J. Berciano, A. Jordanova
Neurosciences and History 2025;13(4): 223-242
Article type: REVIEW
AUTHORS
J. Berciano1, A. Jordanova2,3,4
1Professor emeritus ad honorem. University of Cantabria. Former head of the Neurology Service at Marqués de Valdecilla University Hospital (IDIVAL) and researcher at Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
2Molecular Neurogenomic Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
3Department of Biochemical Sciences. University of Antwerp, Antwerp, Belgium.
4Department of Medical Chemistry and Biochemistry. Medical University of Sofia, Sofia, Bulgaria.
ABSTRACT
Objective. To perform a review of our long-term follow-up studies in a family with dominant inheritance of Charcot-Marie-Tooth disease type 2 (CMT2).
Development. The initial pedigree (1977-1985) comprised 10 affected individuals over three generations and 17 unaffected at-risk members. The clinical picture consisted of a mild peroneal muscular atrophy syndrome with incomplete penetrance in the first two decades of life. Histopathological study demonstrated that the underlying disease is a lumbosacral sensorimotor neuronopathy with length-dependent axonopathy. A tentative mapping of chromosome 12q12 (CMT2G) was performed in 2004. Subsequently, and continuing with serial clinical-electrophysiological examinations and MRI studies of calf and foot muscles, the clinical picture was redrawn, so that by 2016 there were 13 affected members. Starting from this modified pedigree, we redefined the disease-linked region to chromosome 9q and subsequently identified a novel missense variant of the E3 ubiquitin-protein ligase LRSAM1 (p.Cys694Tyr). This mutation does not influence overall protein levels of LRSAM1, nor its ubiquitylation target TSG101. The mutation is associated with several transcriptional changes, including significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration.
Conclusions. The longitudinal study of this large CMT2 family with incomplete penetrance demonstrates its enormous value for a reliable phenotypic definition. This has made possible the identification of the causal genetic variant, which attests to the formidable and sustained coordination between Spanish clinicians and Belgian geneticists. Our findings demonstrate that the isolated genetic entity CMT2G is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P.
KEYWORDS
Axonal degeneration, Charcot-Marie-Tooth disease type 2 (CMT2), CMT2G, CMT2P, electrophysiology, incomplete penetrance, LRSAM1, MRI, neuronopathy, next-generation sequencing, peroneal muscular atrophy, pes cavus, transcriptional changes
SUPPLEMENTARY MATERIAL
Supplementary material Figure S1 (link NAHV13N42025223_242_S1.pdf>
Supplementary material Figure S2 (link NAHV13N42025223_242_S2.pdf>
Supplementary material Table 1 (link NAHV13N42025223_242_T1.pdf>
Neurosciences and History 2025;13(4): 223-242