Congenital myasthenic syndrome
| Congenital myasthenic syndromes | |
|---|---|
| Specialty | Neurology  |
Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the
Types
The types of CMS are classified into three categories:
- Presynaptic symptoms include brief stops in breathing, weakness of the eye, mouth, and throat muscles. These symptoms often result in double vision and difficulty chewing and swallowing.
- Postsynaptic symptoms in infants include severe muscle weakness, feeding and respiratory problems, and delays in the ability to sit, crawl, and walk.
- Synaptic symptoms include early childhood feeding and respiratory problems, reduced mobility, curvature of the spine, and weakness, which causes a delay in motor milestones.
Presentation
The onset of symptoms for all ages may include droopy eyelids. A particular form of postsynaptic CMS (slow-channel CMS) includes severe weakness beginning in infancy or childhood that progresses to respiratory problems, and leads to loss of mobility in adolescence or later life.[citation needed]
Mechanisms
Postsynaptic CMS
CMS is associated with genetic defects that affect proteins of the
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor (AChR) subunits. Mutations of the AChR often result in endplate deficiency. Most of the mutations of the AChR are mutations of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an Arginine into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced Arg is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.
Another common underlying mechanism of CMS is the mutation of the rapsyn protein, coded by the RAPSN gene. Rapsyn interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, functional synapses cannot be created, as the membrane folds do not form properly. Patients with CMS-related mutations of the rapsyn protein typically are either homozygous for N88K or heterozygous for N88K and a second mutation. The major effect of the mutation N88K in rapsyn is to reduce the stability of AChR clusters. The second mutation can be a determining factor in the severity of the disease.[1]
Studies have shown that most patients with CMS that have rapsyn mutations carry the common mutation N88K on at least one allele. However, research has revealed that there is a small population of patients who do not carry the N88K mutation on either of their alleles, but instead have different mutations of the RAPSN gene that codes for rapsyn on both of their alleles. Two novel missense mutations that have been found are R164C and L283P; the result is a decrease in co-clustering of AChR with rapsyn. A third mutation is the intronic base alteration IVS1-15C>A, which causes abnormal splicing of RAPSN RNA. These results show that diagnostic screening for CMS mutations of the RAPSN gene cannot be based exclusively on the detection of N88K mutations.
Dok-7 is a postsynaptic protein that binds and activates MuSK protein, which then leads to AChR clustering and typical folding of the postsynaptic membrane. Mutations of Dok-7 are yet another underlying mechanism of postsynaptic CMS.[2]
Diagnosis
Congenital myasthenic syndrome (CMS) is "often difficult to diagnose because of a broad differential diagnosis and lack of specific laboratory findings. Identification of the underlying mutation is critical, as certain mutations lead to treatment-responsive conditions while others do not."[3] Whole exome sequencing (WES) is often used as a diagnostic tool that allows for the "initiation of specific treatment".[3]
Management
Treatment depends on the form (category) of the disease. Although symptoms are similar to
Postsynaptic fast-channel CMS, in which ACh receptors do not stay open long enough, is treated with cholinesterase inhibitors and
Salbutamol, a selective β(2)-adrenergic receptor agonist, has been found, in adults, to have fewer side effects than Ephedrine and to be more easily obtained in some countries. It has been trialed in children with positive results[9]
As of 2022, the standard of care for DOK7 CMS is either ephedrine or salbutamol.[10]
See also
- Congenital disorder
- Myasthenia gravis
- Lambert-Eaton syndrome
References
- ^ PMID 16945936.
- ^ S2CID 8403500.
- ^ PMID 25194721.
As with other rare childhood neurological conditions, CMS is often difficult to diagnose because of a broad differential diagnosis and lack of specific laboratory findings. Identification of the underlying mutation is critical, as certain mutations lead to treatment-responsive conditions while others do not. This case serves to highlight the importance of WES as a diagnostic tool that will assist in proper diagnosis, and in some circumstances, allow for initiation of specific treatment.
- PMID 25792100.
- PMID 23278578.
- ^ "Search Orphan Drug Designations and Approvals". Archived from the original on 2015-05-21. Retrieved 2015-05-22.
- ^ "Catalyst Using the Expanded Access Program to Conduct Phase IV Study with LEMS Patients". 2015-07-25. Archived from the original on 2015-07-25. Retrieved 2021-02-27.
- PMID 20458068.
- S2CID 15093159.
- ^ "Congenital myasthenic syndromes (treatment)". Genetic and Rare Diseases Information Center (GARD). National Institutes of Health (USA). Archived from the original on 31 January 2022. Retrieved 1 February 2022.