Clinical and genetic data of 14 patients from 12 congenital myasthenic syndrome (CMS) kinships with mutations in the DOK (‘downstream-of-kinase’) 7 gene are presented by researchers from the Friedrich-Baur-Institute, Munich, Germany, and several other centers. The clinical presentation of CMS with DOK7 mutations was variable. Typically, onset of symptoms was in the 2nd year of life, with an awkward or waddling gait. Four patients were hypotonic at birth, whereas 3 developed symptoms in the 2nd or 3rd decade. The majority (12 of 14) had bilateral ptosis but no paresis of eye movements. Facial and bulbar weakness occurred in 9 (64%), and several had difficulties in chewing and swallowing. Respiratory function was impaired in 10 (71%), and 2 with onset at birth needed assisted ventilation in the first months of life. Most developed scoliosis, and some had general or selective muscle atrophy. All but 1 had moderate to severe proximal muscle weakness, and a waddling ‘sinuous gait’ (inward rotation of the knees). Weakness was exercise-dependent, and fluctuated over long periods. In some, symptoms were progressive, with loss of ambulation and respiratory insufficiency in adolescence, whereas in others, severity of symptoms remained constant. AChR antibody testing was negative, and creatine kinase levels were normal. Muscle biopsies showed only nonspecific mild myopathic changes, and no tubular aggregates. Intravenous Edrophonium test was positive in 5 (35.5%), but none benefited from long-term therapy with esterase inhibitors, and some even worsened. Patients with CMS and mutations in other genes differed from CMS with DOK7 mutations. With CHRNE mutations, eye movements are frequently affected, and with CHAT and RAPSN mutations, episodic apneas occur at birth. In contrast, with DOK7 mutations eye movements are usually spared except for ptosis, and respiratory function shows a progressive deterioration. Limb-girdle myasthenia, unlike DOK7 patients is benefited by esterase inhibitor therapy. [1]

COMMENT. The DOK7 mutation congenital myasthenic syndrome has a broad clinical phenotype, with onset varying from birth to adult life. Features distinguishing the DOK7 mutation patients from other known mutation phenotypes include the absence of external ophthalmoplegia, a progressive deterioration of respiratory function, and lack of long-term response to esterase inhibitors.

Since the description of a congenital myasthenic syndrome in 6 infants treated at the Massachusetts General Hospital in 1960, a variety of molecular causes for the syndrome have been identified, including endplate acetylcholine and AChR deficiencies, a slow-channel syndrome, and defects in resynthesis of ACh and kinetics of AChR.

The common feature of CMS is a defect in the neuromuscular junction with exercise-induced weakness of skeletal muscle. In the initial report, cases presented with ptosis, weak cry, and generalized weakness. Diagnosis was delayed until 1 to 4 years after birth, when ptosis and external ophthalmoplegia were the most prominent signs, and generalized weakness and respiratory difficulty were mild in degree. Response to cholinergic drug therapy was poor, and ophthalmoplegia was unrelieved. Except for the resistance to treatment, CMS with DOK7 mutations has an unusual clinical phenotype.