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 exacerbations following infections or intense physical activity.

Fig. 1. Responses to repetitive nerve stimulation before and after fluoxetine treatment (20 mg). A: Decremental response (-18.5%) to low-frequency (3 Hz) repetitive nerve stimulation of the abductor digiti minimi muscle at rest before fluoxetine treatment (sweep speed/sensitivity: 10 ms/div, 2 mV/div). B: Normal response (0.8%) to low-frequency (3 Hz) repetitive nerve stimulation after fluoxetine treatment (sweep speed/sensitivity: 10 ms/div, 5 mV/div). In both panels, decrement was assessed as the percentage amplitude reduction from the first to the fourth response.

Pyridostigmine has been reported to be ineffective in previously described cases with AGRN mutations. In our patient, however, the medication was discontinued due to clinical deterioration.⁴,⁵,⁶ In our patient, salbutamol proved to be effective but had to be used at a low dose because of tachycardia, resulting in only partial benefit. Fluoxetine has been shown to shorten the duration of prolonged AChR channel openings in CMS subtypes such as slow channel syndrome, thereby improving symptoms.⁷ Fluoxetine provided clinical improvement approximately in the fourth week. Its effect on the neuromuscular junction is believed to be indirect and time-dependent, likely mediated by neuromodulatory mechanisms rather than a direct action. Increasing the dose did not enhance its efficacy. A marked improvement in muscle strength, particularly in the neck and proximal limbs, was observed within two hours of initiating pseudoephedrine. Due to dizziness at higher doses, treatment was continued at 30 mg/day. The effectiveness of pseudoephedrine in CMS with an agrin mutation was first demonstrated in a pediatric case in 2020, where it was suggested as an alternative therapeutic option enhancing neuromuscular transmission.⁵ This rapid response supports the notion that pseudoephedrine may provide temporary symptomatic relief, possibly through a mechanism akin to that of anticholinesterases. The identification of only a single heterozygous variant does not allow a definitive causal link between genotype and phenotype to be established. However, the clinical presentation being consistent with previously reported late-onset AGRN-related CMS cases in the literature, together with a positive family history of CMS, supports the phenotypic concordance.⁶

Pyridostigmine is not recommended in patients with AGRN gene mutations. Salbutamol, fluoxetine, and pseudoephedrine represent viable therapeutic alternatives. Both dosage and individual variability necessitate careful monitoring for side effects. While effective treatments for CMS exist, the disease may still worsen as it is rooted in its genetic basis, particularly in the presence of infections, excessive fatigue, sleep deprivation, or certain medications.

Availability of Data and Material

All data generated or analyzed during the study are included in this published article.