The clinical and molecular genetic findings of 22 COLQ-mutant congenital myasthenic syndromes (CMS) are reported from 14 centers mainly in Europe. They represented 10% of the total CMS patients with a genetic diagnosis at these centers. The mutations in acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) are associated with end-plate AChE deficiency. The disease presents at birth (in 11 patients) with hypotonia, ptosis, ophthalmoparesis, facial weakness, weak cry and suck, and respiratory insufficiency. In 4 patients, initial symptoms of muscle weakness and fatigability were delayed until 2 to 7 years of age. Respiratory crises occurred in 10 patients, precipitated by infections in 5. None had arthrogryposis; one had congenital clubfeet. Diurnal fluctuation of symptoms was noted in 8 patients, and disease progression occurred in 9 (41%). Repetitive nerve stimulation caused a decremental response in all but 2. Myopathic potentials were recorded on EMG in 15. A characteristic double CMAP was observed in more than half the patients. None of 8 tested showed AChR antibodies. Serum CK levels were normal. Muscle biopsy in 11 patients was unremarkable in 4 and showed myopathic changes in 4. AChE inhibitor treatment (pyridostigmine) was generally ineffective long-term or caused worsening of symptoms. A surprising short-term beneficial effect was observed in 4 patients. Tensilon test performed in 4 patients was positive in 2. Ephedrine had a beneficial effect in 5 cases treated. Genetic analysis of family members was compatible with a recessive inheritance, nine belonging to consanguineous marriages. Clinical phenotypes were variable. Some patients differed from the classical phenotype, having a mild course without progression. Others had limb-girdle proximal weakness reminiscent of CMS with DOK7 gene mutation, with sparing of eye muscle involvement. [1]

COMMENT. Molecular genetic testing is important in diagnosis and therapy of infants with CMS. The administration of esterase inhibitors in patients with COLQ mutations can result in serious complications, and an initial short-term beneficial effect may be misleading. Ephedrine (2 to 3 mg/kg/day) was the most effective therapy in the above study. Most patients with COLQ mutations are disabled from infancy, and muscle weakness is progressive and complicated by ventilatory insufficiency and scoliosis. Clinical diagnosis is supported by repetitive CMAP, and increased muscle weakness following administration of pyridostigmine. COLQ gene mutations are the third most common cause of CMS, and occur as frequently as DOK7 mutation cases.