PLEC-related CMS is an ultra-rare postsynaptic CMS subtype that usually presents in infancy or early childhood, often in association with epidermolysis bullosa simplex (EBS). The present case expands the recognised clinical spectrum by demonstrating adult-onset disease with a striking upper limb–predominant pattern of weakness, slow progression, and persistent sparing of the lower limbs despite prolonged follow-up. Although CMS are phenotypically heterogeneous, this distribution of weakness is uncommon within the recognised spectrum. One recent report described adult-onset myopathy with distal upper limb weakness due to PLEC mutations, but without evidence of NMJ dysfunction, making the present case clinically distinct and supporting phenotypic overlap between myopathic and myasthenic manifestations of PLEC-related disease [11].

Several findings supported a CMS diagnosis in this patient. These included fatiguable weakness, a reproducible decrement on repetitive nerve stimulation, and clinical improvement following salbutamol. Prior ultrastructural and electrophysiological studies in PLEC-related CMS have demonstrated reduced miniature endplate potentials and progressive destruction of postsynaptic junctional folds, consistent with a postsynaptic defect [12]. The response to salbutamol in this case is consistent with reported therapeutic responses in other postsynaptic CMS subtypes and with in vivo studies demonstrating partial restoration of postsynaptic architecture, including junctional folds [13]. At the same time, the coexistence of hyperCKaemia and myopathic EMG changes supports concomitant structural muscle involvement, illustrating that PLEC-related disease cannot be considered purely synaptic or purely myopathic.

Plectin is a cytolinker protein essential for maintaining structural integrity in tissues exposed to mechanical stress, including skeletal and cardiac muscle, skin, and the NMJ [14]. Consistent with this multifunctional role, pathogenic variants in PLEC give rise to a spectrum of overlapping phenotypes encompassing epidermolysis bullosa simplex (EBS), myopathy, cardiomyopathy, and CMS [2]. In this context, the presence of EBS in this patient provided an important clinical clue prompting consideration of PLEC-related disease.

Cardiac findings further broadened the phenotype. Although cardiac involvement is not typical of most CMS subtypes, it has been reported in plectinopathies, particularly in EBS–muscular dystrophy overlap syndromes [4]. In this case, cardiomyopathy was clinically silent and detected only through targeted investigation: echocardiography showed mildly reduced left ventricular systolic function, while cardiac MRI demonstrated late gadolinium enhancement consistent with myocardial fibrosis. These findings support systematic cardiac assessment in individuals with suspected PLEC-related disease, including echocardiography and, where indicated, cardiac MRI. This may be particularly relevant when β2-agonists are used symptomatically, given their potential cardiovascular effects.

This case also highlights the diagnostic limitations of standard genetic testing approaches. Initial targeted CMS panel testing identified only a single PLEC splice-site variant, whereas trio exome sequencing identified a second non-canonical intronic variant. RNA analysis then demonstrated intron 8 retention with frameshift, supporting pathogenicity and resolving the molecular diagnosis. This illustrates the value of combining phenotype-driven suspicion with broader sequencing strategies and transcript-level analysis when non-canonical variants are suspected. Such approaches are important not only for diagnosis, but also for directing surveillance, treatment decisions, genetic counselling, and readiness for future therapeutic trials.