It is estimated to affect less than one in a million people. Only 50 to 100 cases have so far been described.

A disease that threatens the eyesight and additionally produces a hair anomaly that is apparent to strangers causes harm beyond the physical. It is therefore not surprising that learning the diagnosis is a shock to the patient. This is as true of the affected children as of their parents and relatives. They are confronted with a statement that there are at present no treatment options. They probably have never felt so alone and abandoned in their lives. The question comes to mind, "Why me/my child?" However, there is always hope and especially for affected children, the first priority should be a happy childhood. Too many examinations and doctor appointments take up time and cannot practically solve the problem of a genetic mutation within a few months. It is therefore advisable for parents to treat their child with empathy, but to raise him or her to be independent and self-confident by the teenage years. Openness about the disease and talking with those affected about their experiences, even though its rarity makes it unlikely that others will be personally affected by it, will together assist in managing life.

Sensenbrenner syndrome (OMIM #218330) is a rare (less than 20 cases reported by 2010) multisystem disease first described in 1975. It is inherited in an autosomal recessive fashion, and a number of genes appear to be responsible. Three genes responsible have been identified: intraflagellar transport (IFT)122 (WDR10), IFT43 — a subunit of the IFT complex A machinery of primary cilia, and WDR35 (IFT121: TULP4)

It is also known as Sensenbrenner–Dorst–Owens syndrome, Levin Syndrome I and cranioectodermal dysplasia (CED)

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

Jalili syndrome is a genetic disorder characterized by the combination of cone-rod dystrophy of the retina and amelogenesis imperfecta. It was characterized in 1988 by Dr. I. K. Jalili and Dr. N. J. D. Smith, following the examination of 29 members of an inbred, Arab family living within the Gaza Strip.

Bietti's crystalline dystrophy (BCD), also called Bietti crystalline corneoretinal dystrophy, is a rare autosomal recessive eye disease named after Dr. G. B. Bietti.

BCD is a rare disease and appears to be more common in people with Asian ancestry.

EEM syndrome (or Ectodermal dysplasia, Ectrodactyly and Macular dystrophy syndrome) is an autosomal recessive congenital malformation disorder affecting tissues associated with the ectoderm (skin, hair, nails, teeth), and also the hands, feet and eyes.

No specific treatment is available. Management is only supportive and preventive.

Those who are diagnosed with the disease often die within the first few months of life. Almost all children with the disease die by the age of three.

Corneal-cerebellar syndrome (also known as Der Kaloustian-Jarudi-Khoury syndrome) is an autosomally resessive disease that was first described in 1985. Three cases are known: all are sisters in the same family.

Autoimmune polyendocrine syndrome type 1 is a condition caused in an autosomal recessive manner. Furthermore, it is due to a defect in AIRE gene (which helps to make a protein that is called the autoimmune regulator) mapped to 21q22.3 chromosome location, hence chromosome 21.

The Jalili syndrome is caused by different mutations all with a linkage at the achromatopsia locus 2q11 on the metal transporter gene, CNNM4. Sequence analysis of this gene within Jalili syndrome sufferers has identified homozygosity or compound heterozygosity for several different mutations in the CNNM4 gene.

STGD1 is the most common form of inherited juvenile macular degeneration with a prevalence of approximately 1 in 10,000 births.

Macular corneal dystrophy, also known as Fehr corneal dystrophy named for German ophthalmologist Oskar Fehr (1871-1959), is a rare pathological condition affecting the stroma of cornea. The first signs are usually noticed in the first decade of life, and progress afterwards, with opacities developing in the cornea and attacks of pain. The condition was first described by Arthur Groenouw in 1890.

Several mutations have been implicated as a cause of Oguchi disease. These include mutations in the arrestin gene or the rhodopsin kinase gene.

The condition is more frequent in individuals of Japanese ethnicity.

Walker–Warburg syndrome (WWS), also called Warburg syndrome, Chemke syndrome, HARD syndrome (Hydrocephalus, Agyria and Retinal Dysplasia), Pagon syndrome, cerebroocular dysgenesis (COD) or cerebroocular dysplasia-muscular dystrophy syndrome (COD-MD), is a rare form of autosomal recessive congenital muscular dystrophy. It is associated with brain (lissencephaly, hydrocephalus, cerebellar malformations) and eye abnormalities. This condition has a worldwide distribution. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 per 100,000 live births. It is the most severe form of congenital muscular dystrophy with most children dying before the age of three years.

These are pleomorphic and include

- dolichocephaly (with or without sagittal suture synostosis)

- microcephaly

- pre- and postnatal growth retardation

- brachydactyly

- narrow thorax

- rhizomelic dwarfism

- epicanthal folds

- hypodontia and/or microdontia

- sparse, slow-growing, hyperpigmented, fine hair

- nail dysplasia

- hypohydrosis

- chronic renal failure

- heart defects

- liver fibrosis

- visual deficits

- photophobia

- hypoplasia of the posterior corpus callosum

- aberrant calcium homeostasis

Electroretinography shows gross abnormalities.

Two fetuses of 19 and 23 weeks gestation have also been reported. They showed acromesomelic shortening, craniofacial characteristics with absence of craniosynostosis, small kidneys with tubular and glomerular microscopic cysts, persistent ductal plate with portal fibrosis in the liver, small adrenals, an enlarged cisterna magna and a posterior fossa cyst.

It was concluded by Mousa-Al et al. that the disease is different from a disease known as spastic ataxia-corneal dystrophy syndrome that had been found a year later in 1986 in an inbred Bedouin family. Corneal-cerebellar syndrome differs from the spastic ataxia-corneal dystrophy syndrome by causing mental retardation. Corneal dystrophy is also epithelian instead of being stromal.

Toxic optic neuropathy refers to the ingestion of a toxin or an adverse drug reaction that results in vision loss from optic nerve damage. Patients may report either a sudden loss of vision in both eyes, in the setting of an acute intoxication, or an insidious asymmetric loss of vision from an adverse drug reaction. The most important aspect of treatment is recognition and drug withdrawal.

Among the many causes of TON, the top 10 toxins include:

- Medications

- Ethambutol, rifampin, isoniazid, streptomycin (tuberculosis treatment)

- Linezolid (taken for bacterial infections, including pneumonia)

- Chloramphenicol (taken for serious infections not helped by other antibiotics)

- Isoretinoin (taken for severe acne that fails to respond to other treatments)

- Ciclosporin (widely used immunosuppressant)

- Acute Toxins

- Methanol (component of some moonshine, and some cleaning products)

- Ethylene glycol (present in anti-freeze and hydraulic brake fluid)

Metabolic disorders may also cause this version of disease. Systemic problems such as diabetes mellitus, kidney failure, and thyroid disease can cause optic neuropathy, which is likely through buildup of toxic substances within the body. In most cases, the cause of the toxic neuropathy impairs the tissue’s vascular supply or metabolism. It remains unknown as to why certain agents are toxic to the optic nerve while others are not and why particularly the papillomacular bundle gets affected.

In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.

The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world

with 70% of Northern European cases and 90% of Asian cases. Due to a Founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.

More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.

Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,

Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature.

EEM syndrome is caused by mutations in the "P-cadherin" gene ("CDH3"). Distinct mutations in "CDH3" (located on human chromosome 16) are responsible for the macular dystrophy and spectrum of malformations found in EEM syndrome, due in part to developmental errors caused by the resulting inability of "CDH3" to respond correctly to the "P-cadherin" transcription factor p63.

The gene for p63 ("TP73L", found on human chromosome 3) may also play a role in EEM syndrome. Mutations in this gene are associated with the symptoms of EEM and similar disorders, particularly ectrodactyly.

EEM syndrome is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis–ectodermal dystrophy/dysplasia (APECED), autoimmune polyglandular syndrome type 1, Whitaker syndrome, or candidiasis-hypoparathyroidism–Addison's disease syndrome, is a subtype of autoimmune polyendocrine syndrome (autoimmune polyglandular syndrome) in which multiple endocrine glands dysfunction as a result of autoimmunity. It is a genetic disorder inherited in autosomal recessive fashion due to a defect in the "AIRE" gene (autoimmune regulator), which is located on chromosome 21 and normally confers immune tolerance.

TAA is an old term for a constellation of elements that can lead to a mitochondrial optic neuropathy. The classic patient is a man with a history of heavy alcohol and tobacco consumption. Respectively, this combines nutritional mitochondrial impairment, from vitamin deficiencies (folate and B-12) classically seen in alcoholics, with tobacco-derived products, such as cyanide and ROS. It has been suggested that the additive effect of the cyanide toxicity, ROS, and deficiencies of thiamine, riboflavin, pyridoxine, and b12 result in TAA.

It is associated with LAMP2. The status of this condition as a GSD has been disputed.

Macular corneal dystrophy is inherited in autosomal recessive fashion and is thought to be caused by the lack or abnormal configuration of keratan sulfate. Most cases of MCD are caused by mutations in CHST6 gene.

The gene CHST6 is a carbohydrate sulfotransferase encoding an enzyme designated corneal N-acetylglucosamine-6-sulfotransferase. In MCD type I, various mutations lead to inactivation of the enzyme, in MCD type II, inactivation is caused by large deletions and/or replacements in the gene.