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

Population studies from numerous areas in the world have shown that HHT occurs at roughly the same rate in almost all populations: somewhere around 1 in 5000. In some areas, it is much more common; for instance, in the French region of Haut Jura the rate is 1:2351 - twice as common as in other populations. This has been attributed to a founder effect, in which a population descending from a small number of ancestors has a high rate of a particular genetic trait because one of these ancestors harbored this trait. In Haut Jura, this has been shown to be the result of a particular "ACVRL1" mutation (named c.1112dupG or c.1112_1113insG). The highest rate of HHT is 1:1331, reported in Bonaire and Curaçao, two islands in the Caribbean belonging to the Netherlands Antilles.

Most people with HHT have a normal lifespan. The skin lesions and nosebleeds tend to develop during childhood. AVMs are probably present from birth, but don't necessarily cause any symptoms. Frequent nosebleeds are the most common symptom and can significantly affect quality of life.

Several anti-angiogenesis drugs approved for other conditions, such as cancer, have been investigated in small clinical trials. The anti-VEGF antibody bevacizumab, for instance, has been used off-label in several studies. In the largest study conducted so far, bevacizumab infusion was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis in treated HHT patients. Thalidomide, another anti-angiogenesis drug, was also reported to have beneficial effects in HHT patients. Thalidomide treatment was found to induce vessel maturation in an experimental mouse model of HHT and to reduce the severity and frequency of nosebleeds in the majority of a small group of HHT patients. The blood hemoglobin levels of these treated patients rose as a result of reduced hemorrhage and enhanced blood vessel stabilization.

People with A-T have a highly increased incidence (approximately 25% lifetime risk) of cancers, particularly lymphomas and leukemia, but other cancers can occur. When possible, treatment should avoid the use of radiation therapy and chemotherapy drugs that work in a way that is similar to radiation therapy (radiomimetic drugs), as these are particularly toxic for people with A-T. The special problems of managing cancer are sufficiently complicated that treatment should be done only in academic oncology centers and after consultation with physicians who have specific expertise in A-T. Unfortunately, there is no way to predict which individuals will develop cancer. Because leukemia and lymphomas differ from solid tumors in not progressing from solitary to metastatic stages, there is less need to diagnose them early in their appearance. Surveillance for leukemia and lymphoma is thus not helpful, other than considering cancer as a diagnostic possibility whenever possible symptoms of cancer (e.g. persistent swollen lymph glands, unexplained fever) arise.

Women who are A-T carriers (who have one mutated copy of the ATM gene), have approximately a two-fold increased risk for the development of breast cancer compared to the general population. This includes all mothers of A-T children and some female relatives. Current consensus is that special screening tests are not helpful, but all women should have routine cancer surveillance.

A 2014 review stated that 25% and 30% of identified suffers die in the first two decades of life, mainly due to lack of treatment.

The vWF gene is located on the short arm "p" of chromosome 12 (12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally, type 2 also inherits recessively. vWD occurs in approximately 1% of the population and affects men and women equally.

About two-thirds of people with A-T have abnormalities of the immune system. The most common abnormalities are low levels of one or more classes of immunoglobulins (IgG, IgA, IgM or IgG subclasses), not making antibodies in response to vaccines or infections, and having low numbers of lymphocytes (especially T-lymphocytes) in the blood. Some people have frequent infections of the upper (colds, sinus and ear infections) and lower (bronchitis and pneumonia) respiratory tract. All children with A-T should have their immune systems evaluated to detect those with severe problems that require treatment to minimize the number or severity of infections. Some people with A-T need additional immunizations (especially with pneumonia and influenza vaccines), antibiotics to provide protection (prophylaxis) from infections, and/or infusions of immunoglobulins (gamma globulin). The need for these treatments should be determined by an expert in the field of immunodeficiency or infectious diseases.

This disease is endemic in Portuguese locations Póvoa de Varzim and Vila do Conde (Caxinas), with more than 1000 affected people, coming from about 500 families, where 70% of the people develop the illness. ll the analysed Portuguese families presented the same haplotype (haplotype I) associated with the Met 30 mutation. In northern Sweden, more specifically Piteå, Skellefteå and Umeå, 1.5% of the population has the mutated gene. There are many other populations in the world who exhibit the illness after having developed it independently.

Von Willebrand factor is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF, therefore, shows primarily in organs with extensive small vessels, such as skin, gastrointestinal tract, and uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly.

vWF carries Factor VIII

In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are highly penetrant. In milder cases of type 1 vWD, a complex spectrum of molecular pathology may exist in addition to polymorphisms of the vWF gene alone. The individual's ABO blood group can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.

Susceptibility weighted imaging has been proposed as a tool for identifying CAA-related microhemorrhages.

Biopsies also play a role in diagnosing the condition.

A review from 2000 stated that life expectancy was reduced because of a tendency to develop cancer relatively early as well as deaths due to infections related to immunodeficiency.

By definition, primary immune deficiencies are due to genetic causes. They may result from a single genetic defect, but most are multifactorial. They may be caused by recessive or dominant inheritance. Some are latent, and require a certain environmental trigger to become manifest, like the presence in the environment of a reactive allergen. Other problems become apparent due to aging of bodily and cellular maintenance processes.

A survey of 10,000 American households revealed that the prevalence of diagnosed primary immunodeficiency approaches 1 in 1200. This figure does not take into account people with mild immune system defects who have not received a formal diagnosis.

Milder forms of primary immunodeficiency, such as selective immunoglobulin A deficiency, are fairly common, with random groups of people (such as otherwise healthy blood donors) having a rate of 1:600. Other disorders are distinctly more uncommon, with incidences between 1:100,000 and 1:2,000,000 being reported.

Acquired telangiectasia, not related to other venous abnormalities, for example on the face and trunk, can be caused by factors such as

- Acne rosacea

- Blepharitis

- Environmental damage such as that caused by sun or cold exposure

- Age

- Trauma to skin such as contusions or surgical incisions.

- Radiation exposure such as that experienced during radiotherapy for the treatment of cancer

- Chemotherapy

- Carcinoid syndrome

- Limited systemic sclerosis/scleroderma (a Scleroderma sub-type)

- Chronic treatment with topical corticosteroids may lead to telangiectasia.

- Spider angiomas are a radial array of tiny arterioles that commonly occur in pregnant women and in patients with hepatic cirrhosis and are associated with palmar erythema. In men, they are related to high estrogen levels secondary to liver disease.

- Tempi syndrome

- Smoking

CAA has been identified as occurring either sporadically (generally in elderly populations) or in familial forms such as Flemish, Iowa, and Dutch types. In all cases, it is defined by the deposition of Aβ in the leptomeningal and cerebral vessel walls. CAA occurring in the Flemish type has been observed to be linked to large dense-core plaques observed in this pedigree.

The reason for increased deposition of Aβ in sporadic CAA is still unclear with both increased production of the peptide and abnormal clearance having been proposed as potential causes. Under normal physiology Aβ is cleared from the brain by four pathways: (1) endocytosis by astrocytes and microglial cells, (2) enzymatic degradation by neprilysin or insulysin (3) cleared by way of the blood brain barrier or (4) drained along periarterial spaces. Abnormalities in each of these identified clearance pathways have been linked to CAA.

In familial forms of CAA, the cause of Aβ build up is likely due to increased production rather than poor clearance. Mutations in the amyloid precursor protein (APP), Presenilin (PS) 1 and PS2 genes can result in increased rates of cleavage of the APP into Aβ. An immune mechanism has also been proposed.

Café au lait spots can arise from diverse and unrelated causes:

- Having six or more café au lait spots greater than 5 mm in diameter before puberty, or greater than 15 mm in diameter after puberty, is a diagnostic feature of neurofibromatosis type I, but other features are required to diagnose NF-1.

- Familial multiple café au lait spots have been observed without NF-1 diagnosis.

- They can be caused by vitiligo in the rare McCune–Albright syndrome.

- Legius syndrome

- Tuberous sclerosis

- Fanconi anemia

- Idiopathic

- Ataxia-telangiectasia

- Basal cell nevus syndrome

- Benign congenital skin lesion

- Bloom syndrome

- Chédiak–Higashi syndrome

- Congenital naevus

- Gaucher disease

- Hunter syndrome

- Jaffe–Campanacci syndrome

- Maffucci syndrome

- Multiple mucosal neuroma syndrome

- Noonan syndrome

- Pulmonary Stenosis

- Silver–Russell syndrome

- Watson syndrome

- Wiskott–Aldrich syndrome

Data regarding the epidemiology of angioedema is limited. The incidence of HAE is one in 10,000–50,000 people in the United States and Canada. Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.

LIG4 syndrome (also known as Ligase IV syndrome) is an extremely rare condition caused by mutations in the DNA Ligase IV (LIG4) gene. Some mutations in this gene are associated with a resistance against multiple myeloma and Severe Combined Immunodeficiency. Severity of symptoms depends on the degree of reduced enzymatic activity of Ligase IV or gene expression.

As DNA ligase IV is essential in V(D)J recombination, the mechanism by which immunoglobulins, B cell and T cell receptors are formed, patients with LIG4 syndrome may suffer from less effective or defective V(D)J recombination. Some patients have a severe immunodeficiency characterized by pancytopenia, causing chronic respiratory infections and sinusitis. Clinical features also include Seckel syndrome-like facial abnormalities and microcephaly. Patients also suffer from growth retardation and skin conditions, including photosensitivity, psoriasis and telangiectasia. Although not present in all, patients may also present with hypothyroidism and type II diabetes and possibly malignancies such as acute T-cell leukemia. The clinical phenotype of LIG4 syndrome closely resembles that of Nijmegen breakage syndrome (NBS).

In the past, people used to think that leg varicose veins or telangectasia were caused by high venous pressure or "venous hypertension". However it is now understood that venous reflux disease is usually the cause of these problems (see above for reference for "venous reflux".

Telangiectasia in the legs is often related to the presence of venous reflux within underlying varicose veins. Flow abnormalities within the medium-sized veins of the leg (reticular veins) can also lead to the development of telangiectasia.

Factors that predispose to the development of varicose and telangiectatic leg veins include

- Age: The development of spider veins may occur at any age but usually occurs between 18 and 35 years, and peaks between 50 and 60 years.

- Gender: It used to be thought that females were affected far more than males. However research has shown 79% of adult males and 88% of adult females have leg telangectasia (spider veins).

- Pregnancy: Pregnancy is a key factor contributing to the formation of varicose and spider veins. The most important factor is circulating hormones that weaken vein walls. There's also a significant increase in the blood volume during pregnancy, which tends to distend veins, causing valve dysfunction which leads to blood pooling in the veins. Moreover, later in pregnancy, the enlarged uterus can compress veins, causing higher vein pressure leading to dilated veins. Varicose veins that form during pregnancy may spontaneously improve or even disappear a few months after delivery.

- Lifestyle/occupation: Those who are involved with "prolonged sitting or standing" in their daily activities have an increased risk of developing varicose veins. The weight of the blood continuously pressing against the closed valves causes them to fail, leading to vein distention.

The drug tafamidis has completed a phase II/III 18-month-long placebo controlled clinical trial

and these results in combination with an 18-month follow-on study demonstrated that Tafamidis or Vyndaqel slowed progression of FAP, particularly when administered to patients early in the course of FAP. This drug is now approved by the European Medicines Agency.

The US Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee rejected the drug in June 2012, in a 13-4 vote. The committee stated that there was not enough evidence supporting efficacy of the drug, and requested additional clinical trials.

Café au lait spots are usually present at birth, permanent, and may grow in size or increase in number over time.

Cafe au lait spots are themselves benign and do not cause any illness or problems. However, they may be associated with syndromes such as Neurofibromatosis Type 1 and McCune-Albright syndrome.

The size and shape of the spots do not have any meaning or implications with regards to diagnosis of associated syndromes.

Spider angiomas form due to failure of the sphincteric muscle surrounding a cutaneous arteriole. The central red dot is the dilated arteriole and the red "spider legs" are small veins carrying away the freely flowing blood. If momentary pressure is applied, it is possible to see the emptied veins refilling from the centre. No other angiomas show this phenomenon.

The dilation, in turn, is caused by increased estrogen levels in the blood. Many pregnant women, or women using hormonal contraception, have spider angiomas, due to high estrogen levels in their blood. Individuals with significant hepatic disease also show many spider angiomas, as their liver cannot metabolize circulating estrogens, specifically estrone, which derives from the androgen androstenedione. About 33% of patients with cirrhosis have spider angiomas. As such, microhemorrhages may be observed as spider angiomas.

Hypotrichosis–lymphedema–telangiectasia syndrome is a congenital syndrome characterized by lymphedema (swelling of tissue due to malformation or malfunction of lymphatics), the presence of telegiectasias (small dilated vessels near the surface of the skin), and hypotrichosis or alopecia (hair loss). Lymphedema usually develops in the lower extremities during puberty. Hair is normal at birth, but usually lost during infancy. Telangiectasias may present on the palms and soles more commonly than on the scalp, legs, and genitalia. The syndrome has been reported in association with both autosomal dominant and autosomal recessive inheritance patterns.

It is associated with a rare mutation of the transcription factor gene "SOX18".

In most cases, between the age of 2 and 4 oculomotor signals are present. Between the age of 2 and 8, telangiectasias appears. Usually by the age of 10 the child needs a wheel chair. Individuals with autosomal recessive cerebellum ataxia usually survive till their 20s; in some cases individuals have survived till their 40s or 50s.

Familial transmission is now recognized in a small proportion of people with MacTel type 2; however, the nature of any related genetic defect or defects remains elusive. The MacTel genetic study team hopes that exome analysis in the affected population and relatives may be more successful in identifying related variants.