Clinical features of the DOK7 neuromuscular junction synaptopathy

Abstract

Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a 'limb-girdle' pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from 'limb-girdle' myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.

Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7

“…Symptoms of Dok-7 CMS may deteriorate in early childhood but are then usually stable or slowly progressive. [4][5][6] These cases demonstrate that ephedrine produces a delayed and progressive improvement in muscle strength over months which leads to a relevant improvement in daily activities in Dok-7 CMS. This is in contrast to the negative effect with anticholinesterases and variable response of 3,4-DAP in this type of CMS.…”

“…[13][14][15] Anecdotally, patients with CMS have reported benefit from ephedrine, often tried because of a failed response to other therapies, 16 but this has not been consistent or demonstrable by objective measures. Three of the 15 patients with Dok-7 CMS whose clinical details we previously reported 5 were already prescribed ephedrine prior to the identification of their genetic mutation and had reported benefit. Because CMS due to DOK7 mutations is a rare disorder, numbers are not sufficient for randomized trial designs.…”

“…8,9 The pathophysiologic consequence of Dok-7 CMS appears to arise from impaired activation of MuSK signaling leading to abnormally small, simplified, and unstable neuromuscular junctions affecting both presynaptic and postsynaptic structures 3,6,10 and mild myopathic changes on muscle histology. 5,6 The clinical phenotype is typically characterized by definite onset of weakness in early childhood, although in retrospect symptoms consistent with a CMS may have been present at birth, sparing of the external ocular muscles (EOM) in most cases and a predominant limb-girdle distribution of weakness. [3][4][5] A surprising feature of this form of CMS is the lack of response or worsening of weakness with anticholinesterase treatment and a variable response to 3,4-diaminopyridine (3,4-DAP), 4,5 the conventional CMS treatments.…”

“…5,6 The clinical phenotype is typically characterized by definite onset of weakness in early childhood, although in retrospect symptoms consistent with a CMS may have been present at birth, sparing of the external ocular muscles (EOM) in most cases and a predominant limb-girdle distribution of weakness. [3][4][5] A surprising feature of this form of CMS is the lack of response or worsening of weakness with anticholinesterase treatment and a variable response to 3,4-diaminopyridine (3,4-DAP), 4,5 the conventional CMS treatments.…”

Neurophysiological strategies for the diagnosis of disorders of the neuromuscular junction in children

“…[1][2][3][4][5][6][7][8][9][10] Major advances in our understanding of the function of the neuromuscular junction (NMJ) have resulted. When reading these papers it is interesting to speculate how these patients came to be investigated in the first place.…”