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Congenital myasthenic syndrome 7(CMS7A)

MedGen UID:
863475
Concept ID:
C4015038
Disease or Syndrome
Synonyms: Myasthenic syndrome, congenital, 7, presynaptic; MYASTHENIC SYNDROME, CONGENITAL, 7A, PRESYNAPTIC, AND DISTAL MOTOR NEUROPATHY, AUTOSOMAL DOMINANT
 
Gene (location): SYT2 (1q32.1)
 
Monarch Initiative: MONDO:0014468
OMIM®: 616040

Definition

Presynaptic congenital myasthenic syndrome-7A with distal motor neuropathy (CMS7A) is an autosomal dominant neuromuscular disorder characterized by onset of foot deformities, delayed motor development, and slowly progressive distal muscle weakness resulting in gait difficulties in early childhood. Other features may include hyporeflexia, muscle atrophy, and upper limb involvement. Electrophysiologic studies show low compound muscle action potentials (CMAPs), consistent with a distal hereditary motor neuropathy (dHMN), as well as a decremental response to repetitive stimulation, indicating presynaptic defects at the neuromuscular junction (NMJ), consistent with myasthenic syndrome (summary by Fionda et al., 2021). The complex phenotype of patients with dominant SYT2 mutations likely results from impairment of 2 fundamental functions of SYT2: (1) disturbance of calcium-dependent synchronous presynaptic neurotransmitter release, resulting in a myasthenic disorder, and (2) disruption of exocytosis and endocytosis, causing a degenerative process affecting peripheral motor nerve terminals and resulting in a motor neuropathy (Maselli et al., 2021). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). For a discussion of genetic heterogeneity of dHMN, see 182960. [from OMIM]

Clinical features

From HPO
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Hammertoe
MedGen UID:
209712
Concept ID:
C1136179
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
Foot dorsiflexor weakness
MedGen UID:
356163
Concept ID:
C1866141
Finding
Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased compound muscle action potential amplitude
MedGen UID:
908357
Concept ID:
C4230625
Finding
Reduced level of the compound muscle action potential (CMAP), which is recorded following electrical stimulation of a nerve from surface electrodes overlying a muscle supplied by that nerve.
Compound muscle action potential amplitude facilitation
MedGen UID:
1814194
Concept ID:
C5676616
Finding
Compound muscle action potential amplitude (CMAP) facilitation denotes an increase in tendon reflexes, strength, or CMAP amplitude after 10 seconds of maximal voluntary contraction.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Proximal amyotrophy
MedGen UID:
342591
Concept ID:
C1850794
Disease or Syndrome
Amyotrophy (muscular atrophy) affecting the proximal musculature.

Professional guidelines

PubMed

Tsao CY
Pediatr Neurol 2016 Jan;54:85-7. Epub 2015 Nov 6 doi: 10.1016/j.pediatrneurol.2015.09.019. PMID: 26552645
Witting N, Vissing J
JAMA Neurol 2014 Mar;71(3):350-4. doi: 10.1001/jamaneurol.2013.5590. PMID: 24425145

Recent clinical studies

Etiology

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
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
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
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
Szobor A, Máttyus A, Molnár J
Acta Paediatr Hung 1988-1989;29(3-4):299-312. PMID: 3077607

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
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
Nizamani NB, Talpur KI, Memon MN
J Coll Physicians Surg Pak 2013 Jul;23(7):517-8. PMID: 23823963

Therapy

Shao S, Shi G, Bi FF, Huang K
Curr Neuropharmacol 2023;21(7):1594-1605. doi: 10.2174/1570159X21666230126145652. PMID: 36703579Free PMC Article
Tsao CY
Pediatr Neurol 2016 Jan;54:85-7. Epub 2015 Nov 6 doi: 10.1016/j.pediatrneurol.2015.09.019. PMID: 26552645
Nizamani NB, Talpur KI, Memon MN
J Coll Physicians Surg Pak 2013 Jul;23(7):517-8. PMID: 23823963
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
Mullaney P, Vajsar J, Smith R, Buncic JR
Ophthalmology 2000 Mar;107(3):504-10. doi: 10.1016/s0161-6420(99)00138-4. PMID: 10711889

Prognosis

Zhang S, Ohkawara B, Ito M, Huang Z, Zhao F, Nakata T, Takeuchi T, Sakurai H, Komaki H, Kamon M, Araki T, Ohno K
Hum Mol Genet 2023 Apr 20;32(9):1511-1523. doi: 10.1093/hmg/ddac306. PMID: 36579833Free PMC Article
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
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
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
Szobor A, Máttyus A, Molnár J
Acta Paediatr Hung 1988-1989;29(3-4):299-312. PMID: 3077607

Clinical prediction guides

Zhang S, Ohkawara B, Ito M, Huang Z, Zhao F, Nakata T, Takeuchi T, Sakurai H, Komaki H, Kamon M, Araki T, Ohno K
Hum Mol Genet 2023 Apr 20;32(9):1511-1523. doi: 10.1093/hmg/ddac306. PMID: 36579833Free PMC Article
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
Shi L, Fu AK, Ip NY
Trends Neurosci 2012 Jul;35(7):441-53. Epub 2012 May 25 doi: 10.1016/j.tins.2012.04.005. PMID: 22633140
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

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