Chronic Dyspnea Leading to the Diagnosis of LRP4-positive Myasthenia Gravis

Abstract Introduction:Myasthenia gravis (MG) is an autoimmune disorder that impairs neuromuscular transmission, characterized by muscle weakness. The condition is driven by antibodies that target acetylcholine receptors (AChR), muscle-specific kinase (MuSK), or other AChR-associated proteins in the postsynaptic membrane. While anti-AChR antibodies account for most cases, up to 40% of seronegative patients possess antibodies against MuSK. More recently, studies identified that a subset of double-seronegative patients possessed antibodies against lipoprotein-related protein 4 (LRP4). LRP4 is an agrin receptor, essential for the agrin-induced activation of MuSK, AChR clustering, and neuromuscular junction formation. While MG typically presents with weakness, rarely patients present with chronic progressive dyspnea as presented here.Case Description:A 65-year-old female with antiphospholipid syndrome, stroke, and COVID-19 presented to the outpatient pulmonary clinic with complaints of chronic cough and exertional dyspnea. Despite seeing multiple providers for similar symptoms and extensive evaluations, she was diagnosed with asthma and chronic bronchitis. Her symptoms persisted even with the use of antibiotics, steroids, and bronchodilators.Pulmonary function tests (PFTs) revealed severe restrictive lung disease (Ratio: 84%, FEV1: 1.87 L/72%, FVC: 2.18 L/65%, TLC: 59%, DLCO: 69%), while a high-resolution CT of the chest showed mild mosaic attenuation in the dependent bilateral lower lobes during the expiratory phase. Physical examination demonstrated difficulty with raising her arms above her head and generalized muscle weakness. Autoimmune testing was otherwise unremarkable.Subsequently, she was admitted for a transient ischemic attack (TIA) and Neurology was consulted given muscle weakness. Although initial testing for MUSK and AChR antibodies was negative, subsequent testing for LRP4 antibodies were positive. The patient was started on pyridostigmine and steroids as part of MG treatment, leading to notable improvement in her symptoms. Discussion:Diagnosing seronegative MG can be challenging, as it relies heavily on clinical judgment and physical examination. In this case, the gradual onset of respiratory symptoms led to a delay in diagnosis and a protracted workup involving multiple providers. In some cases, testing for LRP4 antibodies can assist in confirming the diagnosis when more common antibody tests are negative. The clinical significance of LRP4 antibodies compared to other forms of MG is under investigation, but evidence suggests that patients with LRP4 antibodies may experience more severe clinical symptoms. Clinicians should maintain a high index of suspicion for NMD in patients presenting with predominantly restrictive pulmonary function test (PFT) results, especially when there is no evidence of interstitial lung disease (ILD) and residual volume (RV) is normal or elevated.