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Congenital myasthenic syndrome 12(CMS12)

MedGen UID:
765249
Concept ID:
C3552335
Disease or Syndrome
Synonyms: CMS12; Myasthenia, congenital, 12, with tubular aggregates; MYASTHENIC SYNDROME, CONGENITAL, WITH TUBULAR AGGREGATES 1
 
Gene (location): GFPT1 (2p13.3)
 
Monarch Initiative: MONDO:0012518
OMIM®: 610542

Definition

Congenital myasthenic syndrome-12 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Senderek et al., 2011). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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).  https://medlineplus.gov/genetics/condition/congenital-myasthenic-syndrome

Clinical features

From HPO
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Muscle spasm
MedGen UID:
52431
Concept ID:
C0037763
Sign or Symptom
Sudden and involuntary contractions of one or more muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
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.
Proximal amyotrophy
MedGen UID:
342591
Concept ID:
C1850794
Disease or Syndrome
Amyotrophy (muscular atrophy) affecting the proximal musculature.
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
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.
Mildly elevated creatine kinase
MedGen UID:
342469
Concept ID:
C1850309
Finding
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).
Retinoschisis
MedGen UID:
56292
Concept ID:
C0152439
Disease or Syndrome
Splitting of the neuroretinal layers of the retina.
Ophthalmoparesis
MedGen UID:
155551
Concept ID:
C0751401
Sign or Symptom
Ophthalmoplegia is a paralysis or weakness of one or more of the muscles that control eye movement.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCongenital myasthenic syndrome 12

Professional guidelines

PubMed

Özsoy Ö, Cinleti T, Günay Ç, Sarıkaya Uzan G, Giray Bozkaya Ö, Çağlayan AO, Hız Kurul S, Yiş U
Acta Neurol Belg 2023 Dec;123(6):2325-2335. Epub 2023 Sep 1 doi: 10.1007/s13760-023-02370-3. PMID: 37656362

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
Özsoy Ö, Cinleti T, Günay Ç, Sarıkaya Uzan G, Giray Bozkaya Ö, Çağlayan AO, Hız Kurul S, Yiş U
Acta Neurol Belg 2023 Dec;123(6):2325-2335. Epub 2023 Sep 1 doi: 10.1007/s13760-023-02370-3. PMID: 37656362
Vianello A, Racca F, Vita GL, Pierucci P, Vita G
Handb Clin Neurol 2022;189:259-270. doi: 10.1016/B978-0-323-91532-8.00014-8. PMID: 36031308
Vrinten C, van der Zwaag AM, Weinreich SS, Scholten RJ, Verschuuren JJ
Cochrane Database Syst Rev 2014 Dec 17;2014(12):CD010028. doi: 10.1002/14651858.CD010028.pub2. PMID: 25515947Free PMC Article
Engel AG
Curr Neurol Neurosci Rep 2012 Feb;12(1):92-101. doi: 10.1007/s11910-011-0234-7. PMID: 21997714Free PMC Article

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
Kouyoumdjian JA, Estephan EP
Arq Neuropsiquiatr 2023 Dec;81(12):1040-1052. Epub 2023 Dec 29 doi: 10.1055/s-0043-1777749. PMID: 38157872Free PMC Article
Özsoy Ö, Cinleti T, Günay Ç, Sarıkaya Uzan G, Giray Bozkaya Ö, Çağlayan AO, Hız Kurul S, Yiş U
Acta Neurol Belg 2023 Dec;123(6):2325-2335. Epub 2023 Sep 1 doi: 10.1007/s13760-023-02370-3. PMID: 37656362
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
Engel AG
Curr Neurol Neurosci Rep 2012 Feb;12(1):92-101. doi: 10.1007/s11910-011-0234-7. PMID: 21997714Free PMC Article

Therapy

Natera-de Benito D, Bestué M, Vilchez JJ, Evangelista T, Töpf A, García-Ribes A, Trujillo-Tiebas MJ, García-Hoyos M, Ortez C, Camacho A, Jiménez E, Dusl M, Abicht A, Lochmüller H, Colomer J, Nascimento A
Neuromuscul Disord 2016 Feb;26(2):153-9. Epub 2015 Nov 23 doi: 10.1016/j.nmd.2015.10.013. PMID: 26782015
Vrinten C, van der Zwaag AM, Weinreich SS, Scholten RJ, Verschuuren JJ
Cochrane Database Syst Rev 2014 Dec 17;2014(12):CD010028. doi: 10.1002/14651858.CD010028.pub2. PMID: 25515947Free 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
Schara U, Barisic N, Deschauer M, Lindberg C, Straub V, Strigl-Pill N, Wendt M, Abicht A, Müller JS, Lochmüller H
Neuromuscul Disord 2009 Dec;19(12):828-32. Epub 2009 Oct 17 doi: 10.1016/j.nmd.2009.09.008. PMID: 19837590
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

Özsoy Ö, Cinleti T, Günay Ç, Sarıkaya Uzan G, Giray Bozkaya Ö, Çağlayan AO, Hız Kurul S, Yiş U
Acta Neurol Belg 2023 Dec;123(6):2325-2335. Epub 2023 Sep 1 doi: 10.1007/s13760-023-02370-3. PMID: 37656362
Vianello A, Racca F, Vita GL, Pierucci P, Vita G
Handb Clin Neurol 2022;189:259-270. doi: 10.1016/B978-0-323-91532-8.00014-8. PMID: 36031308
Mansukhani SA, Bothun ED, Diehl NN, Mohney BG
Am J Ophthalmol 2019 Apr;200:242-249. Epub 2019 Jan 14 doi: 10.1016/j.ajo.2019.01.004. PMID: 30653958Free 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

Özsoy Ö, Cinleti T, Günay Ç, Sarıkaya Uzan G, Giray Bozkaya Ö, Çağlayan AO, Hız Kurul S, Yiş U
Acta Neurol Belg 2023 Dec;123(6):2325-2335. Epub 2023 Sep 1 doi: 10.1007/s13760-023-02370-3. PMID: 37656362
Vrinten C, van der Zwaag AM, Weinreich SS, Scholten RJ, Verschuuren JJ
Cochrane Database Syst Rev 2014 Dec 17;2014(12):CD010028. doi: 10.1002/14651858.CD010028.pub2. PMID: 25515947Free 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
Engel AG
Curr Neurol Neurosci Rep 2012 Feb;12(1):92-101. doi: 10.1007/s11910-011-0234-7. PMID: 21997714Free PMC Article
Engel AG, Shen XM, Selcen D, Sine SM
J Mol Neurosci 2010 Jan;40(1-2):143-53. Epub 2009 Aug 18 doi: 10.1007/s12031-009-9229-0. PMID: 19688192Free PMC Article

Recent systematic reviews

Vrinten C, van der Zwaag AM, Weinreich SS, Scholten RJ, Verschuuren JJ
Cochrane Database Syst Rev 2014 Dec 17;2014(12):CD010028. doi: 10.1002/14651858.CD010028.pub2. PMID: 25515947Free PMC Article

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