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Título

Phenotipical patterns of congenital myasthenic syndromes

Resumo

Congenital myasthenic syndromes (CMS) comprise a rare group of genetic diseases with phenotype that can be difficult to be distinguished between their selves. In previous study we found that a pure ocular syndrome is not a usual phenotype of CMS, and that usually the phenotype is predominantly limb weakness or predominantly axial weakness (impairment of bulbar, neck and/or respiratory muscles). This study verifies which genes are related to each pattern of CMS phenotype in a large CMS cohort with genetically confirmed cases. The clinical and molecular characteristics of a large cohort of 92 patients with suspected CMS were analyzed. Data from clinical evaluations and ancillary exams were collected and blood samples were submitted to new generation sequencing. After molecular results, 66 patients were considered confirmed cases of CMS. These confirmed cases were stratified into three categories: predominantly limb weakness; predominantly axial weakness and generalized weakness. CHRNE was the defective gene in 36 patients, and was followed by DOK7 (8), RAPSN (5), COL13A1 (4), COLQ (4), GFPT1 (2), GMPPB (2), CHRNA1 (1 receptor deficiency, 1 slow channel) SCN4A (n=1), CHAT (n=1), MUSK (1). Comparison between gene related cases was done with Fisher’s test. Twenty-nine cases were considered as predominantly limb weakness: 19 CHRNE (52% of CHRNE cases), four DOK7 (50%), two RAPSN (40%), two GFPT1 (100%), one GMPPB (50%) and one COLQ (25%). Predominantly axial weakness was considered to be the phenotypical pattern in 14 cases: four DOK7 (50% of DOK7 cases), four COL13A1 (100%), two RAPSN (40%), two COLQ (50%), one MUSK and one SCN4A. 23 cases were considered as generalized weakness: 17 CHRNE (48% of CHRNE cases), one RAPSN (20%), one COLQ (25%), 1 GMPPB (50%), 1 CHRNA1 (receptor deficiency), 1 slow channel, 1 CHAT. CHRNE cases were significantly not related to predominant axial weakness (p=0.0001), and DOK7 cases were not related to generalized weakness (p= 0.0430). COL13A1 cases were related to predominant axial weakness (p=0.0014).
In a cohort larger then our previous, we still find pure ocular symptoms not a phenotype typical of CMS, once no CMS cases had this phenotype. Predominant axial weakness seems to be the less frequent of the three patterns verified, and is related to COL13A1 cases, but it is not expected as a CHRNE phenotype. Similarly, generalized weakness is probably a rare presentation of DOK7 CMS.