EC Neurology

Missense variants in the Microrchidia CW-type zinc finger protein 2 (MORC2) gene were initially identified as a cause of Charcot- Marie-Tooth disease type 2Z (CMT2Z), a hereditary peripheral neuropathy. Subsequent reports revealed that MORC2-related disease has a much wider clinical spectrum, frequently involving the central nervous system through neurodevelopmental disorders, growth impairment and craniofacial dysmorphism. We describe the first reported Greek patient with MORC2-associated disease, a 29-year- old woman found to harbor the recurrent hotspot variant c.754C>T (p.R252W) in the ATPase domain of MORC2. She presented with childhood-onset gait difficulties, mild skeletal deformities, short stature, dysmorphic facial features, learning difficulties diagnosed as attention deficit hyperactivity disorder and dyslexia, and a length-dependent sensorimotor axonal polyneuropathy confirmed by nerve conduction studies. Although the p.R252W variant is most commonly associated with a pure CMT2Z phenotype, our patient displayed overlapping features with the broader neurodevelopmental phenotype known as DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy), a combination reported only a handful of times previously. This case illustrates the pleiotropic nature of MORC2-related disease and supports current evidence indicating that CMT2Z and DIGFAN likely repre- sent different points along a single disease continuum rather than distinct entities, sharing a common pathomechanism related to abnormal DNA methylation and downstream gene repression. Increased clinical awareness of this phenotypic overlap is essential, since patients with apparently isolated peripheral neuropathy may harbor additional systemic or neurodevelopmental features that warrant further evaluation. Recognition of the full clinical spectrum of MORC2-related disorders can help guide genetic counselling, anticipate associated comorbidities and inform future studies aiming to correlate genotype with the variable phenotypic expression of this disease.

Keywords: Microrchidia CW-Type Zinc Finger Protein 2 (MORC2) Gene; Charcot-Marie-Tooth Disease Type 2Z (CMT2Z); Missense Vari- ants; Peripheral Neuropathy

1. Sevilla T., et al. “Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease”. Brain1 (2016): 62-72.
2. Guillen Sacoto MJ., et al. “De novo variants in the ATPASE module of MORC2 cause a neurodevelopmental disorder with growth retardation and variable craniofacial dysmorphism”. American Journal of Human Genetics 2 (2020): 352-363.
3. Albulym OM., et al. “MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs”. Annals of Neurology 3 (2016): 419-427.
4. Sivera R., et al. “Charcot-Marie-Tooth disease due to MORC2 mutations in Spain”. European Journal of Neurology 9 (2021): 3001-3011.
5. Nomura E., et al. “Japanese case of Charcot–Marie–Tooth disease type 2Z with severe retinitis pigmentosa”. Neurology and Clinical Neuroscience 5 (2022): 266-268.
6. Ando M., et al. “Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan”. European Journal of Neurology 10 (2017): 1274-1282.
7. Hyun YS., et al. “Clinico-genetics in Korean Charcot-Marie-Tooth disease type 2Z with MORC2 mutations”. Brain 7 (2016): e40.
8. Stafki SA., et al. “The spectrum of MORC2-related disorders: a potential link to Cockayne syndrome”. Pediatric Neurology 141 (2023): 79-86.
9. Peymani F., et al. “Pleiotropic effects of MORC2 derive from its epigenetic signature”. Brain1 (2026): 163-177.
10. Miressi F., et al. “One multilocus genomic variation is responsible for a severe Charcot-Marie-tooth axonal form”. Brain Sciences 12 (2020): 986.