BACKGROUND: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous disorder of neuromuscular transmission, with more than 35 associated genes. Although CMS typically presents at birth or in early childhood, adult-onset forms are increasingly recognized and frequently mimic seronegative autoimmune myasthenia gravis, causing diagnostic delay. Its prevalence (2.8-14.8 per million) is probably underestimated, particularly for mild, late-onset, or atypical phenotypes.

CASE REPORT: A 42-year-old man with well-controlled seropositive rheumatoid arthritis presented with progressive fatigue, fluctuating proximal weakness (Medical Research Council grade 4/5 with fatigability), bilateral ptosis, and intermittent diplopia. Nerve conduction studies, repetitive nerve stimulation, and electromyography were normal, and a comprehensive autoimmune and myositis antibody panel was negative, prompting genetic testing. Whole-exome and whole-genome sequencing identified a heterozygous pathogenic CHRND variant; additional variants of uncertain or unrelated significance were also detected. Because CHRND-related CMS is classically autosomal recessive and single-fiber electromyography was not performed, a single heterozygous variant cannot be regarded as confirmatory, and the diagnosis is considered suspected rather than definitive. Pyridostigmine produced clinically meaningful improvement—reduced ptosis, resolved diplopia, and improved endurance—that was sustained at the 6-week follow-up.

CONCLUSIONS: CMS should be considered in adults with fatigable weakness and atypical neuromuscular features once autoimmune causes are excluded; however, a single heterozygous variant without confirmatory electrophysiology limits diagnostic certainty. To our knowledge, this is the first report of a suspected CHRND-associated adult-onset CMS with seropositive rheumatoid arthritis. Broad genetic testing is valuable when phenotype and serology diverge, but results must be interpreted cautiously alongside electrophysiological confirmation before a definitive diagnosis.

Keywords: cholinergic neurons, Myasthenia Gravis, Myasthenic Syndromes, Congenital