COLQ – Congenital Myasthenic Syndrome

COLQ encodes the collagenic tail subunit of asymmetric acetylcholinesterase (AChE), anchoring the enzyme in the synaptic basal lamina of the neuromuscular junction. Biallelic loss-of-function and missense mutations in COLQ underlie autosomal recessive Congenital Myasthenic Syndrome, characterized by early-onset fatigable weakness and a decremental response on repetitive nerve stimulation.

Inheritance is autosomal recessive, with multiple reports of affected siblings and consanguineous pedigrees. A recurrent missense variant c.1321A>G (p.Thr441Ala) was identified homozygously in three patients from two unrelated families, segregating with proximal muscle weakness and absent end-plate AChE ([PMID:15248101]).

A large integrative study of 209 patients from 195 unrelated families documented 89 distinct pathogenic or likely pathogenic COLQ variants, including 35 missense, 21 indels, 14 nonsense, 14 splice-site, and 5 large deletions; eight common alleles accounted for 48.5% of cases ([PMID:37231228]). Phenotype severity correlates with variant class: splice-site and truncating alleles confer severe early-onset weakness, whereas missense changes in the C-terminal domain yield a milder course.

Functional assays across multiple models confirm a loss-of-function mechanism. Mutations in the heparin-binding and C-terminal domains abolish anchoring of AChE to perlecan and the MuSK signaling complex, despite normal collagen triple-helix assembly, resulting in end-plate AChE deficiency ([PMID:14702351]; [PMID:23553736]). In Colq–/– mice, absence of ColQ leads to immature neuromuscular junctions, up-regulated acetylcholine receptor subunits, and muscle atrophy, recapitulating key clinical features ([PMID:26993635]).

Clinical management is guided by genotype: acetylcholinesterase inhibitors are ineffective or detrimental in COLQ-CMS, whereas β-adrenergic agonists (ephedrine, salbutamol) yield objective improvement in >98% of treated patients ([PMID:36703579]). No randomized trials exist, but consistent positive responses across >70 patients support first-line use of β-agonists and avoidance of AChE inhibitors.

Collectively, definitive clinical validity is established by >300 probands across >100 families with AR inheritance, segregation data, and concordant functional evidence. Genetic testing for COLQ should be prioritized in early-onset CMS with electrophysiologic decrement, as prompt diagnosis enables targeted therapy.

Key Take-home: COLQ-related CMS is a definitively established autosomal recessive, AChE-deficient disorder; early molecular diagnosis directs effective β-agonist therapy and avoids contraindicated AChE inhibitors.

References

• Neuropediatrics • 2004 • Synaptic congenital myasthenic syndrome in three patients due to a novel missense mutation (T441A) of the COLQ gene PMID:15248101
• Neurogenetics • 2023 • COLQ-related congenital myasthenic syndrome: An integrative view PMID:37231228
• The Journal of Biological Chemistry • 2004 • C-terminal and heparin-binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse PMID:14702351
• Human Mutation • 2013 • Mutations in the C-terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ-MuSK interaction PMID:23553736
• FASEB Journal • 2016 • Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency PMID:26993635
• Current Neuropharmacology • 2023 • Pharmacological Treatments for Congenital Myasthenic Syndromes Caused by COLQ Mutations PMID:36703579

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