Autosomal Dominant Retinal Vasculopathy with Cerebral Leukodystrophy (AD-RVCL) (previously known also as Cerebroretinal Vasculopathy, CRV, or Hereditary Vascular Retinopathy, HVR or Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke, HERNS) is an inherited condition resulting from a frameshift mutation to the TREX1 gene. This genetically inherited condition affects the retina and the white matter of the central nervous system, resulting in vision loss, lacunar strokes and ultimately dementia. Symptoms commonly begin in the early to mid-forties, and treatments currently aim to manage or alleviate the symptoms rather than treating the underlying cause. The overall prognosis is poor, and death can sometimes occur within 10 years of the first symptoms appearing.

AD-RVCL (CRV) Acronym

Autosomal Dominance (genetics) means only one copy of the gene is necessary for the symptoms to manifest themselves.

Retinal Vasculopathy means a disorder that is associated with a disease of the blood vessels in the retina.

Cerebral means having to do with the brain.

Leukodystrophy means a degeneration of the white matter of the brain.

Pathogenesis

The main pathologic process centers on small blood vessels that prematurely “drop out” and disappear. The retina of the eye and white matter of the brain are the most sensitive to this pathologic process. Over a five to ten-year period, this vasculopathy (blood vessel pathology) results in vision loss and destructive brain lesions with neurologic deficits and death.

Most recently, AD-RVCL (CRV) has been renamed. The new name is CHARIOT which stands for Cerebral Hereditary Angiopathy with vascular Retinopathy and Impaired Organ function caused by TREX1 mutations.

Treatment

Currently, there is no therapy to prevent the blood vessel deterioration.

About TREX1

The official name of the TREX1 gene is “three prime repair exonuclease 1.” The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes.

Changes (mutations) to the TREX1 gene can result in a range of conditions one of which is AD-RVCL. The mutations to the TREX1 gene are believed to prevent the production of the 3-prime repair exonuclease 1 enzyme. Researchers suggest that the absence of this enzyme may result in an accumulation of unneeded DNA and RNA in cells. These DNA and RNA molecules may be mistaken by cells for those of viral invaders, triggering immune system reactions that result in the symptoms of AD-RVCL.

Mutations in the TREX1 gene have also been identified in people with other disorders involving the immune system. These disorders include a chronic inflammatory disease called systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin.

The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644

The immune system.

- The immune system is composed of white blood cells or leukocytes.

- There are 5 different types of leukocytes.

- Combined, the 5 different leukocytes represent the 2 types of immune systems (The general or innate immune system and the adaptive or acquired immune system).

- The adaptive immune system is composed of two types of cells (B-cells which release antibodies and T-cells which destroy abnormal and cancerous cells).

How the immune system becomes part of the condition.

During mitosis, tiny fragments of “scrap” single strand DNA naturally occur inside the cell. Enzymes find and destroy the “scrap” DNA. The TREX1 gene provides the information necessary to create the enzyme that destroys this single strand “scrap” DNA. A mutation in the TREX1 gene causes the enzyme that would destroy the single strand DNA to be less than completely effective. The less than completely effective nature of the enzyme allows “scrap” single strand DNA to build up in the cell. The buildup of “scrap” single strand DNA alerts the immune system that the cell is abnormal.

The abnormality of the cells with the high concentration of “scrap” DNA triggers a T-cell response and the abnormal cells are destroyed. Because the TREX1 gene is identical in all of the cells in the body the ineffective enzyme allows the accumulation of “scrap” single strand DNA in all of the cells in the body. Eventually, the immune system has destroyed enough of the cells in the walls of the blood vessels that the capillaries burst open. The capillary bursting happens throughout the body but is most recognizable when it happens in the eyes and brain because these are the two places where capillary bursting has the most pronounced effect.

Characteristics of AD-RVCL

- No recognizable symptoms until after age 40.

- No environmental toxins have been found to be attributable to the condition.

- The condition is primarily localized to the brain and eyes.

- Optically correctable, but continuous, deterioration of visual acuity due to extensive multifocal microvascular abnormalities and retinal neovascularization leading, ultimately, to a loss of vision.

- Elevated levels of alkaline phosphatase.

- Subtle vascular changes in the retina resembling telangiectasia (spider veins) in the parafovea circulation.

- Bilateral capillary occlusions involving the perifovea vessels as well as other isolated foci of occlusion in the posterior pole of the retina.

- Headaches due to papilledema.

- Mental confusion, loss of cognitive function, loss of memory, slowing of speech and hemiparesis due to “firm masses” and white, granular, firm lesions in the brain.

- Jacksonian seizures and grand mal seizure disorder.

- Progressive neurologic deterioration unresponsive to systemic corticosteroid therapy.

- Discrete, often confluent, foci of coagulation necrosis in the cerebral white matter with intermittent findings of fine calcium deposition within the necrotic foci.

- Vasculopathic changes involving both arteries and veins of medium and small caliber present in the cerebral white matter.

- Fibroid necrosis of vessel walls with extravasation of fibrinoid material into adjacent parenchyma present in both necrotic and non-necrotic tissue.

- Obliterative fibrosis in all the layers of many vessel walls.

- Parivascular, adventitial fibrosis with limited intimal thickening.

Conditions with similar symptoms that AD-RVCL can be misdiagnosed as:

- Brain tumors

- Diabetes

- Macular degeneration

- Telangiectasia (Spider veins)

- Hemiparesis (Stroke)

- Glaucoma

- Hypertension (high blood pressure)

- Systemic Lupus Erythematosus (SLE (same original pathogenic gene, but definitely a different disease because of a different mutation in TREX1))

- Polyarteritis nodosa

- Granulomatosis with polyangiitis

- Behçet's disease

- Lymphomatoid granulomatosis

- Vasculitis

Clinical Associations

- Raynaud's phenomenon

- Anemia

- Hypertension

- Normocytic anemia

- Normochromic anemia

- Gastrointestinal bleeding or telangiectasias

- Elevated alkaline phosphatase

Definitions

- Coagulation necrosis

- Endothelium

- Fibrinoid

- Fibrinoid necrosis

- Frameshift mutation

- Hemiparesis

- Jacksonian seizure

- Necrotic

- Necrosis

- Papilledema

- Perivascular

- Retinopathy

- Telangiectasia

- Vasculopathy

- Vascular

What AD-RVCL is not:

- Infection

- Cancer

- Diabetes

- Glaucoma

- Hypertension

- A neurological disorder

- Muscular dystrophy

- Systemic Lupus Erythematosis (SLE)

- Vasculitis

Things that have been tried but turned out to be ineffective or even make things worse:

- Antibiotics

- Steroids

- X-Ray therapy

- Immunosuppression

History of AD-RVCL (CRV)

- 1985 – 1988: CRV (Cerebral Retinal Vasculopathy) was discovered by John P. Atkinson, MD at Washington University School of Medicine in St. Louis, MO

- 1988: 10 families worldwide were identified as having CRV

- 1991: Related disease reported, HERNS (Hereditary Endiotheliopathy with Retinopathy, Nephropathy and Stroke – UCLA

- 1998: Related disease reported, HRV (Hereditary Retinal Vasculopathy) – Leiden University, Netherlands

- 2001: Localized to Chromosome 3.

- 2007: The specific genetic defect in all of these families was discovered in a single gene called TREX1

- 2008: Name changed to AD-RVCL Autosomal Dominant-Retinal Vasculopathy with Cerebral Leukodystrophy

- 2009: Testing for the disease available to persons 21 and older

- 2011: 20 families worldwide were identified as having CRV

- 2012: Obtained mouse models for further research and to test therapeutic agents

A few studies have worked on providing details related to the outlook of disease progression. Two studies show that each year 0.5% of people who have never had bleeding from their brain cavernoma, but had symptoms of seizures, were affected by bleeding. In contrast, patients who have had bleeding from their brain cavernoma in the past had a higher risk of being affected by subsequent bleeding. The statistics for this are very broad, ranging from 4%-23% a year. Additional studies suggest that women and patients under the age of 40 are at higher risk of bleeding, but similar conducted studies did not reach the same conclusion. However, when cavernous hemangiomas are completely excised, there is very little risk of growth or rebleeding. In terms of life expectancy, not enough data has been collected on patients with this malformation in order to provide a representative statistical analysis.

Susac's syndrome (retinocochleocerebral vasculopathy) is a very rare form of microangiopathy characterized by encephalopathy, branch retinal artery occlusions and hearing loss. The cause is unknown but the current thinking is that antibodies are produced against endothelial cells in tiny arteries which leads to damage and the symptoms related to the illness. Despite this being an extremely rare disease, there are 4 registries collecting data on the illness; two are in the United States, one is in Germany and the fourth is in Portugal.

Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital disorder affecting all or a part of a cerebral hemisphere.

Susac's syndrome is named for Dr. John Susac (1940–2012), of Winter Haven, Florida, who first described it in 1979. Susac's syndrome is a very rare disease, of unknown cause, and many persons who experience it do not display the bizarre symptoms named here. Their speech can be affected, such as the case of a female of late teens who suffered speech issues and hearing problems, and many experience unrelenting and intense headaches and migraines, some form of hearing loss, and impaired vision. The problem usually corrects itself, but this can take up to five years. In some cases, subjects can become confused. The syndrome usually affects women around the age of 18 years, with female to male ratio of cases of 2:1.

William F. Hoyt was the first to call the syndrome "Susac syndrome" and later Robert Daroff asked Dr. Susac to write an editorial in Neurology about the disorder and to use the eponym of Susac syndrome in the title, forever linking this disease with him.

In pathology, hypertrophic decidual vasculopathy, abbreviated HDV, is the histomorphologic correlate of gestational hypertension, as may be seen in intrauterine growth restriction (IUGR) and HELLP syndrome.

The name of the condition describes its appearance under the microscope; the smooth muscle of the decidual (or maternal) blood vessels is hypertrophic, i.e. the muscle part of the blood vessels feeding the placenta is larger due to cellular enlargement.

Eales disease most commonly affects healthy young adults. Male predominance (up to 97.6%) has been reported in a majority of the series. The predominant age of onset of symptoms is between 20 and 30 years. The disease is now seen more commonly in the Indian subcontinent.

A number of conditions may cause the appearance of livedo reticularis:

- Cutis marmorata telangiectatica congenita, a rare congenital condition

- Sneddon syndrome – association of livedoid vasculitis and systemic vascular disorders, such as strokes, due to underlying genetic cause

- Idiopathic livedo reticularis – the most common form of livedo reticularis, completely benign condition of unknown cause affecting mostly young women during the winter: It is a lacy purple appearance of skin in extremities due to sluggish venous blood flow. It may be mild, but ulceration may occur later in the summer.

- Secondary livedo reticularis:

- Vasculitis autoimmune conditions:

- Livedoid vasculitis – with painful ulceration occurring in the lower legs

- Polyarteritis nodosa

- Systemic lupus erythematosus

- Dermatomyositis

- Rheumatoid arthritis

- Lymphoma

- Pancreatitis

- Chronic pancreatitis

- Tuberculosis

- Drug-related:

- Adderall (side effect)

- Amantadine (side effect)

- Bromocriptine (side effect)

- Beta IFN treatment, "i.e." in multiple sclerosis

- Livedo reticularis associated with rasagiline

- Methylphenidate and dextroamphetamine-induced peripheral vasculopathy

- Gefitinib

- Obstruction of capillaries:

- Cryoglobulinaemia – proteins in the blood that clump together in cold conditions

- Antiphospholipid syndrome due to small blood clots

- Hypercalcaemia (raised blood calcium levels which may be deposited in the capillaries)

- Haematological disorders of polycythaemia rubra vera or thrombocytosis (excessive red cells or platelets)

- Infections (syphilis, tuberculosis, Lyme disease)

- Associated with acute renal failure due to cholesterol emboli status after cardiac catheterization

- Arteriosclerosis (cholesterol emboli) and homocystinuria (due to Chromosome 21 autosomal recessive Cystathionine beta synthase deficiency)

- Intra-arterial injection (especially in drug addicts)

- Ehlers-Danlos syndrome – connective tissue disorder, often with many secondary conditions, may be present in all types

- Pheochromocytoma

- Livedoid vasculopathy and its association with factor V Leiden mutation

- FILS syndrome (polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature)

- Primary hyperoxaluria, oxalosis (oxalate vasculopathy)

- Cytomegalovirus infection (very rare clinical form, presenting with persistent fever and livedo reticularis on the extremities and cutaneous necrotizing vasculitis of the toes)

- Generalized livedo reticularis induced by silicone implants for soft tissue augmentation

- As a rare skin finding in children with Down syndrome

- Idiopathic livedo reticularis with polyclonal IgM hypergammopathy

- CO angiography (rare, reported case)

- A less common skin lesion of Churg-Strauss syndrome

- Erythema nodosum-like cutaneous lesions of sarcoidosis showing livedoid changes in a patient with sarcoidosis and Sjögren's syndrome

- Livedo vasculopathy associated with IgM antiphosphatidylserine-prothrombin complex antibody

- Livedo vasculopathy associated with plasminogen activator inhibitor-1 promoter homozygosity and prothrombin G20210A heterozygosity

- As a first sign of metastatic breast carcinoma (very rare)

- Livedo reticularis associated with renal cell carcinoma (rare)

- Buerger's disease (as an initial symptom)

- As a rare manifestation of Graves hyperthyroidism

- Associated with pernicious anaemia

- Moyamoya disease (a rare, chronic cerebrovascular occlusive disease of unknown cause, characterized by progressive stenosis of the arteries of the circle of Willis leading to an abnormal capillary network and resultant ischemic strokes or cerebral hemorrhages)

- Associated with the use of a midline catheter

- Familial primary cryofibrinogenemia.

Glomeruloid hemangioma is a distinctive vascular neoplasm first described in 1990 when found to be associated with Crow-Fukase syndrome and Castleman's disease.

In the treatment of a brain cavernous hemangioma, neurosurgery is usually the treatment chosen. Research needs to be conducted on the efficacy of treatment with stereotactic radiation therapy, especially on the long-term. However, radiotherapy is still being studied as a form of treatment if neurosurgery is too dangerous due the location of the cavernoma. Genetic researchers are still working on determining the cause of the illness and the mechanism behind blood vessel formation. Clinical trials are being conducted to better assess when it is appropriate to treat a patient with this malformation and with what treatment method. Additionally, long term studies are being conducted because there is no information related to the long-term outlook of patients with cavernoma. A registry exists known as The International Cavernous Angioma Patient Registry collects information from patients diagnosed with cavernoma in order to facilitate discovery of non-invasive treatments.

In children and some adults, FSGS presents as a nephrotic syndrome, which is characterized by edema (associated with weight gain), hypoalbuminemia (low serum albumin, a protein in the blood), hyperlipidemia and hypertension (high blood pressure). In adults, it may also present as kidney failure and proteinuria, without a full-blown nephrotic syndrome.

Fetal thrombotic vasculopathy is a chronic disorder characterized by thrombosis in the fetus leading to vascular obliteration and hypoperfusion.

It is associated with cerebral palsy and stillbirth.

There are currently several known genetic causes of the hereditary forms of FSGS.

Some researchers found SuPAR as a cause of FSGS.

Another gene that has been associated with this syndrome is the COL4A5 gene.

It is a disorder related to excessive neuronal proliferation and hamartomatous overgrowth affecting the cortical formation. The excessive proliferation is postulated to occur early and to possibly continue beyond the normal proliferative period. Epidermal growth factor is thought to play an important role in the excessive proliferation and the pathogenesis of HME.

Large and especially giant congenital nevi are at higher risk for malignancy degeneration into melanoma. Because of the premalignant potential, it is an acceptable clinical practice to remove congenital nevi electively in all patients and relieve the nevocytic overload.

The cause of this condition is not known. However, in a significant number of patients, DNA of the bacterium "Mycobacterium tuberculosis" was detected by PCR.

Other than identifying and treating any underlying conditions in secondary livedo, idiopathic livedo reticularis may improve with warming the area.

It is also possible to classify angiopathy by the associated condition:

- Diabetic angiopathy

- Congophilic angiopathy

It can be diagnosed by histomorphologic examination of the placenta and is characterized by fetal vessel thrombosis and clustered fibrotic chorionic villi without blood vessels.

Focal proliferative nephritis is a type of glomerulonephritis seen in 20% to 35% of cases of lupus nephritis, classified as type III. As the name suggests, lesions are seen in less than half of the glomeruli. Typically, one or two foci within an otherwise normal glomerulus show swelling and proliferation of endothelial and mesangial cells, infiltration by neutrophils, and/or fibrinoid deposits with capillary thrombi. Focal glomerulonephritis is usually associated with only mild microscopic hematuria and proteinuria; a transition to a more diffuse form of renal involvement is associated with more severe disease.

The morphologic features of mild and moderate HDV include:

- Perivascular inflammatory cells,

- +/-Vascular thrombosis,

- Smooth muscle hypertrophy, and

- Endothelial hyperplasia.

Severe HDV is characterized by:

- Atherosis - foamy macrophages within vascular wall, and

- Fibrinoid necrosis of vessel wall (amorphous eosinophilic vessel wall).

Note: *faciobrachial deficits greater than that of the lower limb

The exact cause of lipodermatosclerosis is unknown. Venous disease, such as venous incompetence, venous hypertension, and body mass ("obesity") may be relevant to the underlying pathogenesis.

Increased blood pressure in the veins (venous hypertension) can cause diffusion of substances, including fibrin, out of capillaries. Fibrotic tissue may predispose the tissue to ulceration. Recurrent ulceration and fat necrosis is associated with lipodermatosclerosis. In advanced lipodermatosclerosis the proximal leg swells from chronic venous obstruction and the lower leg shrinks from chronic ulceration and fat necrosis resulting in the inverted coke bottle appearance of the lower leg.

Lipodermatosclerosis is most commonly diagnosed in middle-aged women.

The origin of lipodermatosclerosis is probably multifactorial, involving tissue hypoxia, leakage of proteins into the interstitium, and leukocyte activation. Studies of patients with lipodermatosclerosis have demonstrated significantly decreased concentrations of cutaneous oxygen associated with decreased capillary density. Capillaries are virtually absent in areas of fibrotic scars, leading to a condition known as atrophie blanche or livedoid vasculopathy.

Cases of cerebral softening in infancy versus in adulthood are much more severe due to an infant's inability to sufficiently recover brain tissue loss or compensate the loss with other parts of the brain. Adults can more easily compensate and correct for the loss of tissue use and therefore the mortality likelihood in an adult with cerebral softening is less than in an infant.

Predisposing factors for Postoperative PVR are preoperative PVR, aphakia, high levels of vitreous proteins, duration of retinal detachment before corrective surgery, the size of the retinal hole or tear, intra-ocular inflammation, vitreous hemorrhage, and trauma to the eye. An equation to calculate the patient's risk for acquiring PVR is:

1 is added if the risk factor is present and 0 if the risk factor is absent. A patient is at a high risk for developing PVR is the PVR score is >6.33.