SUMMARY:
- Congenital myasthenic syndromes (CMS) are inherited conditions characterized by skeletal muscle weakness that results from defects of signal transmission at the neuromuscular junction.
- Inheritance of CMS may be autosomal dominant or autosomal recessive and pathogenic/likely pathogenic (P/LP) variants have been reported in over 30 genes.
- Disease severity and progression are highly variable depending on the underlying genetic defect.
CLINICAL SCENARIOS FOR MOLECULAR TESTING:
Patient Considerations
- The following scenarios are reasonable based on published guidelines and/or current clinical understanding:
- Patients with a suspected or clinical diagnosis of Congenital Myasthenic Syndromes.
- Symptoms and presentation may include:
- Fatigable weakness particularly in the ocular, bulbar, or limb muscles, arthrogryposis, feeding difficulties, ptosis, facial or bulbar weakness, generalized weakness
- Cardinal non-molecular findings supporting a clinical diagnosis may include (taken directly from Al-Muhaizea and Almobarak, 2017):
- Decreased EMG response of compound muscle action potential on low frequency stimulation
- Positive response to ACE inhibitors; negative response to immunosuppressive therapy
- Absence of anti-AChR and anti-MuSK antibodies
- Symptoms and presentation may include:
- Patients with a suspected or clinical diagnosis of Congenital Myasthenic Syndromes.
Additional Considerations
- Are any tests required prior to molecular testing? No.
- If the patient has a clinical diagnosis, is molecular testing ever indicated? Yes
- Is repeat testing ever warranted? No
- If the indication for testing is reproductive carrier screening, please see this reference library: Reproductive Carrier Screening
Medical Management
- Are results expected to lead to a change in medical management? Yes
- Molecular testing has demonstrated an impact to clinical care in this setting for most individuals by:
- Guiding medication recommendations for affected individuals, as some medications are contraindicated based on genotype
- Informing prognosis
- Informing reproductive decision-making
- Molecular testing has demonstrated an impact to clinical care in this setting for most individuals by:
TEST CONSIDERATIONS:
- For patients with suspected or confirmed CMS, the following genes have clinical utility:
- AGRN, ALG14, ALG2, CHAT, CHRNA1, CHRNB1, CHRND, CHRNE, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, RAPSN, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, UNC13A, VAMP1
- Based on the current commercial laboratory offerings, such targeted panels are commonly available.
- AGRN, ALG14, ALG2, CHAT, CHRNA1, CHRNB1, CHRND, CHRNE, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, RAPSN, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, UNC13A, VAMP1
Published Guidelines and/or Key Reference Articles:
Published Guidelines
- N/A
Key Reference Articles
- Finsterer J. Congenital myasthenic syndromes. Orphanet J Rare Dis. 2019 Feb 26;14(1):57. doi: 10.1186/s13023-019-1025-5. PMID: 30808424; PMCID: PMC6390566.
GeneReviews
- Abicht A, Müller JS, Lochmüller H. Congenital Myasthenic Syndromes Overview. 2003 May 9 [Updated 2021 Dec 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1168/
Related Content:
- N/A