Hidden diagnoses among patients with double seronegative myasthenia gravis

Double seronegative myasthenia gravis (dSnMG) is defined as myasthenia gravis (MG) without detectable antibodies to acetylcholine receptor (AChR) and muscle-specific kinase (MuSK). Absence of a disease-specific biomarker and clinical heterogeneity can significantly complicate diagnostic pathway. This study aimed to identify cases misdiagnosed as dSnMG.

The study included 33 patients [64% females, median age at onset 30 (22.5-40) years, median age at testing 46 (34-58) years] previously diagnosed with dSnMG. Disease severity was assessed using MG-ADL and QMG at testing, peak MGFA, intensive care unit (ICU) hospitalization and MG crisis history. Indirect immunofluorescence was performed to detect low-density lipoprotein receptor-related protein 4 (LRP4) antibodies. Whole exome sequencing (WES) was conducted, along with genetic testing for myotonic dystrophy type 1 and 2 (DM1 and DM2) and oculopharyngeal muscular dystrophy (OPMD).

Mean MG-ADL and QMG scores at testing were 1 (0-3) and 6 (3-9), respectively. More than half of the patients had ocular MG (52%). One patient experienced myasthenic crisis. One patient tested positive for LRP4 antibodies, and one was diagnosed with paraneoplastic Lambert-Eaton myasthenic syndrome. WES showed likely pathogenic variant c.517G > A in the CHRNA1 gene associated with autosomal dominant slow channel congenital myasthenic syndrome and only one variant c.2368G > A in the MUSK gene. One patient displayed a DM2 premutation (32-35 CCTG repeats).

This study highlights the importance of considering alternative diagnoses in patients with dSnMG and emphasizes the value of comprehensive testing. Early recognition of causative etiologies can significantly improve patient management and outcome and prevent unnecessary exposure to prolonged immunosuppression.