Résumé :
|
Congenital myasthenic syndromes (CMS) differ from autoimmune myasthenia by an early onset of symptoms, a possible familial history, and the absence of autoimmunity. Among CMS, there is a large genetic heterogeneity. Ten genes have been described so far, coding for proteins implicated in the neuromuscular transmission. Mutations of DOK7 have been recently described in recessive forms of CMS. This gene, localized to 4p16.2, is coding for a post-synaptic protein responsible for activating phosphorylation of MuSK. We report clinical and molecular data of 13 patients with CMS caused by DOK7 mutations. The onset of symptoms varies from birth to early childhood. All patients display a characteristic “limb-girdle” pattern of weakness, with frequent ocular, facial, bulbar or respiratory involvement. The disease course is variable but often progressive, with fluctuations of symptoms, and may lead to loss of ambulation in adulthood. In electromyography, decrement without repetitive response is determinant for the diagnosis. Muscle biopsy shows type I fiber predominance and type II fiber atrophy. This pattern can be suggestive of CMS, although it is non-specific. In addition, we observed an increase of the lipid content of the fibers in 5/12 biopsies. Cholinesterase inhibitors are not efficient and may even worsen CMS caused by DOK7 mutations. We identified several novel mutations in our patients. The frameshift mutation c.1124_1127dupTGCC is present in half of the alleles. DOK7 is associated with a distinct phenotype of CMS, and appears to be among the most frequent genes mutated, with CHRNE and RAPSN. Supported by APHP, Inserm, ANR Maladies Rares, CMCU and AFM.
|