Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7

Abstract

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.

Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

“…Numerous mutations have been identified in DOK7 Muller et al, 2007;Anderson et al, 2008;Selcen et al, 2008;Vogt et al, 2009;Ben Ammar et al, 2010). Nearly all patients carry a common 1124_1127dupTGCC mutation in exon 7.…”

Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

“…In 2006, mutations in the DOK7 gene were identified to cause a form of CMS with limb-girdle weakness where patients do not benefit from pyridostigmine treatment [4]. Subsequently, detailed clinical analysis of DOK7 patients revealed that many of them show external eye muscle involvement (often ptosis, less frequent ophthalmoplegia) contrary to the original concept of pure limb girdle weakness [4][5][6][7][8][9].…”

Syndromes myasthéniques congénitaux de l’enfant : stratégies thérapeutiques médicamenteuses

“…Généralement bien tolérés, ils permettent une diminution au moins partielle des symptômes dans les SMC post-synaptiques mais peuvent nécessiter une association à d'autres traitements [1]. Ils risquent d'aggraver les SMC par déficits en AchE, les syndromes du canal lent et les déficits en Dok-7 [2]. Dans ces cas, leur utilisation prudente doit être réservée aux patients qui ne tolèrent pas les autres thérapeutiques.…”

“…Comme dans notre observation, la 3,4 DAP a permis une progression thérapeutique efficace et parfaitement tolérée. Cependant, comme pour la pyridostigmine, son administration doit être prudente dans les SMC par déficit en Dok-7 [2]. L'utilisation de la 3,4 DAP dans les syndromes pré-synaptiques serait intéressante mais ceci reste à confirmer [5].…”