Therapeutic Management in an AGRN -Related Congenital Myasthenic Syndrome Patient

Dear Editor,Congenital myasthenic syndrome (CMS) presents with fluctuating muscle weakness and fatigue as a result of a mutation in a protein that leads to a transmission disorder at the neuromuscular junction.1 It typically manifests at birth or in early childhood.The clinical presentation and treatment of CMS vary depending on the type of mutation and the affected site. 2 The agrin protein, along with LRP4, activates MUSK, which enables the clustering of acetylcholine receptors at the postsynaptic membrane.3 Mutations in the AGRN gene are rare, and there is limited information in the literature regarding their management.Here, we share our experience in the treatment of an adult CMS patient with an AGRN mutation.An 18-year-old female patient, clinically diagnosed with CMS, was found to carry a heterozygous mutation in the AGRN gene (DNA change c.3004G>C; protein change p.Gly1002Arg).Both MUSK and acetylcholine receptor antibodies were negative.Symptoms including ptosis, diplopia, proximal muscle weakness, and neck weakness had begun at age 12.These symptoms worsened with pyridostigmine.Treatment with ephedrine resulted in transient lethargy.She had no prior significant medical history.Parental consanguinity (first cousins) was noted.Family history was positive for CMS in a 2-year-old maternal first cousin who had presented with head drop and generalized weakness.The patient presented to the Neuromuscular Clinic of Dokuz Eylul University Hospital with exertional dyspnea, diplopia, ptosis, and muscle weakness, including the neck.On examination, there was marked bilateral asymmetric left ptosis, no gaze limitation, but diplopia on upward gaze; neck flexion, bilateral shoulder abduction, and hip flexion were graded as 3/5 (per the Medical Research Council scale).The MG-ADL (Myasthenia Gravis-Activities of Daily Living) score was 16.Decrement at rest was noted on repetitive nerve stimulation (RNS) (Fig. 1).The patient, weighing 48 kg, was started on 2 mg/day salbutamol suspension.At a dose of 4 mg/day, tachycardia developed, so the dose was reduced to 2 mg/day.At this dose, partial improvement in muscle strength (4/5) was observed in the extremities and neck; diplopia and ptosis resolved (MG-ADL: 9).However, full recovery was not achieved upon discharge.In the neuromuscular outpatient clinic, fluoxetine 20 mg/ day was initiated.One month later, following clinical improvement (MG-ADL: 4), RNS yielded normal responses (Fig. 1).The dose of fluoxetine was increased to 40 mg and then 60 mg at monthly intervals.However, no additional benefit was seen with dose escalation.After a clinically stable period of three months, she presented again with symptom recurrence and was rehospitalized (MG-ADL: 12).Salbutamol was discontinued, and pseudoephedrine was initiated at 30 mg/day, divided into two doses.Within two hours of administration, proximal extremity and neck flexion strength improved from 3/5 to 5/5 (MG-ADL: 3).However, dizziness developed at a dose of 60 mg/day, leading to the maintenance dose being set at 30 mg/day.The current treatment regimen includes fluoxetine 20 mg/day and pseudoephedrine 30 mg/day.Clinical follow-up continues to show transient exacerba-