Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up

- A description of clinical findings in 9 patients with a CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit.
- Phenotype is characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP.
- Facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness are also observed.
- A wide spectrum of phenotypes can be associated with a single mutation even in a single kinship.
- The course in our cohort is moderately heterogeneous: proportion of patients with a progressive or fluctuating course is 33%.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.