CMS4A
MCID: MYS059
MIFTS: 27

Myasthenic Syndrome, Congenital, 4a, Slow-Channel (CMS4A)

Categories: Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

MalaCards integrated aliases for Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

Name: Myasthenic Syndrome, Congenital, 4a, Slow-Channel 58 76 30 6
Cms4a 58 12 76
Myasthenia, Familial Infantile, 1 76 74
Cms Ia1 12 76
Cms1a1 12 76
Congenital Myasthenic Syndrome Type Ia1, Formerly; Cms1a1, Formerly 58
Myasthenic Syndrome, Congenital, Type 4a, Slow-Channel 41
Congenital Myasthenic Syndrome Type Ia1, Formerly 58
Congenital Myasthenic Syndrome 4a Slow-Channel 12
Congenital Myasthenic Syndrome Type Ia1 76
Congenital Myasthenic Syndrometype Ia1 12
Congenital Myasthenic Syndrome 4a 12
Cms Ia1, Formerly 58
Cms1a1, Formerly 58

Characteristics:

OMIM:

58
Inheritance:
autosomal dominant
autosomal recessive (rare)

Miscellaneous:
poor response to acetylcholinesterase inhibitors
variable age at onset (range infancy to young adult)
most cases are autosomal dominant, recessive inheritance has rarely been reported


HPO:

33
myasthenic syndrome, congenital, 4a, slow-channel:
Onset and clinical course congenital onset
Inheritance autosomal dominant inheritance autosomal recessive inheritance


Classifications:



Summaries for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

UniProtKB/Swiss-Prot : 76 Myasthenic syndrome, congenital, 4A, slow-channel: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre- synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS4A is a slow-channel myasthenic syndrome. It is caused by kinetic abnormalities of the AChR, resulting in prolonged AChR channel opening episodes, prolonged endplate currents, and depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane.

MalaCards based summary : Myasthenic Syndrome, Congenital, 4a, Slow-Channel, also known as cms4a, is related to congenital myasthenic syndrome and myasthenic syndrome, congenital, 4c, associated with acetylcholine receptor deficiency. An important gene associated with Myasthenic Syndrome, Congenital, 4a, Slow-Channel is CHRNE (Cholinergic Receptor Nicotinic Epsilon Subunit). Affiliated tissues include testes, and related phenotypes are ptosis and dysphagia

Disease Ontology : 12 A congenital myasthenic syndrome characterized by postsynaptic neuromuscular junction defects, early-onset progressive muscle weakness, and prolonged opening and activity of the acetylcholine receptor channel that has material basis in heterozygous or rarely biallelic mutation in the CHRNE gene on chromosome 17p13.

OMIM : 58 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). (605809)

Related Diseases for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Diseases in the Slow-Channel Congenital Myasthenic Syndrome family:

Myasthenic Syndrome, Congenital, 1a, Slow-Channel Myasthenic Syndrome, Congenital, 4a, Slow-Channel
Myasthenic Syndrome, Congenital, 2a, Slow-Channel Myasthenic Syndrome, Congenital, 3a, Slow-Channel

Diseases related to Myasthenic Syndrome, Congenital, 4a, Slow-Channel via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 congenital myasthenic syndrome 31.0 C17orf107 CHRNE
2 myasthenic syndrome, congenital, 4c, associated with acetylcholine receptor deficiency 11.6
3 myasthenic syndrome, congenital, 4b, fast-channel 9.6 C17orf107 CHRNE

Symptoms & Phenotypes for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Human phenotypes related to Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

33 (show all 21)
# Description HPO Frequency HPO Source Accession
1 ptosis 33 HP:0000508
2 dysphagia 33 HP:0002015
3 feeding difficulties in infancy 33 HP:0008872
4 myopathy 33 HP:0003198
5 respiratory insufficiency due to muscle weakness 33 HP:0002747
6 strabismus 33 HP:0000486
7 respiratory distress 33 HP:0002098
8 ophthalmoparesis 33 HP:0000597
9 easy fatigability 33 HP:0003388
10 generalized hypotonia 33 HP:0001290
11 limb muscle weakness 33 HP:0003690
12 fatigable weakness 33 HP:0003473
13 emg: decremental response of compound muscle action potential to repetitive nerve stimulation 33 HP:0003403
14 weak cry 33 HP:0001612
15 poor suck 33 HP:0002033
16 bulbar palsy 33 HP:0001283
17 type 2 muscle fiber atrophy 33 HP:0003554
18 sudden episodic apnea 33 HP:0002882
19 apneic episodes precipitated by illness, fatigue, stress 33 HP:0002872
20 decreased miniature endplate potentials 33 HP:0003402
21 generalized hypotonia due to defect at the neuromuscular junction 33 HP:0003397

Symptoms via clinical synopsis from OMIM:

58
Head And Neck Eyes:
ptosis
ophthalmoparesis

Muscle Soft Tissue:
easy fatigability
limb muscle weakness
bulbar muscle weakness
generalized hypotonia due to defect at the neuromuscular junction
decremental compound muscle action potential (cmap) response to repetitive nerve stimulation
more
Abdomen Gastrointestinal:
dysphagia
poor suck
poor feeding due to muscle weakness

Respiratory:
respiratory insufficiency due to muscle weakness (in some patients)

Clinical features from OMIM:

605809

Drugs & Therapeutics for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Search Clinical Trials , NIH Clinical Center for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Genetic Tests for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Genetic tests related to Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

# Genetic test Affiliating Genes
1 Myasthenic Syndrome, Congenital, 4a, Slow-Channel 30 CHRNE

Anatomical Context for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

MalaCards organs/tissues related to Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

42
Testes

Publications for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Articles related to Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

# Title Authors Year
1
New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. ( 8872460 )
1996
2
Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. ( 7531341 )
1995
3
A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome. ( 7538206 )
1995
4
[Hereditary myasthenic syndromes with late onset. Value of electrophysiological tests]. ( 7863154 )
1994
5
The slow channel syndrome. Two new cases. ( 3651795 )
1987

Variations for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

UniProtKB/Swiss-Prot genetic disease variations for Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

76
# Symbol AA change Variation ID SNP ID
1 CHRNE p.Thr284Pro VAR_000292 rs121909510
2 CHRNE p.Leu289Phe VAR_000293 rs121909511
3 CHRNE p.Leu98Pro VAR_019567 rs28929768
4 CHRNE p.Leu241Phe VAR_019568 rs28999110
5 CHRNE p.Val285Ala VAR_077364

ClinVar genetic disease variations for Myasthenic Syndrome, Congenital, 4a, Slow-Channel:

6 (show top 50) (show all 166)
# Gene Variation Type Significance SNP ID Assembly Location
1 CHRNE NM_000080.3(CHRNE): c.850A> C (p.Thr284Pro) single nucleotide variant Pathogenic rs121909510 GRCh37 Chromosome 17, 4804155: 4804155
2 CHRNE NM_000080.3(CHRNE): c.850A> C (p.Thr284Pro) single nucleotide variant Pathogenic rs121909510 GRCh38 Chromosome 17, 4900860: 4900860
3 CHRNE NM_000080.3(CHRNE): c.865C> T (p.Leu289Phe) single nucleotide variant Pathogenic rs121909511 GRCh37 Chromosome 17, 4804140: 4804140
4 CHRNE NM_000080.3(CHRNE): c.865C> T (p.Leu289Phe) single nucleotide variant Pathogenic rs121909511 GRCh38 Chromosome 17, 4900845: 4900845
5 CHRNE NM_000080.3(CHRNE): c.422C> T (p.Pro141Leu) single nucleotide variant Likely pathogenic rs121909512 GRCh37 Chromosome 17, 4805305: 4805305
6 CHRNE NM_000080.3(CHRNE): c.422C> T (p.Pro141Leu) single nucleotide variant Likely pathogenic rs121909512 GRCh38 Chromosome 17, 4902010: 4902010
7 CHRNE NM_000080.3(CHRNE): c.250C> T (p.Arg84Ter) single nucleotide variant Pathogenic rs121909513 GRCh37 Chromosome 17, 4805606: 4805606
8 CHRNE NM_000080.3(CHRNE): c.250C> T (p.Arg84Ter) single nucleotide variant Pathogenic rs121909513 GRCh38 Chromosome 17, 4902311: 4902311
9 CHRNE NM_000080.3(CHRNE): c.971delT (p.Ile324Thrfs) deletion Pathogenic rs879255562 GRCh38 Chromosome 17, 4899529: 4899529
10 CHRNE NM_000080.3(CHRNE): c.971delT (p.Ile324Thrfs) deletion Pathogenic rs879255562 GRCh37 Chromosome 17, 4802824: 4802824
11 CHRNE NM_000080.3(CHRNE): c.721C> T (p.Leu241Phe) single nucleotide variant Pathogenic rs28999110 GRCh37 Chromosome 17, 4804366: 4804366
12 CHRNE NM_000080.3(CHRNE): c.721C> T (p.Leu241Phe) single nucleotide variant Pathogenic rs28999110 GRCh38 Chromosome 17, 4901071: 4901071
13 CHRNE NM_000080.3(CHRNE): c.614_620delGGGCCAT (p.Trp205Serfs) deletion Pathogenic rs753828284 GRCh38 Chromosome 17, 4901172: 4901178
14 CHRNE NM_000080.3(CHRNE): c.614_620delGGGCCAT (p.Trp205Serfs) deletion Pathogenic rs753828284 GRCh37 Chromosome 17, 4804467: 4804473
15 CHRNE NM_000080.3(CHRNE): c.37G> A (p.Gly13Arg) single nucleotide variant Uncertain significance rs372635387 GRCh37 Chromosome 17, 4806322: 4806322
16 CHRNE NM_000080.3(CHRNE): c.37G> A (p.Gly13Arg) single nucleotide variant Uncertain significance rs372635387 GRCh38 Chromosome 17, 4903027: 4903027
17 CHRNE NM_000080.3(CHRNE): c.488C> T (p.Ser163Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs121909516 GRCh37 Chromosome 17, 4805239: 4805239
18 CHRNE NM_000080.3(CHRNE): c.488C> T (p.Ser163Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs121909516 GRCh38 Chromosome 17, 4901944: 4901944
19 CHRNE NM_000080.3(CHRNE): c.892_894delTCT (p.Ser298del) deletion Pathogenic rs398122830 GRCh37 Chromosome 17, 4804111: 4804113
20 CHRNE NM_000080.3(CHRNE): c.892_894delTCT (p.Ser298del) deletion Pathogenic rs398122830 GRCh38 Chromosome 17, 4900816: 4900818
21 CHRNE NM_000080.3(CHRNE): c.710G> T (p.Arg237Leu) single nucleotide variant Pathogenic rs201434993 GRCh37 Chromosome 17, 4804377: 4804377
22 CHRNE NM_000080.3(CHRNE): c.710G> T (p.Arg237Leu) single nucleotide variant Pathogenic rs201434993 GRCh38 Chromosome 17, 4901082: 4901082
23 CHRNE NM_000080.3(CHRNE): c.1017C> G (p.Ser339=) single nucleotide variant Benign/Likely benign rs114454383 GRCh37 Chromosome 17, 4802778: 4802778
24 CHRNE NM_000080.3(CHRNE): c.1017C> G (p.Ser339=) single nucleotide variant Benign/Likely benign rs114454383 GRCh38 Chromosome 17, 4899483: 4899483
25 CHRNE NM_000080.3(CHRNE): c.1402G> C (p.Val468Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs139171143 GRCh37 Chromosome 17, 4802111: 4802111
26 CHRNE NM_000080.3(CHRNE): c.1402G> C (p.Val468Leu) single nucleotide variant Conflicting interpretations of pathogenicity rs139171143 GRCh38 Chromosome 17, 4898816: 4898816
27 CHRNE NM_000080.3(CHRNE): c.45C> T (p.Leu15=) single nucleotide variant Benign/Likely benign rs34563587 GRCh37 Chromosome 17, 4806314: 4806314
28 CHRNE NM_000080.3(CHRNE): c.45C> T (p.Leu15=) single nucleotide variant Benign/Likely benign rs34563587 GRCh38 Chromosome 17, 4903019: 4903019
29 CHRNE NM_000080.3(CHRNE): c.519C> T (p.Ala173=) single nucleotide variant Benign/Likely benign rs33970119 GRCh37 Chromosome 17, 4804902: 4804902
30 CHRNE NM_000080.3(CHRNE): c.519C> T (p.Ala173=) single nucleotide variant Benign/Likely benign rs33970119 GRCh38 Chromosome 17, 4901607: 4901607
31 CHRNE NM_000080.3(CHRNE): c.53G> T (p.Gly18Val) single nucleotide variant Benign/Likely benign rs4790235 GRCh37 Chromosome 17, 4806052: 4806052
32 CHRNE NM_000080.3(CHRNE): c.53G> T (p.Gly18Val) single nucleotide variant Benign/Likely benign rs4790235 GRCh38 Chromosome 17, 4902757: 4902757
33 CHRNE NM_000080.3(CHRNE): c.1327delG (p.Glu443LysfsTer64) deletion Pathogenic rs763258280 GRCh37 Chromosome 17, 4802186: 4802186
34 CHRNE NM_000080.3(CHRNE): c.1327delG (p.Glu443LysfsTer64) deletion Pathogenic rs763258280 GRCh38 Chromosome 17, 4898891: 4898891
35 CHRNE NM_000080.4(CHRNE): c.130dup (p.Glu44Glyfs) duplication Pathogenic rs762368691 GRCh38 Chromosome 17, 4902680: 4902680
36 CHRNE NM_000080.4(CHRNE): c.130dup (p.Glu44Glyfs) duplication Pathogenic rs762368691 GRCh37 Chromosome 17, 4805975: 4805975
37 CHRNE NM_000080.3(CHRNE): c.1425C> T (p.Leu475=) single nucleotide variant Conflicting interpretations of pathogenicity rs151193377 GRCh37 Chromosome 17, 4802088: 4802088
38 CHRNE NM_000080.3(CHRNE): c.1425C> T (p.Leu475=) single nucleotide variant Conflicting interpretations of pathogenicity rs151193377 GRCh38 Chromosome 17, 4898793: 4898793
39 CHRNE NM_000080.3(CHRNE): c.1416C> T (p.Leu472=) single nucleotide variant Benign/Likely benign rs145456588 GRCh38 Chromosome 17, 4898802: 4898802
40 CHRNE NM_000080.3(CHRNE): c.1416C> T (p.Leu472=) single nucleotide variant Benign/Likely benign rs145456588 GRCh37 Chromosome 17, 4802097: 4802097
41 CHRNE NM_000080.3(CHRNE): c.966C> T (p.Cys322=) single nucleotide variant Benign/Likely benign rs56377005 GRCh38 Chromosome 17, 4899534: 4899534
42 CHRNE NM_000080.3(CHRNE): c.966C> T (p.Cys322=) single nucleotide variant Benign/Likely benign rs56377005 GRCh37 Chromosome 17, 4802829: 4802829
43 CHRNE NM_000080.3(CHRNE): c.103T> C (p.Tyr35His) single nucleotide variant Conflicting interpretations of pathogenicity rs144169073 GRCh37 Chromosome 17, 4806002: 4806002
44 CHRNE NM_000080.3(CHRNE): c.103T> C (p.Tyr35His) single nucleotide variant Conflicting interpretations of pathogenicity rs144169073 GRCh38 Chromosome 17, 4902707: 4902707
45 CHRNE NM_000080.4(CHRNE): c.1042G> A (p.Glu348Lys) single nucleotide variant Uncertain significance rs757968612 GRCh37 Chromosome 17, 4802670: 4802670
46 CHRNE NM_000080.4(CHRNE): c.1042G> A (p.Glu348Lys) single nucleotide variant Uncertain significance rs757968612 GRCh38 Chromosome 17, 4899375: 4899375
47 CHRNE NM_000080.3(CHRNE): c.1093delG (p.Ala365Profs) deletion Pathogenic rs886043239 GRCh37 Chromosome 17, 4802619: 4802619
48 CHRNE NM_000080.3(CHRNE): c.1093delG (p.Ala365Profs) deletion Pathogenic rs886043239 GRCh38 Chromosome 17, 4899324: 4899324
49 CHRNE NM_000080.3(CHRNE): c.1220-5G> A single nucleotide variant Conflicting interpretations of pathogenicity rs188564977 GRCh38 Chromosome 17, 4899112: 4899112
50 CHRNE NM_000080.3(CHRNE): c.1220-5G> A single nucleotide variant Conflicting interpretations of pathogenicity rs188564977 GRCh37 Chromosome 17, 4802407: 4802407

Expression for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

Search GEO for disease gene expression data for Myasthenic Syndrome, Congenital, 4a, Slow-Channel.

Pathways for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

GO Terms for Myasthenic Syndrome, Congenital, 4a, Slow-Channel

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