Retinal Vasculopathy With Cerebral Leukodystrophy Research Articles

Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant systemic microvascular disease. Neurological disorders and visual disturbance are highlighted as manifestations of RVCL; however, there are few reports focused on nephropathy. Herein, we describe detailed renal histopathological findings in a daughter and father with RVCL, proven by TREX1 genetic analysis. A kidney biopsy of the daughter, 35-year-old with asymptomatic proteinuria, revealed unique and various glomerular changes. Atypical double contour (not tram track-like) of the capillary wall was widely found, an apparent characteristic finding. Glomerular findings were varied due to a combination of new and old segmental mesangial proliferative changes, mesangiolysis, and segmental glomerulosclerosis-like lesions; these changes may be related to endothelial cell damage. Collapsed tufts were also found and thought to be the result of ischemia due to arterial changes. Glomerular findings in a kidney biopsy of the father revealed similarity to the daughter's glomerulus at a relatively advanced stage, but the degree of variety in the glomerular findings was much less. Kidney biopsy findings suggesting endothelial cell damage of unknown etiology need to be considered for possible RVCL.

The first Turkish family with the diagnosis of retinal vasculopathy with cerebral leukodystrophy (RVCL) where a new mutation was found

The first Turkish family with the diagnosis of retinal vasculopathy with cerebral leukodystrophy (RVCL) where a new mutation was found

DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice

TREX1/DNASE III, the most abundant 3′-5′ DNA exonuclease in mammalian cells, is tail-anchored on the endoplasmic reticulum (ER). Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Goutières syndrome (AGS). Mutations in the C-terminus of TREX1 cause loss of localization to the ER and dysregulation of oligosaccharyltransferase (OST) activity, and are associated with retinal vasculopathy with cerebral leukodystrophy (RVCL) and in some cases with systemic lupus erythematosus (SLE). Here we investigate mice with conditional expression of the most common RVCL mutation, V235fs, and another mouse expressing a conditional C-terminal mutation, D272fs, associated with a case of human SLE. Mice homozygous for either mutant allele express the encoded human TREX1 truncations without endogenous mouse TREX1, and both remain DNase active in tissues. The two mouse strains are similar phenotypically without major signs of retinal, cerebral or renal disease but exhibit striking elevations of autoantibodies in the serum. The broad range of autoantibodies is primarily against non-nuclear antigens, in sharp contrast to the predominantly DNA-related autoantibodies produced by a TREX1-D18N mouse that specifically lacks DNase activity. We also found that treatment with an OST inhibitor, aclacinomycin, rapidly suppressed autoantibody production in the TREX1 frame-shift mutant mice. Together, our study presents two new mouse models based on TREX1 frame-shift mutations with a unique set of serologic autoimmune-like phenotypes.

I-05 Dual functions of TREX1 in autoimmune diseases

Background TREX1 is an endoplasmic reticulum (ER)-associated exonuclease and a critical negative regulator of innate immunity. TREX1 mutations are associated with several autoimmune and autoinflammatory diseases, including Aicardi–Goutieres syndrome (AGS), familial chilblain lupus, systemic lupus erythematosus (SLE), and retinal vasculopathy with cerebral leukodystrophy (RVCL). Both DNase-dependent and –independent functions have been described for TREX1 N-terminal DNase domain and C-terminal ER localization domain, respectively. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to activate the cGAS-STING-TBK1 signalling pathway leading to type I interferon (IFN) response and autoimmunity. Methods and results We recently showed that inhibiting TBK1 by a potent small molecule inhibitor, Compound II, was able to ameliorate autoimmune disease phenotypes of Trex1-/- mice, increase mouse survival, and dampen the IFN gene signature in TREX1 mutant patient lymphoblasts. We are also interested in a group of dominant frame-shift (fs) mutations that encode DNase-active but mislocalized proteins. We found that TREX1 C-terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilising its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release, immune activation and autoantibody production. Proper glycosylation of proteins in immunity is critical for their function, and protein glycosylation is also important for preventing self-immune recognition and production of autoantibodies. We recently established the TREX1-V235fs knock-in mouse to better understand the disease associated with TREX1-fs mutations. Conclusion Together, our past and ongoing studies reveal dual functions of TREX1 in regulating self-DNA and self-glycan metabolism, and suggest potential therapeutic targets and options for TREX1 mutant-associated autoimmune diseases.

Genetic aspects of migraine

Migraine is a common disease characterized by severe headache with nausea, vomiting and hypersensitivity to sounds, light, smell. Neurological symptoms during aura period develop in 25% of patients. Genes responsible for migraine development have been identified. The mutations in familial hemiplegic migraine are better investigated. The serotonin system plays a key role in the migraine pathogenesis. It was described the syndrome of migraine-like headache occurring due impaired serotonin metabolism in patients with celiac disease. Celiac disease is a chronic polysyndrome disease, enteropathy. Arteriopathies associated with migraine are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (syndrome CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary systemic angiopathy (HSA), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).

Multiple sclerosis-like lesions and type I interferon signature in a patient with RVCL.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare late-onset autosomal dominant systemic microvascular disease due to C-terminal truncation mutations in the three prime repair exonuclease 1 gene, TREX1 .1 Patients present with varying degrees of progressive bilateral vision loss, renal impairment, and neurologic symptoms. Cerebral MRI shows either confluent tumorlike signal alterations or multiple small white matter lesions.2,3 Herein we demonstrate a case of RVCL caused by a novel TREX1 mutation with distinct lesions on cerebral MRI and type I interferon (IFN) activation.

Adult-Onset Genetic Leukoencephalopathies. Focus on the More Recently Defined Forms.

Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brain white matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range of overlapping neurological manifestations possibly associated with variable systemic involvement are found in these disorders making clinical diagnosis challenging. Advances in molecular genetics enabled the identification of the responsible genes of an increasing number of previously undefined forms. This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of which have an autosomal dominant inheritance. The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinal microangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will be detailed because of the vascular based myelin damage and the recent genetic characterization. Other adult onset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD) due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X-associated tremor/ataxia syndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variants of the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally, palliative, curative and experimental treatment options are here summarized.

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain

BackgroundMutations in the TREX1 and NOTCH3 genes cause retinal vasculopathy with cerebral leukodystrophy (RVCL) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), respectively. Both are hereditary small vessel diseases of the brain (HSVDB). MethodsWe performed mutational analyses of TREX1 in genomic DNA from 39 unrelated patients who were NOTCH3-negative in genetic testing, selected out of 72 unrelated consecutive patients with HSVDB. ResultsOnly one patient had a TREX1 sequence variation, a heterozygous TREX1 c.294dupA, putatively resulting in a truncated protein, p.C99MfsX3. The medical history of the patient's family was scrutinized, which revealed that heterozygous TREX1 p.C99MfsX3 was not segregating with the HSVDB. Re-examination of the NOTCH3 sequence data of the proband led to the identification of a homozygous NOTCH3 c.1630C>T (p.R544C) mutation, which segregated with the HSVDB in the family. The proband had a slightly more severe phenotype in comparison with her heterozygous p.R544C sister. ConclusionTREX1 mutation is not a common cause of HSVDB. TREX1 p.C99MfsX3 is not a dominant mutation. Homozygosity of the NOTCH3 p.R544C has a modestly deleterious effect on the CADASIL phenotype. The NOTCH3 mutation may cause CADASIL through a gain-of-toxic function effect, which can be modified by other genetic or environmental factors and results in the phenotypic variation of CADASIL.

Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.

Migraine and Genetic and Acquired Vasculopathies

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.