Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease

Abstract

Background Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL‐S) is a small vessel disease caused by C‐terminal truncating TREX1 mutations. The disease is typically characterized by vascular retinopathy and focal and global brain dysfunction. Systemic manifestations have also been reported but not yet systematically investigated. Methods In a cross‐sectional study, we compared the clinical characteristics of 33 TREX1 mutation carriers (MC+) from three Dutch RVCL‐S families with those of 37 family members without TREX1 mutation (MC‐). All participants were investigated using personal interviews, questionnaires, physical, neurological and neuropsychological examinations, blood and urine tests, and brain MRI. Results In MC+, vascular retinopathy and Raynaud's phenomenon were the earliest symptoms presenting from age 20 onwards. Kidney disease became manifest from around age 35, followed by liver disease, anaemia, markers of inflammation and, in some MC+, migraine and subclinical hypothyroidism, all from age 40. Cerebral deficits usually started mildly around age 50, associated with white matter and intracerebral mass lesions, and becoming severe around age 60–65. Conclusions Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is a rare, but likely underdiagnosed, systemic small vessel disease typically starting with vascular retinopathy, followed by multiple internal organ disease, progressive brain dysfunction, and ultimately premature death.

Lesion evolution and neurodegeneration in RVCL-S

“…mutation carriers from the Netherlands in which FLAIR lesion volume for individuals younger than age 40 (N=11) was 0.19 cc similar to our median volume of 0.16 cc 47 .…”

Genetics of migraine aura: an update

“…CADASIL is caused by mutations, typically affecting the number of cysteines, in Notch3 that plays an important role in vascular smooth muscle cell functioning [40,41]. Another small vessel disease in which migraine with (and without) aura is often present is retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) [42,43]. RVCL-S is caused by carboxyl terminal truncating mutations in TREX1 [44].…”

“…RVCL-S is caused by carboxyl terminal truncating mutations in TREX1 [44]. In addition to migraine (with and without aura), mutation carriers typically suffer from retinal vasculopathy, focal and global neurological symptoms and systemic manifestations including impaired liver and renal function [42][43][44]. In RVCL-S migraine onset appears later in life (> 40 years) [43,45].…”

“…In addition to migraine (with and without aura), mutation carriers typically suffer from retinal vasculopathy, focal and global neurological symptoms and systemic manifestations including impaired liver and renal function [42][43][44]. In RVCL-S migraine onset appears later in life (> 40 years) [43,45]. This might indicate that migraine is a secondary phenomenon due to the progressive cerebral vasculopathy seen in patients with RVCL-S. Of note, in another cerebral small vessel disease, Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) that is caused by a single point mutation (E693Q) in the amyloid precursor protein (APP) gene, there also is an increased prevalence of migraine with aura [46].…”

Letter to the Editor

“…Nancy Monroy-Jaramillo 1 , Aurelio Cerón 2 , Elizabeth León 2 , Verónica Rivas 3 , Adriana Ochoa-Morales 1 , María Georgina Arteaga-Alcaraz 4 , Fausto Carlos Nocedal-Rustrian 5 , Cecilia Gallegos 6 , María Elisa Alonso-Vilatela 1 , Teresa Corona 3…”