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Congenital myasthenic syndrome 9(CMS9)

MedGen UID:
895641
Concept ID:
C4225368
Disease or Syndrome
Synonym: Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency
 
Gene (location): MUSK (9q31.3)
 
Monarch Initiative: MONDO:0014587
OMIM®: 616325

Definition

Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients may show a favorable response to amifampridine (summary by Engel 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
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Neck muscle weakness
MedGen UID:
66808
Concept ID:
C0240479
Finding
Decreased strength of the neck musculature.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
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.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Hypernasal speech
MedGen UID:
107884
Concept ID:
C0566620
Finding
A type of speech characterized by the presence of an abnormally increased nasal airflow during speech associated with structural abnormality of the nasal passages.
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).
Ophthalmoplegia
MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Paralysis of one or more extraocular muscles that are responsible for eye movements.

Professional guidelines

PubMed

Bobadilla-Quesada EJ, Natera-de Benito D, Carrera-García L, Ortez C, Exposito-Escudero J, Jimenez-Mallebrera C, Jou C, Codina A, Corbera J, Moya O, Saez V, Gonzalez-Quereda L, Gallano P, Colomer J, Cuadras D, Medina J, Yoldi ME, Nascimento A
Neuromuscul Disord 2020 Sep;30(9):719-726. Epub 2020 Jul 24 doi: 10.1016/j.nmd.2020.07.009. PMID: 32819792
Arredondo J, Lara M, Gospe SM Jr, Mazia CG, Vaccarezza M, Garcia-Erro M, Bowe CM, Chang CH, Mezei MM, Maselli RA
Hum Mutat 2015 Sep;36(9):881-93. Epub 2015 Jul 24 doi: 10.1002/humu.22823. PMID: 26080897Free PMC Article
Kinali M, Beeson D, Pitt MC, Jungbluth H, Simonds AK, Aloysius A, Cockerill H, Davis T, Palace J, Manzur AY, Jimenez-Mallebrera C, Sewry C, Muntoni F, Robb SA
J Neuroimmunol 2008 Sep 15;201-202:6-12. Epub 2008 Aug 15 doi: 10.1016/j.jneuroim.2008.06.026. PMID: 18707767

Recent clinical studies

Etiology

Polavarapu K, Sunitha B, Töpf A, Preethish-Kumar V, Thompson R, Vengalil S, Nashi S, Bardhan M, Sanka SB, Huddar A, Unnikrishnan G, Arunachal G, Girija MS, Porter A, Azuma Y, Lorenzoni PJ, Baskar D, Anjanappa RM, Keertipriya M, Padmanabh H, Harikrishna GV, Laurie S, Matalonga L, Horvath R, Nalini A, Lochmüller H
Brain 2024 Jan 4;147(1):281-296. doi: 10.1093/brain/awad315. PMID: 37721175Free PMC Article
Megarbane A, Bizzari S, Deepthi A, Sabbagh S, Mansour H, Chouery E, Hmaimess G, Jabbour R, Mehawej C, Alame S, Hani A, Hasbini D, Ghanem I, Koussa S, Al-Ali MT, Obeid M, Talea DB, Lefranc G, Lévy N, Leturcq F, El Hayek S, Delague V, Urtizberea JA
J Neuromuscul Dis 2022;9(1):193-210. doi: 10.3233/JND-210652. PMID: 34602496Free PMC Article
Zhao Y, Li Y, Bian Y, Yao S, Liu P, Yu M, Zhang W, Wang Z, Yuan Y
Ann Clin Transl Neurol 2021 Apr;8(4):898-907. Epub 2021 Mar 23 doi: 10.1002/acn3.51346. PMID: 33756069Free PMC Article
Souza PV, Batistella GN, Lino VC, Pinto WB, Annes M, Oliveira AS
Arq Neuropsiquiatr 2016 Sep;74(9):750-760. doi: 10.1590/0004-282X20160106. PMID: 27706425
Sieb JP, Kraner S, Steinlein OK
Semin Pediatr Neurol 2002 Jun;9(2):108-19. doi: 10.1053/spen.2002.33803. PMID: 12138995

Diagnosis

Megarbane A, Bizzari S, Deepthi A, Sabbagh S, Mansour H, Chouery E, Hmaimess G, Jabbour R, Mehawej C, Alame S, Hani A, Hasbini D, Ghanem I, Koussa S, Al-Ali MT, Obeid M, Talea DB, Lefranc G, Lévy N, Leturcq F, El Hayek S, Delague V, Urtizberea JA
J Neuromuscul Dis 2022;9(1):193-210. doi: 10.3233/JND-210652. PMID: 34602496Free PMC Article
Ramdas S, Beeson D
Neuromuscul Disord 2021 Oct;31(10):943-954. doi: 10.1016/j.nmd.2021.07.400. PMID: 34736634
Zhao Y, Li Y, Bian Y, Yao S, Liu P, Yu M, Zhang W, Wang Z, Yuan Y
Ann Clin Transl Neurol 2021 Apr;8(4):898-907. Epub 2021 Mar 23 doi: 10.1002/acn3.51346. PMID: 33756069Free PMC Article
Souza PV, Batistella GN, Lino VC, Pinto WB, Annes M, Oliveira AS
Arq Neuropsiquiatr 2016 Sep;74(9):750-760. doi: 10.1590/0004-282X20160106. PMID: 27706425
Sieb JP, Kraner S, Steinlein OK
Semin Pediatr Neurol 2002 Jun;9(2):108-19. doi: 10.1053/spen.2002.33803. PMID: 12138995

Therapy

Hesami O, Ramezani M, Ghasemi A, Fatehi F, Okhovat AA, Ziaadini B, Kariminejad A, Nafissi S
Orphanet J Rare Dis 2024 Mar 12;19(1):113. doi: 10.1186/s13023-024-03116-x. PMID: 38475910Free PMC Article
Eirís-Puñal J, Fuentes-Pita P, Gómez-Lado C, Pérez-Gay L, López-Vázquez A, Quintas-Rey R, Barros-Angueira F, Pardo J
Rev Neurol 2020 Sep 16;71(6):221-224. doi: 10.33588/rn.7106.2020265. PMID: 32895905
Lorenzoni PJ, Scola RH, Kay CS, Filla L, Miranda AP, Pinheiro JM, Chaouch A, Lochmüller H, Werneck LC
J Neurol Sci 2013 Aug 15;331(1-2):155-7. Epub 2013 Jun 19 doi: 10.1016/j.jns.2013.05.017. PMID: 23790237
Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, Harper CM, Engel AG
Neurology 2009 Jul 21;73(3):228-35. doi: 10.1212/WNL.0b013e3181ae7cbc. PMID: 19620612Free PMC Article
Kinali M, Beeson D, Pitt MC, Jungbluth H, Simonds AK, Aloysius A, Cockerill H, Davis T, Palace J, Manzur AY, Jimenez-Mallebrera C, Sewry C, Muntoni F, Robb SA
J Neuroimmunol 2008 Sep 15;201-202:6-12. Epub 2008 Aug 15 doi: 10.1016/j.jneuroim.2008.06.026. PMID: 18707767

Prognosis

Hyde LF, Kong Y, Zhao L, Rao SR, Wang J, Stone L, Njaa A, Collin GB, Krebs MP, Chang B, Fliesler SJ, Nishina PM, Naggert JK
Int J Mol Sci 2022 Oct 9;23(19) doi: 10.3390/ijms231912005. PMID: 36233305Free PMC Article
Mensch A, Cordts I, Scholle L, Joshi PR, Kleeberg K, Emmer A, Beck-Woedl S, Park J, Haack TB, Stoltenburg-Didinger G, Zierz S, Deschauer M
J Neuromuscul Dis 2022;9(4):533-541. doi: 10.3233/JND-220822. PMID: 35694932
Zhao Y, Li Y, Bian Y, Yao S, Liu P, Yu M, Zhang W, Wang Z, Yuan Y
Ann Clin Transl Neurol 2021 Apr;8(4):898-907. Epub 2021 Mar 23 doi: 10.1002/acn3.51346. PMID: 33756069Free PMC Article
Durmus H, Shen XM, Serdaroglu-Oflazer P, Kara B, Parman-Gulsen Y, Ozdemir C, Brengman J, Deymeer F, Engel AG
Neuromuscul Disord 2018 Apr;28(4):315-322. Epub 2017 Nov 28 doi: 10.1016/j.nmd.2017.11.013. PMID: 29395675Free PMC Article
Lorenzoni PJ, Scola RH, Kay CS, Filla L, Miranda AP, Pinheiro JM, Chaouch A, Lochmüller H, Werneck LC
J Neurol Sci 2013 Aug 15;331(1-2):155-7. Epub 2013 Jun 19 doi: 10.1016/j.jns.2013.05.017. PMID: 23790237

Clinical prediction guides

Boon HTM, Jacobs B, Wouter VR, Kamsteeg EJ, Kuks JBM, Vincent A, Eymard B, Voermans NC
J Neuromuscul Dis 2022;9(4):525-532. doi: 10.3233/JND-220798. PMID: 35466948
Zhao Y, Li Y, Bian Y, Yao S, Liu P, Yu M, Zhang W, Wang Z, Yuan Y
Ann Clin Transl Neurol 2021 Apr;8(4):898-907. Epub 2021 Mar 23 doi: 10.1002/acn3.51346. PMID: 33756069Free PMC Article
Prior DE, Cooper BA, Zhang B, Ghosh PS
Muscle Nerve 2021 May;63(5):751-757. Epub 2021 Feb 28 doi: 10.1002/mus.27208. PMID: 33604899
Eirís-Puñal J, Fuentes-Pita P, Gómez-Lado C, Pérez-Gay L, López-Vázquez A, Quintas-Rey R, Barros-Angueira F, Pardo J
Rev Neurol 2020 Sep 16;71(6):221-224. doi: 10.33588/rn.7106.2020265. PMID: 32895905
Lorenzoni PJ, Scola RH, Kay CS, Filla L, Miranda AP, Pinheiro JM, Chaouch A, Lochmüller H, Werneck LC
J Neurol Sci 2013 Aug 15;331(1-2):155-7. Epub 2013 Jun 19 doi: 10.1016/j.jns.2013.05.017. PMID: 23790237

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