These antibodies flow from the mother's blood through the placenta and into the fetus's blood and tissue.[3][19][20][21] TNMG affects about 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis[20] and has been reported to occur in the offspring of mothers who have MG that is in remission.[22]
Fetal acetylcholine receptor inactivation syndrome
In rare cases, the FARIS form of TNMG develops in the fetus. It occurs when the mother's antibodies are directed at the fetal form of the nAChR and flow from her circulation through the placenta and into the fetus's circulation and tissues. The fetal and adult nAChR proteins consists of 4 subunit proteins, (α2, β, γ, δ) and (α2, β, ε, δ), respectively, with the fetal form persisting in the fetus until its γ subunit is replaced by the ε subunit to form the adult nAChR; this occurs by about the 33rd week of gestation.[20] Some publications have termed the more severe forms of FARIS as arthrogryposis multiplex congenita. i.e., AMC, because its offspring, among other severe abnormalities, have arthrogryposis, i.e., disabling joint contractures.[23]
Symptoms
It is very likely and therefore to be anticipated that a fetus/newborn will have TNMG if: a) one or more of its siblings was previously diagnosed as having TNMG[2] or b) if he/she is the offspring of a mother with MG and exhibits reduced, rapidly declining, or absent fetal movements.[20] (Fetal movements are movements caused by the fetus's own muscle activity). Women perceive the first of their offspring's movements between the 16th and 20th weeks of their pregnancy after which the number of these movements may increase to a peak by 29 to 38 week of gestation. A fetus may show a gradual and slight decline in the number of its movements during its third trimester due to its improved coordination and/or reduced amniotic fluid volume coupled with increases in its size. However, sharp declines in its movements are warnings that the fetus has serious abnormalities or difficulties (e.g., inadequate tissue oxygen levels).[24]
Transient neonatal myasthenia gravis
About 50% of TNMG cases first show symptoms at birth with the remaining showing symptoms 6 to 72 hours or, uncommonly, up to several days after birth.[25] This delay may be due to the immunosuppressing actions of α-fetoprotein which is elevated in pregnant women and newborns[26] and/or the transfer of cholinesterase inhibitor medications used during labor from the mother to her newborn.[9] The afflicted offspring typically show skeletal muscle hypotonia (i.e., poor muscle tone) and weaknesses that are most prominent in head and neck muscles and cause facial diplegia (i.e., paralysis or weakness of the skeletal muscles on both sides of the face), reduced control of swallowing; weak crying, sucking, and chewing; the inability to keep the jaw in place; feeding difficulties; and breathing difficulties which, while rare, may require mechanical ventilation[2][16][20] In a review study only one in 15 newborns with TNMG needed intubation and mechanical ventilation for its respiratory distress.[25] Some infants with TNMG develop jaundice; this jaundice may be due to inadequate fluid intake rather than direct damage to the liver. In the majority of TNMG newborns, their dysfunctions, including those that are severe or life-threatening, improve and then end within a short time after their maternal TNMG-causing antibodies have dissipated, generally within 3 to 4 months after their birth.[2][16][20]
Fetal acetylcholine receptor inactivation syndrome
Fetuses and newborns with FARIS generally have a more severe disease than those with TNMB. FARIS is caused by antibodies blocking the fetal type of nAChRs. This blockage causes disorders that begin during the early phases of fetal development and result in tissue and organ malformations as well as other disorders that are not fully reversible and may last a lifetime.[2] In a review of 46 FARIS cases including those that would be classified as the severest form of FARIS (sometimes termed fetal acetylcholine receptor antibody-related disorder, i.e., FARAD): a) half of the cases occurred in mothers who, while having MG, had not previously been diagnosed as having it; b) 7 pregnancies were terminated because of serious symptoms and/or organ malformations in the fetus; c) 4 offspring died after birth due mainly to respiratory failure; and d) surviving infants had weaknesses in or muscle contractures of the bulbar and respiratory skeletal muscles that caused facial muscle weaknesses, leg/arm muscle weaknesses, velopharyngeal insufficiency (i.e., speech deficits due to poor movement of the soft palate), feeding difficulties, hearing losses, weakness of the diaphragm, pyloric stenosis (i.e., narrowing of the opening in the stomach that connects to the beginning of the small intestine), and central nervous system deficiencies such as autism, language disorders (i.e., impaired processing of linguistic information), the attention deficit hyperactivity disorder, and intellectual impairments. The cause(s) for the cited central nervous system's defects is not understood.[23] Other studies on the severe form of FARIS reported on cases of fetuses and newborns that suffered polyhydramnios, i.e., excessive amniotic fluid in the amniotic sac, arthrogryposis, i.e., congenital joint contractures, and esophageal atresia, i.e., the esophagus ending in a pouch rather than entering the stomach.[20][23]
Diagnosis
The congenital myasthenic syndrome (i.e., CMGS) and Juvenile MG (i.e., JMG) must be distinguished from TNMG/FARIS. Individuals with one of the CMGS inherited genetic disease do not have circulating antibodies to the adult nAChR, MuSK, or LRP4 proteins.[17] Individuals with JMG do have these circulating antibodies but in no case have they presented with symptoms at ages less than 8 months.[12] The presence of classic TNMG symptoms in the offspring of mothers who have MG is regarded as sufficient evidence for the diagnosis of TNMG in their offspring. However, the offspring of about 88% of mothers with MG do not have TNMG,[25] and the offspring of TNMG may not have "classic" MG symptoms,[17] i.e., may not have clinical abnormalities clear enough to support the diagnosis of TNMG.[10][20] In these cases, the identification of antibodies to the adult nAChR, MuSK, or LRP4 protein or to the fetal nAChR in the offspring's circulation is the definitive standard for diagnosing TNMG and FARIS, respectively.[12][14][16][23]
Treatment
Women with MG should be monitored with standard prenatal care screenings, e.g., regular assessments of fetal growth, self-monitoring of fetal movements starting at 24 weeks of gestation, and medical ultrasound scans before 24 weeks of gestation. It is particularly important that the newborn of mothers with MG be closely monitored for any signs or symptoms of respiratory depression that may lead to respiratory failure and the need to be treated with mechanical ventilation.[2]
Transient neonatal myasthenia gravis
A review of 147 cases of TNMG concluded that 4 days of hospital monitoring was sufficient to detect respiratory depression and other serious complications of TNMG such as bulbar MG muscle involvement which is associated with an increased risk of leading to respiratory depression.[25] The treatment of TNMG is mainly supportive and dependent on the severity of the newborn's symptoms, i.e., it ranges from small oral feedings to mechanical ventilation but nonetheless is based on knowing that these symptoms will disappear or at least not worsen in most cases after 3 to 4 months.[2][16] A recent review[2] recommended the treatments listed in the following Table for TNMG-afflicted offspring based on the severity of their symptoms. (In this Table: a positive pharmacological challenge test is one showing definite improvement in myasthenic muscle weakness within 10–15 minutes of administering a single intramuscular or subcutaneous injection of neostigmine;[2] intravenous immunoglobulin therapy is the infusion of a mixture of human antibodies that have a wide range of anti-inflammatory and other actions of clinical benefit in treating TNMG;[27] and plasmapheresis is the removal of plasma from MG patients or exchange of their plasma with normal human plasma to reduce the MG-causing antibody levels and thereby the symptoms of TNMG.[28]) Note that newborns undergoing mechanical ventilation should not receive acetylcholinesterase inhibitors because these inhibitors may increase airway mucous secretions and thereby impair this ventilation and increase airway infections.[1]
Severity grade | Symptoms | Treatments |
---|---|---|
Very mild | Fluctuating mild hypotonia, oral feeding possible | Close observation and breastfeeding support |
Mild | Persistent or intermittent hypotonia, feeding difficulties | Consider low-dose acetylcholinesterase inhibitor (e.g., neostigmine or pyridostigmine) before feeding if results of a pharmacological challenge test are positive |
Moderate | Inadequate Oral feeding but no respiratory distress | Nasogastric tube feedings, an acetylcholinesterase inhibitor, and consider giving intravenous immunoglobulin |
Severe | Respiratory distress | Support of respiration, acetylcholinesterase inhibitor, and regular intravenous immunoglobulin and/or plasmapheresis |
Fetal acetylcholine receptor inactivation syndrome
A male infant born with FARIS had severe symptoms. He required mechanical ventilation from birth to 3 weeks of age and also had profoundly weak trunk, facial, and bulbar skeletal muscles that improved slowly and only partially over several years. At the age of 4.9 years, he had persistent facial diplegia with severe language difficulties, a weak voice, drooling, and substantially reduced stamina all of which showed little or no response to the oral acetylcholinesterase inhibitor, pyridostigmine.[29] However, treatment with oral salbutamol, a drug that stimulates the beta-2 adrenergic receptor,[17] greatly reduced these symptoms within 48 hours.[29] In a subsequent study of 16 individuals with FARIS aged less than 4 weeks, 4 full weeks, 10 weeks, and 6 months to 17 years, oral salbutamol caused symptom improvements in 13 (81.3%) with all three who were 10 weeks old or younger showing improvements.[23] In further studies, 21 pregnant women that ended up having FARIS-afflicted offspring were administered an immunotherapeutic regimen consisting of intravenous immunoglobulin or plasmapheresis with or without high-dose corticosteroids from their first trimester onward. Compared to 65 immunotherapy-untreated women that had FARIS offspring, this treatment was significantly effective in preventing death and other severe FARIS disorders in the offspring. These beneficial effects were less pronounced when the immunotherapies were given to women later in their pregnancies. The two studies concluded that oral salbutamol is a symptomatic treatment option for neonates as well as older individuals with FARIS[23][29] and suggested that, while further studies are needed, infusions of the cited immunotherapeutic agents into pregnant women who are known or strongly suspected of carrying fetuses that have FARIS may reduce the severity of their fetuses' symptoms and disorders.[23]
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