Abstract
BackgroundBeing a newly defined disease, RVCL-S is underrecognized by clinicians globally. It is an autosomal dominantly inherited small vessel disease caused by the heterozygous C-terminal frameshift mutation in TREX1 gene. RVCL-S is featured by cerebral dysfunction, retinopathy, and vasculopathy in multiple internal organs. Misdiagnosis may cause devastating consequences in patients, such as iatrogenic PML caused by misuse of immunosuppressants. Thus, increasing awareness of this disease is in urgent need.ResultsWe uncovered a large Chinese origin RVCL-S pedigree bearing the TREX1 mutation. A comprehensive characterization combining clinical, genetic, and neuropathological analysis was performed. The Intrafamilial comparison showed highly heterogeneous clinical phenotypes. Mutation carriers in our pedigree presented with retinopathy (8/13), seizures (2/13), increased intracranial pressure (1/13), mild cognitive impairment (3/13), stroke-like episode (3/13), mesenteric ischemia (1/13), nephropathy (9/13), ascites (3/13), hypertension (9/13), hyperlipidemia (3/8), hypoalbuminemia (3/8), normocytic anemia (3/8), subclinical hypothyroidism (1/8), hyperfibrinogenemia (1/8), hyperparathyroidism (2/8), and abnormal inflammatory markers (4/8). The constellation of symptoms is highly varied, making RVCL-S a challenging diagnosis. Comparison with reported RVCL-S pedigrees further revealed that the mesenteric ischemia is a novel clinical finding and the MRS pattern of brain lesions is emulating neoplasm and tumefactive demyelination.ConclusionOur reports characterize a highly heterogeneous RVCL-S pedigree, highlight the probability of misdiagnosis in clinical practice, and broaden the clinical spectrum of RVCL-S.
Highlights
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominantly inherited small vessel disease caused by the heterozygous C-terminal frameshift mutation in TREX1 gene [1]
It is used to be named as cerebroretinal vasculopathy (CRV), hereditary vascular retinopathy (HVR), hereditary systemic angiopathy (HSA), and hereditary endotheliopathy, Xie et al Orphanet J Rare Dis (2021) 16:56 retinopathy, nephropathy and stroke (HERNS) according to the organ of dominant involvement
Clinical findings Patient 1 (III‐7, proband) has multisystemic manifestations involving eye, brain, kidney, and mesentery A 35-year-old man presented to us because of being attacked by a generalized tonic–clonic seizure three days ago. He had a history of worsening eyesight for six years as well as chronic kidney disease (CKD) and hypertension for three years
Summary
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominantly inherited small vessel disease caused by the heterozygous C-terminal frameshift mutation in TREX1 gene [1]. The encoded protein TREX1 is a DNA-specific 3′–5′ exonuclease, widely expressed in mammalian cells. Small as it is, TREX1 plays a pivotal role in DNA repair, protein glycosylation, and innate immune regulation. Mutant TREX1 may cause subcellular mislocalization, glycosylation defects, and dysregulated innate immune regulation, leading to the wide array of symptoms in RVCL-S. Being a newly defined disease, RVCL-S is underrecognized by clinicians globally It is an autosomal dominantly inherited small vessel disease caused by the heterozygous C-terminal frameshift mutation in TREX1 gene. Increasing awareness of this disease is in urgent need
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