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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
Shoulder girdle muscle weakness
MedGen UID:
96533
Concept ID:
C0427063
Finding
The shoulder, or pectoral, girdle is composed of the clavicles and the scapulae. Shoulder-girdle weakness refers to lack of strength of the muscles attaching to these bones, that is, lack of strength of the muscles around the shoulders.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Fasciculations
MedGen UID:
5124
Concept ID:
C0015644
Sign or Symptom
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.
Sleep apnea
MedGen UID:
11458
Concept ID:
C0037315
Disease or Syndrome
An intermittent cessation of airflow at the mouth and nose during sleep is known as sleep apnea. Apneas that last at least 10 seconds are considered significant, but individuals with sleep apnea may experience apneas lasting from 20 seconds up to 2 or 3 minutes. Patients may have up to 15 events per hour of sleep.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
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.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
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.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
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.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Weakness of facial musculature
MedGen UID:
98103
Concept ID:
C0427055
Disease or Syndrome
Reduced strength of one or more muscles innervated by the facial nerve (the seventh cranial nerve).
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.
Distal lower limb amyotrophy
MedGen UID:
324515
Concept ID:
C1836451
Disease or Syndrome
Muscular atrophy of distal leg muscles.
Axial muscle weakness
MedGen UID:
334472
Concept ID:
C1843697
Finding
Reduced strength of the axial musculature (i.e., of the muscles of the head and neck, spine, and ribs).
Proximal muscle weakness in upper limbs
MedGen UID:
356424
Concept ID:
C1866012
Finding
A lack of strength of the proximal muscles of the arms.
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.
Anti-muscle-specific tyrosine kinase antibody
MedGen UID:
866697
Concept ID:
C4021044
Finding
The presence of autoantibodies (immunoglobulins) in the serum that react against muscle specific kinase (anti-MuSK Ab).
Anti-acetylcholine receptor antibody positivity
MedGen UID:
868186
Concept ID:
C4022578
Finding
The presence of autoantibodies (immunoglobulins) in the blood circulation that react against neuromuscular junction acetylcholine receptors.
Hypernasal speech
MedGen UID:
99115
Concept ID:
C0454555
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.
Tongue atrophy
MedGen UID:
66828
Concept ID:
C0241423
Finding
Wasting of the tongue.
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.
Upgaze palsy
MedGen UID:
1369853
Concept ID:
C4476705
Disease or Syndrome
A limitation of the ability to direct one's gaze above the horizontal meridian.

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
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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

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
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 MHM, 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
Brain 2023 Oct 3;146(10):4233-4246. doi: 10.1093/brain/awad153. PMID: 37186601Free 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
Ramdas S, Beeson D
Neuromuscul Disord 2021 Oct;31(10):943-954. doi: 10.1016/j.nmd.2021.07.400. PMID: 34736634
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
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
Burke G, Hiscock A, Klein A, Niks EH, Main M, Manzur AY, Ng J, de Vile C, Muntoni F, Beeson D, Robb S
Neuromuscul Disord 2013 Feb;23(2):170-5. Epub 2012 Dec 5 doi: 10.1016/j.nmd.2012.11.004. PMID: 23219351
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

Lin CV, Thomas CAD, Huynh TL, Wei DT, Young JN, Aivazian AS, McInnes A, Xu J, Cook SE, Vazquez J, Maselli RA
Hum Gene Ther 2024 Feb;35(3-4):123-131. doi: 10.1089/hum.2023.173. PMID: 38299967
Yu MKL, Chiu AYY, Chau SK, Rosa Duque JS, Wong WHS, Chan SHS
Muscle Nerve 2023 Nov;68(6):857-864. Epub 2023 Oct 14 doi: 10.1002/mus.27982. PMID: 37837303
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
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

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