TRIM2 – Charcot-Marie-Tooth disease

TRIM2 encodes an E3 ubiquitin ligase critical for the degradation of neurofilament light chain, with emerging evidence implicating it in peripheral neuropathies. Its function in neuronal integrity makes it a biologically plausible candidate for Charcot-Marie-Tooth disease (CMT), a heterogeneous group of inherited distal symmetric polyneuropathies. This association has been explored through both single‐patient case studies and multi‐patient series.

A seminal case report identified a patient with early-onset CMT who harbored a homozygous missense mutation, c.2000A>C (p.Asp667Ala), in TRIM2. The patient presented with peripheral neuropathy and bilateral vocal cord paralysis, features that expanded the clinical spectrum of TRIM2-related neuropathy (PMID:25893792).

Subsequently, a multi-patient study reported on two unrelated patients with compound heterozygous mutations in TRIM2. These patients not only demonstrated early-onset axonal neuropathy but also exhibited cranial nerve involvement, including vocal cord paralysis, dysphagia, dyspnea, and additional signs such as motor delay and bilateral talipes equinovarus (PMID:32815244). Such findings have been instrumental in broadening the phenotypic framework associated with TRIM2 mutations.

The genetic findings are underpinned by an autosomal recessive mode of inheritance. Although detailed familial segregation data are limited in the reports, the observation of homozygous and compound heterozygous variants in independent families supports a recessive inheritance pattern for this CMT subtype.

Mechanistic insights further reinforce the gene-disease relationship. TRIM2’s established role in the ubiquitination and subsequent degradation of neurofilament light chain aligns well with the axonal degeneration observed in patients. Such functional evidence, while not exhaustive, provides a moderate level of support that complements the robust genetic data.

In summary, the integration of genetic and functional findings across independent studies provides strong evidence that TRIM2 mutations are causally linked to early-onset Charcot-Marie-Tooth disease. This compelling evidence is of high utility for diagnostic decision-making and guides both clinical assessment and future research directions.

References

• Human genetics • 2015 • Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis PMID:25893792
• Journal of the peripheral nervous system : JPNS • 2020 • Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease PMID:32815244

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