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Congenital myasthenic syndrome 16(CMS16)

MedGen UID:
481742
Concept ID:
C3280112
Disease or Syndrome
Synonyms: Congenital myasthenic syndrome, acetazolamide-responsive; SCN4A-Related Congenital Myasthenic Syndrome
 
Gene (location): SCN4A (17q23.3)
 
Monarch Initiative: MONDO:0013620
OMIM®: 614198

Definition

Congenital myasthenic syndrome is a disorder characterized by variable degrees of muscle fatigability caused by impaired transmission of electrical signals at the neuromuscular junction (NMJ) (summary by Arnold et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). [from OMIM]

Additional description

From MedlinePlus Genetics
Some individuals have episodes of breathing problems that may be triggered by fevers or infection. Severely affected individuals may also experience short pauses in breathing (apnea) that can lead to a bluish appearance of the skin or lips (cyanosis).

Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood. Facial muscles, including muscles that control the eyelids, muscles that move the eyes, and muscles used for chewing and swallowing, are most commonly affected. However, any of the muscles used for movement (skeletal muscles) can be affected in this condition. Due to muscle weakness, affected infants may have feeding difficulties. Development of motor skills such as crawling or walking may be delayed. The severity of the myasthenia varies greatly, with some people experiencing minor weakness and others having such severe weakness that they are unable to walk.  https://medlineplus.gov/genetics/condition/congenital-myasthenic-syndrome

Clinical features

From HPO
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Fatigable weakness
MedGen UID:
451076
Concept ID:
C0947912
Disease or Syndrome
A type of weakness that occurs after a muscle group is used and lessens if the muscle group has some rest. That is, there is diminution of strength with repetitive muscle actions.
Periodic paralysis
MedGen UID:
488958
Concept ID:
C1279412
Disease or Syndrome
Episodes of muscle weakness.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
EMG: decremental response of compound muscle action potential to repetitive nerve stimulation
MedGen UID:
892749
Concept ID:
C4021728
Finding
A compound muscle action potential (CMAP) is a type of electromyography (EMG). CMAP refers to a group of almost simultaneous action potentials from several muscle fibers in the same area evoked by stimulation of the supplying motor nerve and are recorded as one multipeaked summated action potential. This abnormality refers to a greater than normal decrease in the amplitude during the course of the investigation.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Anti-acetylcholine receptor antibody positivity
MedGen UID:
868186
Concept ID:
C4022578
Finding
The presence of autoantibodies (immunoglobulins) in the blood circulation that react against ganglioside-monosialic acid (GM1), which is a type of glycosphingolipid with one sialic acid. GM1 is located on the outer layer of the plasma membrane, and plays a vital role in neurogenesis, nerve development, differentiation and repair after injury.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
External ophthalmoplegia
MedGen UID:
57662
Concept ID:
C0162292
Disease or Syndrome
Paralysis of the external ocular muscles.
Bilateral ptosis
MedGen UID:
356120
Concept ID:
C1865916
Disease or Syndrome

Professional guidelines

PubMed

McMacken G, Whittaker RG, Wake R, Lochmuller H, Horvath R
J Neurol 2023 Jun;270(6):3112-3119. Epub 2023 Mar 4 doi: 10.1007/s00415-023-11643-z. PMID: 36869887Free PMC Article
Witting N, Vissing J
JAMA Neurol 2014 Mar;71(3):350-4. doi: 10.1001/jamaneurol.2013.5590. PMID: 24425145

Recent clinical studies

Etiology

Öztürk S, Güleç A, Erdoğan M, Demir M, Canpolat M, Gümüş H, Çağlayan AO, Dündar M, Per H
Pediatr Neurol 2022 Nov;136:43-49. Epub 2022 Aug 18 doi: 10.1016/j.pediatrneurol.2022.08.001. PMID: 36099689
O'Connell K, Rooney T, Alabaf S, Ramdas S, Beeson D, Palace J
Muscle Nerve 2022 Sep;66(3):345-348. Epub 2022 Jun 24 doi: 10.1002/mus.27653. PMID: 35661384
Estephan EP, Zambon AA, Thompson R, Polavarapu K, Jomaa D, Töpf A, Helito PVP, Heise CO, Moreno CAM, Silva AMS, Kouyoumdjian JA, Morita MDP, Reed UC, Lochmüller H, Zanoteli E
Eur J Neurol 2022 Mar;29(3):833-842. Epub 2021 Nov 17 doi: 10.1111/ene.15173. PMID: 34749429
Hamasaki Y, Hamada R, Muramatsu M, Matsumoto S, Aya K, Ishikura K, Kaneko T, Iijima K
BMC Nephrol 2020 Aug 24;21(1):363. doi: 10.1186/s12882-020-02010-5. PMID: 32838745Free PMC Article
Nogajski JH, Kiernan MC, Ouvrier RA, Andrews PI
J Clin Neurosci 2009 Jan;16(1):1-11. Epub 2008 Nov 18 doi: 10.1016/j.jocn.2008.05.001. PMID: 19017561

Diagnosis

Öztürk S, Güleç A, Erdoğan M, Demir M, Canpolat M, Gümüş H, Çağlayan AO, Dündar M, Per H
Pediatr Neurol 2022 Nov;136:43-49. Epub 2022 Aug 18 doi: 10.1016/j.pediatrneurol.2022.08.001. PMID: 36099689
O'Connell K, Rooney T, Alabaf S, Ramdas S, Beeson D, Palace J
Muscle Nerve 2022 Sep;66(3):345-348. Epub 2022 Jun 24 doi: 10.1002/mus.27653. PMID: 35661384
Estephan EP, Zambon AA, Thompson R, Polavarapu K, Jomaa D, Töpf A, Helito PVP, Heise CO, Moreno CAM, Silva AMS, Kouyoumdjian JA, Morita MDP, Reed UC, Lochmüller H, Zanoteli E
Eur J Neurol 2022 Mar;29(3):833-842. Epub 2021 Nov 17 doi: 10.1111/ene.15173. PMID: 34749429
Hamasaki Y, Hamada R, Muramatsu M, Matsumoto S, Aya K, Ishikura K, Kaneko T, Iijima K
BMC Nephrol 2020 Aug 24;21(1):363. doi: 10.1186/s12882-020-02010-5. PMID: 32838745Free PMC Article
Nogajski JH, Kiernan MC, Ouvrier RA, Andrews PI
J Clin Neurosci 2009 Jan;16(1):1-11. Epub 2008 Nov 18 doi: 10.1016/j.jocn.2008.05.001. PMID: 19017561

Therapy

McMacken G, Whittaker RG, Wake R, Lochmuller H, Horvath R
J Neurol 2023 Jun;270(6):3112-3119. Epub 2023 Mar 4 doi: 10.1007/s00415-023-11643-z. PMID: 36869887Free PMC Article
Hamasaki Y, Hamada R, Muramatsu M, Matsumoto S, Aya K, Ishikura K, Kaneko T, Iijima K
BMC Nephrol 2020 Aug 24;21(1):363. doi: 10.1186/s12882-020-02010-5. PMID: 32838745Free PMC Article
McMacken G, Whittaker RG, Evangelista T, Abicht A, Dusl M, Lochmüller H
J Neurol 2018 Jan;265(1):194-203. Epub 2017 Nov 30 doi: 10.1007/s00415-017-8689-3. PMID: 29189923Free PMC Article
Gallenmüller C, Müller-Felber W, Dusl M, Stucka R, Guergueltcheva V, Blaschek A, von der Hagen M, Huebner A, Müller JS, Lochmüller H, Abicht A
Neuromuscul Disord 2014 Jan;24(1):31-5. Epub 2013 Aug 7 doi: 10.1016/j.nmd.2013.08.002. PMID: 24183479Free PMC Article
Colomer J, Müller JS, Vernet A, Nascimento A, Pons M, Gonzalez V, Abicht A, Lochmüller H
Neuromuscul Disord 2006 May;16(5):329-33. Epub 2006 Apr 18 doi: 10.1016/j.nmd.2006.02.009. PMID: 16621558

Prognosis

Freed AS, Schwarz AC, Brei BK, Clowes Candadai SV, Thies J, Mah JK, Chabra S, Wang L, Innes AM, Bennett JT
Am J Med Genet A 2021 Mar;185(3):827-835. Epub 2020 Dec 9 doi: 10.1002/ajmg.a.62011. PMID: 33296147
Rodríguez Cruz PM, Cossins J, Estephan EP, Munell F, Selby K, Hirano M, Maroofin R, Mehrjardi MYV, 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, Gratacos M, Macaya A, Dusl M, Senderek J, Töpf A, Hofer M, Knight R, Ramdas S, Jayawant S, Lochmüller H, Palace J, Beeson D
Brain 2019 Jun 1;142(6):1547-1560. doi: 10.1093/brain/awz107. PMID: 31081514Free PMC Article
Rahman MA, Azuma Y, Nasrin F, Takeda J, Nazim M, Bin Ahsan K, Masuda A, Engel AG, Ohno K
Sci Rep 2015 Aug 18;5:13208. doi: 10.1038/srep13208. PMID: 26282582Free PMC Article
Ohno K, Engel AG
Acta Myol 2005 Oct;24(2):50-4. PMID: 16550914
Engel AG
Ann Neurol 1984 Nov;16(5):519-34. doi: 10.1002/ana.410160502. PMID: 6095730

Clinical prediction guides

Hentschel A, Czech A, Münchberg U, Freier E, Schara-Schmidt U, Sickmann A, Reimann J, Roos A
Orphanet J Rare Dis 2021 Feb 9;16(1):73. doi: 10.1186/s13023-020-01669-1. PMID: 33563298Free PMC Article
McMacken G, Whittaker RG, Evangelista T, Abicht A, Dusl M, Lochmüller H
J Neurol 2018 Jan;265(1):194-203. Epub 2017 Nov 30 doi: 10.1007/s00415-017-8689-3. PMID: 29189923Free PMC Article
Witting N, Vissing J
JAMA Neurol 2014 Mar;71(3):350-4. doi: 10.1001/jamaneurol.2013.5590. PMID: 24425145
Ohno K, Engel AG
Acta Myol 2005 Oct;24(2):50-4. PMID: 16550914
Engel AG
Ann Neurol 1984 Nov;16(5):519-34. doi: 10.1002/ana.410160502. PMID: 6095730

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