Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes

Abstract

Dok ('downstream-of-kinase') family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic 'limb-girdle' pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that 'limb-girdle myasthenia (LGM) with tubular aggregates' previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations.

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.…”

“…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.…”

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.…”

Clinical and genetic basis of congenital myasthenic syndromes

“…The clinical spectrum is very wide, occurring with wrist weakness and lower cervical and facial involvement and some forms with bulbar and ophthalmoparesis involvement. It represents an important differential diagnosis of limb-girdle muscular dystrophies (LGMD) and initiates predominance of type 1 fibers, atrophy of type 2 fibers, and "target" fiber formations 34,35 . An LGMD-like pattern of weakness, ptosis and mild facial weakness with moderate to severe bulbar symptoms and laryngeal stridor and vocal cord palsy occurs in mutations of the last codon.…”

“…Muscle biopsy discloses generally unspecific findings. Clinical worsening is common after pyridostigmine use and clinical improvement frequently observed after ephedrine, salbutamol and albuterol use 34,35,36 .…”