Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes

Abstract

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.

Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes

“…Despite the clear clinical heterogeneity, a number of distinguishing features have been observed in this subgroup including the onset of symptoms in the neonatal period, evidence of delayed motor milestones, frequent early respiratory complications, sometimes needing ventilator support, and ocular involvement with evidence of ptosis, ophthalmoparesis and sometimes abnormally slow pupillary reactions. 9 The neurophysiological findings are invariably abnormal and can be diagnostically helpful when repetitive…”

“…These are the pre-synaptic acetyltransferase CHAT 6 , the gene COLQ 7-8-9 encoding the triple stranded collagenic tail of the synaptic acetylcholinesterase (AChE), the genes encoding the different subunits of the postsynaptic acetylcholine receptors (AChR) CHRNA1, CHRNB1, CHRND, CHRNE and CHRNG, the RAPSN gene encoding the postsynaptic protein rapsyn 10 , the postsynaptic muscle specific kinase (MUSK) gene 11 , the postsynaptic sodium channel (SCN4) 12 , the DOK7 gene encoding the postsynaptic Dok-7 protein [13][14] , the LAMB2 encoding the synaptic Laminin B2 protein 15 , the AGRN gene encoding the postsynaptic agrin protein 16 and the PLEC1 gene encoding the postsynaptic protein plectin. 17-18-19 Genetic classification of the different CMS cohorts reveals that the majority of CMS patients have mutations in genes expressing postsynaptic endplate proteins [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (table 1). Despite tremendous progress in identifying the molecular basis of the different CMS subtypes, almost half of the CMS population remains genetically undiagnosed.…”

COLQ variant associated with Devon Rex and Sphynx feline hereditary myopathy

“…Their defined molecular basis in human patients supports targeted and efficient therapies for disease management and improved prognosis (see reviews: Ohno & Engel 2003; Mihaylova et al . 2008; Engel et al . 2012; Hantai et al .…”

“…2003a; Engel & Sine 2005; Mihaylova et al . 2008). COLQ missense variants in humans have been identified in all three domains (Mihaylova et al .…”

“…COLQ missense variants in humans have been identified in all three domains (Mihaylova et al . 2008; Engel et al . 2015).…”