Congenital myasthenic syndromes (CMS) are a group of rare genetic disorders that affect the neuromuscular junction, which is the point where nerve cells communicate with the muscles. These syndromes result in muscle weakness and fatigue, especially during prolonged activity.
Congenital myasthenic syndromes genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key points about Congenital Myasthenic Syndrome (CMS) include:
- Genetic Basis: CMS is typically inherited, and various genetic mutations can lead to the condition. Mutations may affect proteins involved in transmitting signals between nerve cells and muscles, leading to impaired communication at the neuromuscular junction.
- Symptoms: The primary symptom of CMS is muscle weakness that becomes more pronounced with physical activity. Common manifestations include difficulty swallowing, breathing problems, and weakness in the facial muscles. Symptoms can vary widely among individuals with different forms of CMS.
- Onset and Severity: Symptoms may appear at birth or during early childhood. The severity of CMS can also vary, with some individuals experiencing mild muscle weakness while others may have more significant challenges with motor functions.
- Diagnosis: Diagnosis involves clinical evaluation, electromyography (EMG), nerve conduction studies, and genetic testing. These tests help to identify the specific genetic mutation causing CMS.
- Subtypes: There are different subtypes of CMS, each associated with specific genetic mutations. These subtypes can influence the course of the disease and the response to treatment. Up to 35 genes are involved in this group of disorders, which are classified into 14 groups according to pathomechanical characteristics. It may be inherited autosomal recessively or dominantly.
- Treatment: Although there is no cure for CMS, various treatment options aim to manage symptoms and improve quality of life. Acetylcholinesterase inhibitors, such as pyridostigmine, are commonly prescribed to enhance communication between nerves and muscles. Other treatment approaches may include immunosuppressive drugs or, in some cases, surgical interventions.
- Prognosis: The prognosis for individuals with CMS varies depending on the specific subtype and the severity of symptoms. With appropriate management, many people with CMS can lead relatively everyday lives, although some may experience ongoing challenges.
Individuals with suspected CMS need to consult with healthcare professionals, such as neurologists or geneticists, for accurate diagnosis and personalized treatment plans.
Of the 35 causative genes of CMS, pathogenic variants have been most frequently observed in the AChR subunit ε (CHRNE), choline Q (COLQ), rapsin (RAPSN), Dok-7 (DOK7) and glutamine-fructose-6-phosphate transaminase 1 (GFPT1) genes. This test analyzes some pathogenic variants of the RAPSN gene, whose protein, rapsin, allows the association and multimerization of the acetylcholine receptor or AChR.
The c.264C A (p.Asn88Lys) mutation is one of the most essential pathogenic variants widely described in the literature. It is a semi-conservative amino acid substitution that impacts the protein's secondary structure, affecting the ACh receptor's multimerization and hindering synaptic transmission in the neuromuscular junction. It follows an autosomal recessive inheritance pattern found in patients with myasthenic syndrome in both homozygosis and compound heterozygosis. It is the most frequent variant in Europeans, with an allele frequency of 0.0026 compared to a worldwide frequency of 0.0015.
The Congenital Myasthenic Syndrome genetic test analyzes the four most frequent pathogenic mutations of the RAPSN gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
