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Congenital myasthenic syndrome 4A(CMS1A1, FORMERLY; CMS4A)

MedGen UID:
908188
Concept ID:
C4225413
Disease or Syndrome
Synonyms: CONGENITAL MYASTHENIC SYNDROME TYPE Ia1; Myasthenic syndrome, congenital, 4a, slow-channel; MYASTHENIC SYNDROME, CONGENITAL, 4A, SLOW-CHANNEL, AUTOSOMAL RECESSIVE
 
Gene (location): CHRNE (17p13.2)
 
Monarch Initiative: MONDO:0011600
OMIM®: 605809

Definition

Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; acetylcholinesterase inhibitors and amifampridine should be avoided (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
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Poor suck
MedGen UID:
324693
Concept ID:
C1837142
Finding
An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
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.
Generalized hypotonia due to defect at the neuromuscular junction
MedGen UID:
343014
Concept ID:
C1853950
Finding
Decreased miniature endplate potentials
MedGen UID:
381306
Concept ID:
C1853952
Finding
An abnormal reduction in the amplitude of the miniature endplate potentials, i.e. the postsynaptic response to transmitter released from an individual vesicle at the neuromuscular junction.
Bulbar palsy
MedGen UID:
898626
Concept ID:
C4082299
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Type 2 muscle fiber atrophy
MedGen UID:
355249
Concept ID:
C1864580
Pathologic Function
Atrophy (wasting) affecting primary type 2 muscle fibers. This feature in general can only be observed on muscle biopsy.
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 distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Apneic episodes precipitated by illness, fatigue, stress
MedGen UID:
812792
Concept ID:
C3806462
Finding
Recurrent episodes of apnea that are precipitated by factors such as illness, fatigue, or stress.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Sudden episodic apnea
MedGen UID:
871194
Concept ID:
C4025671
Disease or Syndrome
Recurrent bouts of sudden, severe apnea that may be life-threatening.
Weak cry
MedGen UID:
65892
Concept ID:
C0234860
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).
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
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.

Recent clinical studies

Etiology

Männikkö R, Wong L, Tester DJ, Thor MG, Sud R, Kullmann DM, Sweeney MG, Leu C, Sisodiya SM, FitzPatrick DR, Evans MJ, Jeffrey IJM, Tfelt-Hansen J, Cohen MC, Fleming PJ, Jaye A, Simpson MA, Ackerman MJ, Hanna MG, Behr ER, Matthews E
Lancet 2018 Apr 14;391(10129):1483-1492. Epub 2018 Apr 5 doi: 10.1016/S0140-6736(18)30021-7. PMID: 29605429Free PMC Article
Rodríguez Cruz PM, Palace J, Beeson D
Curr Opin Neurol 2014 Oct;27(5):566-75. doi: 10.1097/WCO.0000000000000134. PMID: 25159927

Prognosis

Männikkö R, Wong L, Tester DJ, Thor MG, Sud R, Kullmann DM, Sweeney MG, Leu C, Sisodiya SM, FitzPatrick DR, Evans MJ, Jeffrey IJM, Tfelt-Hansen J, Cohen MC, Fleming PJ, Jaye A, Simpson MA, Ackerman MJ, Hanna MG, Behr ER, Matthews E
Lancet 2018 Apr 14;391(10129):1483-1492. Epub 2018 Apr 5 doi: 10.1016/S0140-6736(18)30021-7. PMID: 29605429Free PMC Article

Clinical prediction guides

Männikkö R, Wong L, Tester DJ, Thor MG, Sud R, Kullmann DM, Sweeney MG, Leu C, Sisodiya SM, FitzPatrick DR, Evans MJ, Jeffrey IJM, Tfelt-Hansen J, Cohen MC, Fleming PJ, Jaye A, Simpson MA, Ackerman MJ, Hanna MG, Behr ER, Matthews E
Lancet 2018 Apr 14;391(10129):1483-1492. Epub 2018 Apr 5 doi: 10.1016/S0140-6736(18)30021-7. PMID: 29605429Free PMC Article

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