CHRNE-related congenital myasthenic syndrome (CMS 4C): familial phenotype and marked response to salbutamol in myasthenic crisis

Abstract

Case Presentation: A female patient presented with neonatal hypotonia, initially described as a “floppy infant,” followed by lifelong fluctuating bilateral ptosis. In adulthood, she developed progressive proximal lower limb weakness, particularly when climbing stairs, with worsening after pregnancies, as well as intermittent dysphagia. Family history was strongly positive, with four affected siblings, supporting a hereditary neuromuscular disorder.Repetitive nerve stimulation demonstrated a decremental response greater than 10%. Genetic testing confirmed a homozygous mutation in the CHRNE gene, establishing the diagnosis of congenital myasthenic syndrome type 4C (OMIM 608931).In 2022, during hospitalization for cholecystectomy, the patient developed a severe myasthenic crisis requiring orotracheal intubation on two occasions. No immunomodulatory therapies were administered. Intravenous salbutamol was initiated, resulting in rapid and sustained clinical improvement.She is currently maintained on pyridostigmine and salbutamol, with stable clinical status, no respiratory or bulbar symptoms, and preserved functional capacity, including regular physical activity. Discussion: CHRNE-related CMS is a postsynaptic disorder caused by dysfunction of the epsilon subunit of the acetylcholine receptor, leading to impaired neuromuscular transmission. Clinical manifestations are heterogeneous, ranging from severe neonatal presentations to milder, slowly progressive phenotypes, often contributing to delayed diagnosis.This case highlights important diagnostic challenges, including phenotypic overlap with autoimmune myasthenia gravis and the possibility of normal electrophysiological findings under anticholinesterase therapy. The marked familial aggregation supports an autosomal recessive inheritance pattern.Therapeutically, CMS differs fundamentally from autoimmune myasthenia gravis, as immunomodulatory treatments are ineffective. Instead, β2-adrenergic agonists, such as salbutamol, have demonstrated significant clinical benefit, likely by enhancing neuromuscular junction stability. The pronounced response observed in this patient—including during a life-threatening myasthenic crisis—underscores the potential role of these agents even in acute settings, where evidence remains limited. Additionally, this case reinforces the importance of genetic confirmation to guide treatment and avoid unnecessary interventions, such as thymectomy or exposure to immunosuppressive therapies. Final Comments: This report emphasizes the need for heightened clinical suspicion of congenital myasthenic syndromes in patients with early-onset, fluctuating weakness and positive family history. Genetic diagnosis is essential for precision medicine, enabling targeted and effective treatment. β2-adrenergic agonists represent a key therapeutic strategy, with the potential to significantly improve outcomes, including in severe presentations such as myasthenic crisis.