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Congenital myasthenic syndrome 3A(CMS3A)

MedGen UID:
898378
Concept ID:
C4225372
Disease or Syndrome
Synonym: Myasthenic syndrome, congenital, 3a, slow-channel
 
Gene (location): CHRND (2q37.1)
 
Monarch Initiative: MONDO:0014583
OMIM®: 616321

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 AChR 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
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
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
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.
Prolonged miniature endplate currents
MedGen UID:
350370
Concept ID:
C1864238
Finding
An abnormal prolongation of the miniature endplate potentials, i.e. the postsynaptic response to transmitter released from an individual vesicle at the neuromuscular junction.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
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.
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.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting. Infant head lag is observed when the head seems to flop around or lags posteriorly behind the trunk. Several articles have maintained that head lag should be absent by age 3 to 4 months.
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.
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).

Professional guidelines

PubMed

McMacken G, Whittaker RG, Wake R, Lochmuller H, Horvath R
J Neurol 2023 Jun;270(6):3112-3119. Epub 2023 Mar 4 doi: 10.1007/s00415-023-11643-z. PMID: 36869887Free PMC Article

Recent clinical studies

Therapy

McMacken G, Whittaker RG, Wake R, Lochmuller H, Horvath R
J Neurol 2023 Jun;270(6):3112-3119. Epub 2023 Mar 4 doi: 10.1007/s00415-023-11643-z. PMID: 36869887Free PMC Article

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