Azulay et al. (1994) reported a woman with proximal muscle weakness of the myasthenic type. Family history was not reported.
Shankar et al. (2002) reported 2 Indian sisters with classic features of limb-girdle myasthenia.
... Azulay et al. (1994) reported a woman with proximal muscle weakness of the myasthenic type. Family history was not reported. Shankar et al. (2002) reported 2 Indian sisters with classic features of limb-girdle myasthenia. Beeson et al. (2006) summarized the clinical features of 19 of 21 index patients with limb-girdle myasthenia and the affected brother of case 11, all of whom had mutations in DOK7 (610285). All patients displayed electromyographic (EMG) evidence of a defect in neuromuscular transmission and all but 3 patients developed weakness within the first 5 years of life. The clinical onset of disease was generally characterized by difficulty in walking after initially achieving normal walking milestones. Features typically seen in patients with mutations in rapsyn (601592), such as congenital joint deformity and squint, were not present. In adulthood, a proximal weakness of the affected patients' upper and lower extremities was evident, and most had weakness in the trunk and neck regions. All of the patients had weak facial muscles, and all but 2 patients had ptosis. Eye movements were generally unaffected. Anticholinesterase medication either had no effect or made the weakness worse, although a short-lived initial response was occasionally seen. Beeson et al. (2006) also undertook an analysis of motorpoint muscle biopsies, which showed that many features of the neuromuscular junction (NMJ) were normal, including the quantal release per unit area of synaptic content and the size and kinetics of the miniature end-plate currents. However, 2 major abnormalities were identified: reduced size of the NMJs and reduced postsynaptic folding. Beeson et al. (2006) noted that another genetic congenital myasthenic syndrome with a limb girdle-like pattern of muscle weakness is associated with tubular aggregates in muscle biopsies (CMSTA1; 610542). Tubular aggregates were present in the 1 patient from the study by Slater et al. (2006) in whom no DOK7 mutation was found, but were not present in patients with DOK7 mutations. The patient with tubular aggregates was later found by Belaya et al. (2012) to carry compound heterozygous mutations in the DPAGT1 gene (191350.0002 and 191350.0003; see CMSTA2, 614750). In contrast with patients harboring DOK7 mutations, patients with tubular aggregates tend to respond well to anticholinesterase medication, suggesting that the phenotypes constitute separate disorders. Selcen et al. (2008) reported 16 patients with DOK7-related congenital myasthenia. The age at onset ranged from the first day of life to age 5 years, and there was great variability in disease severity and rate of progression. Some patients had mild static weakness limited to limb-girdle muscles, whereas others had severe generalized disease with marked muscle atrophy. Ten patients had intermittent worsenings lasting from days to weeks. All patients reported fatigue on exertion and proximal muscle weakness. Other common features included ptosis (14 patients), facial weakness (13), bulbar symptoms (11), and respiratory difficulties (13). Oculoparesis was less common (6), and only 3 showed decreased fetal movements. In general, there was a poor response to cholinesterase inhibitors and cholinergic agents. The authors found no consistent correlation between the clinical severity and expression of DOK7 at the endplate; in fact, some patients with severe disease showed almost normal expression. Electron microscopy of endplates showed variable changes, including degeneration of junctional folds, reduced nerve terminals, or degeneration of subsynaptic organelles, but some endplates appeared normal. In vitro microelectrode studies showed decreased numbers of released quanta and decreased synaptic response to acetylcholine. Acetylcholine receptors (AChR) were decreased in areas of degenerating junctional folds, but AChR kinetics were normal. Selcen et al. (2008) noted that the studies did not reveal a clear correlation between histologic or electrophysiologic findings and disease severity in individual patients, but indicated that changes in the structural integrity of the endplate likely contributed to the decreased safety margin of neuromuscular transmission. Huze et al. (2009) reported a brother and sister, born of distantly related Swiss parents, with CMS. The proband was a 42-year-old woman who reported being unable to run and ptosis since early childhood. Physical examination showed mild facial weakness and slight muscle weakness. Her 36-year-old brother also presented CMS with similar manifestations: he had difficulty in running since early childhood, mild right ptosis, normal ocular pursuit, and intermittent mild masticatory difficulties. Both patients had a thin thorax and flat feet. Diplopia, bulbar symptoms, and dyspnea were never reported. Repetitive stimulation of certain muscles at 3 Hz resulted in a clear decrement of the CMAPs. Skeletal muscle biopsy showed type 2 fiber atrophy and pre- and postsynaptic alterations, including fragmented synaptic gutters, absence of nerve terminals characteristic of denervation, and newly formed synaptic caps. Both patients showed remarkable clinical improvement after treatment with ephedrine. Genetic analysis revealed a homozygous mutation in the AGRN gene (G1709R; 103320.0001). Mutant agrin was expressed and localized correctly in patient muscle, but the overall organization of the neuromuscular junction was perturbed.
Beeson et al. (2006) identified frameshift mutations in the DOK7 gene (610285) in 16 unrelated patients with limb-girdle type congenital myasthenic syndrome. In 3 additional patients, a frameshift mutation was ... - Mutations in the DOK7 Gene Beeson et al. (2006) identified frameshift mutations in the DOK7 gene (610285) in 16 unrelated patients with limb-girdle type congenital myasthenic syndrome. In 3 additional patients, a frameshift mutation was identified in combination with a nonsense mutation, a splice site mutation, and a missense change of a conserved residue. These mutations were found in homozygosity or compound heterozygosity, consistent with recessive inheritance seen in this phenotype. Beeson et al. (2006) also identified C-terminal domain frameshift mutations in DOK7 in DNA available from 6 of 7 patients included in the study by Slater et al. (2006). The seventh patient reported by Slater et al. (2006) was found by Belaya et al. (2012) to carry compound heterozygous mutations in the DPAGT1 gene (191350.0002 and 191350.0003; see 614750). Among 16 patients with limb-girdle congenital myasthenic syndrome, Selcen et al. (2008) identified 17 different mutations in the DOK7 gene, including 10 novel mutations (see, e.g., 610285.0009; 610285.0010). All of the mutations resulted in a termination codon or a frameshift, except for 3 that resulted in the in-frame deletion of 1 or more exons. In vitro functional expression studies in murine myotubes showed that many of the mutations resulted in decreased axial length and density of AChR clusters at the endplate. Selcen et al. (2008) concluded that the pathogenesis of the disorder results from destruction and simplification of synaptic structures with resultant decrease in neuromuscular transmission. - Mutations in the AGRN Gene In a Swiss brother and sister with CMS, Huze et al. (2009) identified a homozygous mutation in the AGRN gene (G1709R; 103320.0001). Mutant agrin was expressed and localized correctly in patient muscle, but the overall organization of the neuromuscular junction was perturbed, affecting both the pre- and postsynaptic regions.