TREX1 and Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations

TREX1 encodes the major 3′→5′ DNA exonuclease and heterozygous C-terminal frameshift mutations cause Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations (RVCL-S), a rare autosomal dominant microangiopathy marked by progressive retinal and cerebral ischemia (PMID:29028736).

An initial observational report described a 31-year-old man with family history of RVCL-S presenting with scattered cotton wool spots and paracentral acute middle maculopathy. Ultra-widefield fluorescein angiography demonstrated peripheral capillary nonperfusion correlating with areas of ischemia, and monthly intravitreal bevacizumab over 6 months reduced vascular leakage, establishing superficial and deep plexus ischemia as early diagnostic signs (PMID:29028736).

In a large extended pedigree carrying the p.Val235GlyfsTer6 C-terminal TREX1 frameshift, 17 of 29 relatives exhibited RVCL-S manifestations, including retinal vasculopathy, white matter lesions, and systemic features. Experimental therapy with the JAK inhibitor ruxolitinib in the index patient normalized elevated CXCL10 mRNA in peripheral blood mononuclear cells and stabilized clinical activity over 4 years, identifying a biomarker and potential treatment approach (PMID:36895907).

Postmortem liver pathology in 11 individuals from three unrelated kindreds harboring p.Val235GlyfsTer6 revealed nodular regenerative hyperplasia, fibrous bands, and widespread vascular remodeling, extending the RVCL-S phenotype beyond the central nervous system and retina (PMID:36871865).

A 39-year-old woman with systemic lupus erythematosus and RVCL-S carried a heterozygous TREX1 c.294dupA (p.Cys99fs) and exhibited corpus callosum atrophy on MRI, underscoring phenotypic overlap and the importance of genetic testing in atypical presentations (PMID:39119967).

Functional studies demonstrate that TREX1 C-terminal frameshifts disrupt endoplasmic reticulum localization and oligosaccharyltransferase complex interactions, leading to cytosolic mislocalization and dominant-negative effects. JAK inhibition further implicates aberrant CXCL10 signaling in pathogenesis and offers a targeted therapeutic strategy (PMID:25213617; PMID:36895907).

Integration of multiple autosomal dominant pedigrees with rigorous segregation (≥17 affected relatives) and concordant functional assays supports a Strong clinical validity for TREX1 in RVCL-S. Genetic testing for TREX1 C-terminal frameshift variants is essential for accurate diagnosis, family counseling, and may inform therapeutic interventions.

Key Take-home: Screening for heterozygous C-terminal TREX1 frameshifts in patients with unexplained retinal and cerebral small-vessel disease enables definitive diagnosis and opens avenues for targeted therapy.

References

• Retinal cases & brief reports • 2018 • SUPERFICIAL AND DEEP CAPILLARY ISCHEMIA AS A PRESENTING SIGN OF RETINAL VASCULOPATHY WITH CEREBRAL LEUKOENCEPHALOPATHY AND SYSTEMIC MANIFESTATIONS PMID:29028736
• Frontiers in neurology • 2023 • Case report: JAK inhibition as promising treatment option of fatal RVCLS due to TREX1 mutation (pVAL235Glyfs*6). PMID:36895907
• Human pathology • 2023 • Liver pathology in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: vasculopathic disease beyond nodular regenerative hyperplasia. PMID:36871865
• Immunity, inflammation and disease • 2024 • Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations in conjunction with systemic lupus erythematosus: Missed diagnosis or misdiagnosis? PMID:39119967
• Neurological sciences • 2015 • TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. PMID:25213617

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