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Endplate acetylcholinesterase deficiency(CMS5)

MedGen UID:
400481
Concept ID:
C1864233
Disease or Syndrome
Synonyms: CMS5; COLQ-Related Congenital Myasthenic Syndrome; MYASTHENIC SYNDROME, CONGENITAL, 5
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): COLQ (3p25.1)
OMIM®: 603034
Orphanet: ORPHA98915

Disease characteristics

Excerpted from the GeneReview: Congenital Myasthenic Syndromes
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations. [from GeneReviews]
Authors:
Angela Abicht  |  Juliane Müller  |  Hanns Lochmüller   view full author information

Additional descriptions

From OMIM
Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).  http://www.omim.org/entry/603034
From GHR
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://ghr.nlm.nih.gov/condition/congenital-myasthenic-syndrome

Clinical features

Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
Drooping of the upper lid due to deficient development or paralysis of the levator palpebrae muscle.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature of the lumbar portion of the spinal column.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Failure to adequately provide oxygen to cells of the body and to remove excess carbon dioxide from them. (Stedman, 25th ed)
Weak cry
MedGen UID:
65892
Concept ID:
C0234860
Finding
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Scoliosis
MedGen UID:
195976
Concept ID:
C0700208
Finding
The presence of an abnormal lateral curvature of the spine.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
A reduction in the strength of muscles in multiple anatomic sites.
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.
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.
Decreased muscle mass
MedGen UID:
373256
Concept ID:
C1837108
Finding
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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.
Type 2 muscle fiber atrophy
MedGen UID:
355249
Concept ID:
C1864580
Finding
Atrophy (wasting) affecting primary type 2 muscle fibers. This feature in general can only be observed on muscle biopsy.
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.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
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.
Abnormality of the immune system
MedGen UID:
867388
Concept ID:
C4021753
Pathologic Function
An abnormality of the immune system.
MedGen UID:
505539
Concept ID:
CN003103

Recent clinical studies

Etiology

Rimfeld K, Kovas Y, Dale PS, Plomin R
J Pers Soc Psychol 2016 Nov;111(5):780-789. Epub 2016 Feb 11 doi: 10.1037/pspp0000089. PMID: 26867111Free PMC Article
Liewluck T, Selcen D, Engel AG
Muscle Nerve 2011 Nov;44(5):789-94. Epub 2011 Sep 23 doi: 10.1002/mus.22176. PMID: 21952943Free PMC Article

Diagnosis

Rimfeld K, Kovas Y, Dale PS, Plomin R
J Pers Soc Psychol 2016 Nov;111(5):780-789. Epub 2016 Feb 11 doi: 10.1037/pspp0000089. PMID: 26867111Free PMC Article
Chan SH, Wong VC, Engel AG
Pediatr Neurol 2012 Aug;47(2):137-40. doi: 10.1016/j.pediatrneurol.2012.04.022. PMID: 22759693Free PMC Article
Bestue-Cardiel M, Sáenz de Cabezón-Alvarez A, Capablo-Liesa JL, López-Pisón J, Peña-Segura JL, Martin-Martinez J, Engel AG
Neurology 2005 Jul 12;65(1):144-6. doi: 10.1212/01.wnl.0000167132.35865.31. PMID: 16009904

Therapy

Chan SH, Wong VC, Engel AG
Pediatr Neurol 2012 Aug;47(2):137-40. doi: 10.1016/j.pediatrneurol.2012.04.022. PMID: 22759693Free PMC Article
Liewluck T, Selcen D, Engel AG
Muscle Nerve 2011 Nov;44(5):789-94. Epub 2011 Sep 23 doi: 10.1002/mus.22176. PMID: 21952943Free PMC Article
Bestue-Cardiel M, Sáenz de Cabezón-Alvarez A, Capablo-Liesa JL, López-Pisón J, Peña-Segura JL, Martin-Martinez J, Engel AG
Neurology 2005 Jul 12;65(1):144-6. doi: 10.1212/01.wnl.0000167132.35865.31. PMID: 16009904
Breningstall GN, Kurachek SC, Fugate JH, Engel AG
J Child Neurol 1996 Jul;11(4):345-6. doi: 10.1177/088307389601100416. PMID: 8807428

Prognosis

Rimfeld K, Kovas Y, Dale PS, Plomin R
J Pers Soc Psychol 2016 Nov;111(5):780-789. Epub 2016 Feb 11 doi: 10.1037/pspp0000089. PMID: 26867111Free PMC Article

Clinical prediction guides

Rimfeld K, Kovas Y, Dale PS, Plomin R
J Pers Soc Psychol 2016 Nov;111(5):780-789. Epub 2016 Feb 11 doi: 10.1037/pspp0000089. PMID: 26867111Free PMC Article
Liewluck T, Selcen D, Engel AG
Muscle Nerve 2011 Nov;44(5):789-94. Epub 2011 Sep 23 doi: 10.1002/mus.22176. PMID: 21952943Free PMC Article
Stum M, Girard E, Bangratz M, Bernard V, Herbin M, Vignaud A, Ferry A, Davoine CS, Echaniz-Laguna A, René F, Marcel C, Molgó J, Fontaine B, Krejci E, Nicole S
Hum Mol Genet 2008 Oct 15;17(20):3166-79. Epub 2008 Jul 21 doi: 10.1093/hmg/ddn213. PMID: 18647752
Hutchinson DO, Walls TJ, Nakano S, Camp S, Taylor P, Harper CM, Groover RV, Peterson HA, Jamieson DG, Engel AG
Brain 1993 Jun;116 ( Pt 3):633-53. PMID: 8390325

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