To report a homozygous variant of uncertain significance in the CHRNE gene in two siblings presenting with symptoms consistent with congenital myasthenic syndrome that is responsive to pyridostigmine.

A 17-year-old female and a 9-year-old male born to consanguineous parents, with no significant perinatal complications or family history, developed predominantly proximal weakness around 4-5 years of age. The sister additionally developed bilateral fatigable ptosis. Both siblings underwent genetic testing that revealed a homozygous mutation in the CHRNE gene for a variant of uncertain clinical significance, c.322C>T (p.Pro108Ser). Since the mutation was in the CHRNE gene, which codes for the epsilon subunit of the acetylcholine receptor, the brother was initially treated with fluoxetine, which had no response. The sister was previously treated with pseudoephedrine for 2 weeks without response. Both siblings began a trial of pyridostigmine and showed improvement of their symptoms, contrary to slow-channel mutation cases that can worsen with acetylcholinesterase inhibitors. EMG/NCS with RNS on the sister was performed 48 hours after stopping pyridostigmine and showed significant decrements on RNS of the left facial nerve and left spinal accessory nerve.

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Two siblings born to consanguineous parents both shared a homozygous mutation in the CHRNE gene, presenting similarly with symptoms consistent with congenital myasthenic syndrome, responded favorably to pyridostigmine. Given then, we rationalize that the homozygous c.322C>T (p.Pro108Ser) variant in the CHRNE gene causes an acetylcholine receptor deficiency type of congenital myasthenic syndrome.