High clinical heterogeneity in a Chinese pedigree of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)

Abstract

Background 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. 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. Results We 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. Conclusion Our reports characterize a highly heterogeneous RVCL-S pedigree, highlight the probability of misdiagnosis in clinical practice, and broaden the clinical spectrum of RVCL-S.

A case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: Long‐term treatment with repeated courses of immunotherapy

“…We found increases in IL‐6 levels in the blood and CSF in this case. One RVCL‐S case with elevated blood IL‐6 levels has been reported previously 5 . This increase in IL‐6 levels may suggest that autoimmune activation contributes to RVCL‐S 5 .…”

“…One RVCL-S case with elevated blood IL-6 levels has been reported previously. 5 This increase in IL-6 levels may suggest that autoimmune activation contributes to RVCL-S. 5 However, the mechanism underlying the increase in IL-6 levels in RVCL-S remains unknown.…”

“…Because of retinal microangiopathy, tumor-like lesion with a ring-shaped contrasting effect in the brain, and the family history, RVCL-S was suspected. Upon obtaining informed consent, genetic testing was conducted, revealing a described heterozygous TREX1 gene mutation, NM_033629.6: c.703dup (p. V235Gfs*6), that has been previously reported [2][3][4][5] (Figure 1D). We started treatment with three courses of IVMP, one course of IVIg, and oral aspirin.…”

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients

“…Importantly, this is the first study investigating the role of TREX1 mutations in a large multi-ethnic cohort of unrelated CADASIL-like patients, who did not carry causative mutations in NOTCH3 . Previous literature investigated the role of TREX1 in multigenerational families or small groups of related patients from Asia (Taiwan, China, Japan), Europe (Italy, Nederland, Germany, Switzerland), USA (St. Louis, Los Angeles) and Mexico ( Soong et al, 2013 ) , ( Xie et al, 2021 ) , ( Saito et al, 2019 ) , ( DiFrancesco et al, 2015 ) , ( Pelzer et al, 2013 ) , ( Hedderich et al, 2020 ) , ( Dhamija et al, 2015 ) , ( Monroy-Jaramillo et al, 2018 ). Our study expands the clinical endophenotypes associated to TREX1 coding mutations and the genetic spectrum at the basis of CADASIL-like phenotype and warrants additional studies in larger cohorts.…”

Algorithms for comparing large pedigree graphs

“…A lot of practical work recently carried out show the massive importance of pedigrees. Among the most recent work done is Xie et al [16], where the studied a chinese pedigree for retinal vasculopathy and how cerebral leukoencephalopathy can be deduced. Also, in [17] developed an R package that uses pedigree and genomic data to analyze genetic connectedness.…”