Background and aims Mutations in myelin protein zero (MPZ) gene are a known cause of Charcot-Marie-Tooth disease. We describe three relatives carrying a likely pathogenic MPZ variant, exhibiting acute or subacute inflammatory-onset demyelinating neuropathies triggered by systemic immune disturbances. Methods We describe a familial case series involving two sisters and one male cousin. The proband (patient A) presented in his 40s with acute-onset demyelinating neuropathy compatible with Guillain-Barré syndrome. In the evolution, he presented three relapses, compatible with chronic inflammatory demyelinating polyneuropathy. He was initially responsive to intravenous immunoglobulin (IVIg) before developing a progressive, treatment-resistant form. Nerve biopsy was compatible with hereditary neuropathy. His cousin, in her 50s (patient B), was diagnosed with anti-myelin associated glycoprotein neuropathy. Immunosuppressive treatment is ongoing, with objective clinical response. Her sister (patient C) developed in her 50s a dysautonomia-predominant demyelinating neuropathy after COVID-19 infection, requiring cardiac defibrillator implantation. No immunomodulatory treatment was necessary in her case. All three harboured the heterozygous c.448G>T (p.Val150Leu) MPZ variant. Results Comprehensive investigations including blood work, nerve conduction studies, cerebrospinal fluid analysis and genetic testing confirmed a shared likely pathogenic c.448G>T (p.Val150Leu) MPZ variant. The temporal relationship between symptom onset and systemic immune stressors was consistent across cases. Discussion We propose that MPZ-related neuropathy may exhibit heightened vulnerability to inflammatory triggers. This predisposition could reflect disrupted protein homeostasis within Schwann cells, linking endoplasmic reticulum stress and immune activation. Further studies are needed to explore mechanisms of immune susceptibility in hereditary neuropathies.
Ezaru et al. (Thu,) studied this question.