Expanding the phenotypic spectrum ofTRIM2-associatedCharcot-Marie-Toothdisease

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of distal symmetric polyneuropathies due to progressive and length-dependent degeneration of peripheral nerves. Cranial nerve involvement has been described in association with various CMT-genes mutations, such asGDAP1,TRPV4,MFN2,MTMR2andEGR2. Compound heterozygous mutations in theTRIM2gene, encoding an E3 ubiquitin ligase, were previously identified in two patients with early-onset axonal CMT (CMT2). One of them also had bilateral vocal cord paralysis. The aim of this study is to further delineate the phenotypic and molecular genetic features of TRIM2-related CMT. We studied clinical, genetic and neurophysiological aspects of two unrelated CMT2 patients. Genetic analysis was performed by next generation sequencing of a multigene CMT panel. Patients presented with congenital hypotonia and bilateral clubfoot, delayed motor milestones, and severely progressive axonal neuropathy. Interestingly, along with vocal cord paralysis, they exhibited clinical features secondary to the involvement of several other cranial nerves, such as facial weakness, dysphagia, dyspnoea and acoustic impairment. Genetic analysis revealed two novelTRIM2mutations in each patient. Our results expand the genotypic and phenotypic spectrum ofTRIM2deficiency showing that cranial nerves involvement is a core feature in this CMT2-subtype. Its finding should prompt physicians to suspectTRIM2neuropathy. Conversely, patients carryingTRIM2variants should be carefully evaluated for the presence of cranial nerve dysfunction in order to prevent and manage its impact on auditory and respiratory function and nutrition.