Haematologists have identified a number of variants. These can be classified as below.

- Overhydrated hereditary stomatocytosis

- Dehydrated HSt (hereditary xerocytosis; hereditary hyperphosphatidylcholine haemolytic anaemia)

- Dehydrated with perinatal ascites

- Cryohydrocytosis

- 'Blackburn' variant.

- Familial pseudohyperkalaemia

There are other families that do not fall neatly into any of these classifications.

Stomatocytosis is also found as a hereditary disease in Alaskan malamute and miniature schnauzer dogs.

The cause for these hereditary conditions is now understood to be various mutations in the erythrocyte membrane protein, band 3. It is this protein which mediates the cation leaks which are characteristic of this disease.

Congenital dyserythropoietic anemia type II (CDA II), or hereditary erythroblastic multinuclearity with positive acidified serum lysis test (HEMPAS) is a rare genetic anemia in humans characterized by hereditary erythroblastic multinuclearity with positive acidified serum lysis test.

HPFH may alleviate the severity of certain hemoglobinopathies and thalassemias, and is selected for in populations with a high prevalence of these conditions (which in turn are often selected for in areas where malaria is endemic). Thus, it has been found to affect Americans of African and Greek descent.

Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the "CPOX" gene. Mutations in "CPOX" usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.

In contrast with other porphyrias, which typically present with either cutaneous lesions after exposure to sunlight or acute neurovisceral attack at any age (most commonly in adulthood), harderoporphyria is characterized by jaundice, anemia enlarged liver and spleen, often presenting in the neonatal period. Later in life, these individuals may present with photosensitivity similar to that found in cutaneous porphyrias.

Biochemically, harderoporphyria presents with a distinct pattern of increased harderoporphyrin (2-vinyl-4,6,7-tripropionic acid porphyrin) in urine and particularly in feces, a metabolite that is not seen in significant quantities in any other porphyria. Enzyme tests show markedly reduced activity of coproporphyrinogen oxidase, compared to both unaffected individuals and those affected with hereditary coproporphyria, consistent with recessive inheritance.

Harderoporphyria is a rare condition, with less than 10 cases reported worldwide. It may be underdiagnosed, as it does not have the typical presentation associated with a porphyria. It was identified as a variant type of coproporphyria in 1983, in a family with three children identified at birth with jaundice and hemolytic anemia. There is no standard treatment for harderoporphyria; care is mainly focused on the management of symptoms.

This is usually caused by mutations in the "β or α" globin gene cluster, or the γ promoter gene region. . The percentage of incorrect expression might be as low as 10-15% or as high as 100% of the total hemoglobin, usually higher in homozygotes than in heterozygotes.

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

The anemia associated with CDA type II can range from mild to severe, and most affected individuals have jaundice, hepatosplenomegaly, and the formation of hard deposits in the gallbladder called bilirubin gallstones. This form of the disorder is usually diagnosed in adolescence or early adulthood. An abnormal buildup of iron typically occurs after age 20, leading to complications including heart disease, diabetes, and cirrhosis.

Usually, a common form of treatment for the condition is a type of hand cream which moisturises the hard skin. However, currently the condition is incurable.

Hereditary gelsolin amyloidosis is a cutaneous condition inherited in an autosomal dominant fashion.

The condition was first described in 1969, by the Finnish ophthalmologist Jouko Meretoja, and is also known as Familial amyloid neuropathy type IV, Meretoja syndrome, Hereditary amyloidosis, Finnish type.

The disorder primarily associated with eye, skin and cranial nerve symptoms. It is a form of amyloidosis, where the amyloid complexes are formed from fragments of the protein gelsolin in the plasma, due to a mutation in the GSN gene (c.654G>A or c.654G>T).

Affected male and carrier female dogs generally begin to show signs of the disease at two to three months of age, with proteinuria. By three to four months of age, symptoms include for affected male dogs: bodily wasting and loss of weight, proteinuria & hypoalbuminemia. Past nine months of age, hypercholesterolemia may be seen. In the final stages of the disease, at around 15 months of age for affected males, symptoms are reported as being renal failure, hearing loss and death. Since the condition is genetically dominant, diagnosis would also include analysis of the health of the sire and dam of the suspected affected progeny if available.

Essential fructosuria is a genetic condition that is inherited in an autosomal recessive manner. Mutations in the "KHK" gene, located on chromosome 2p23.3-23.2 are responsible. The incidence of essential fructosuria has been estimated at 1:130,000. The actual incidence is likely higher, because those affected are asymptomatic.

Albright's hereditary osteodystrophy is a form of osteodystrophy, and is classified as the phenotype of pseudohypoparathyroidism type 1A; this is a condition in which the body does not respond to parathyroid hormone.

This condition is associated with genetic imprinting. It is thought to be inherited in an autosomal dominant pattern, and seems to be associated with a Gs alpha subunit deficiency.

Samoyed Hereditary Glomerulopathy is caused by a nonsense mutation in codon 1027 of the COL4A5 gene on the X chromosome (glycine to stop codon), which is similar to Alport's syndrome in humans. The disease is simply inherited, X-linked dominant, with males generally having more severe symptoms than females. Clinically, from the age of three to four months, proteinuria in both sexes is seen. In dogs older than this, renal failure in combination with more or less pronounced hearing loss occurs swiftly, and death at the age of 8 to 15 months is expected. In heterozygous females, whereby only one of the two X chromosomes carry the mutation, the disease develops slowly.

The disease is specific to the Samoyed in that, the Samoyed, is the only breed of dog to show the more rapid progression to renal failure and death, as well as affecting males to a much more severe degree than females. The Samoyed, however is not the only breed of dog to suffer from life-threatening renal diseases. Proteinuria has been found consistently in Samoyeds, Doberman Pinschers, and Cocker spaniels.

Administration of cytidine monophosphate and uridine monophosphate reduces urinary orotic acid and ameliorates the anemia.

Administration of uridine, which is converted to UMP, will bypass the metabolic block and provide the body with a source of pyrimidine.

Uridine triacetate is a drug approved by FDA to be used in the treatment of hereditary orotic aciduria.

Orotic aciduria is a disease yielding an excessive excretion of orotic acid in urine. It causes a characteristic form of anemia and may be associated with mental and physical retardation.

Orotic acid is an intermediate product in pyrimidine synthesis pathway, a subsequent product of which plays a role in conversion between dihydrofolate and tetrahydrofolate. Orotic aciduria is associated with megaloblastic anemia due to decreased pyrimidine synthesis, which leads to decreased nucleotide-lipid cofactors needed for erythrocyte membrane synthesis in the bone marrow.

Essential fructosuria, caused by a deficiency of the enzyme hepatic fructokinase, is a clinically benign condition characterized by the incomplete metabolism of fructose in the liver, leading to its excretion in urine. Fructokinase (sometimes called ketohexokinase) is the first enzyme involved in the degradation of fructose to fructose-1-phosphate in the liver. This defective degradation does not cause any clinical symptoms, fructose is either excreted unchanged in the urine or metabolized to fructose-6-phosphate by alternate pathways in the body, most commonly by hexokinase in adipose tissue and muscle.

Palmoplantar keratodermas are a heterogeneous group of disorders characterized by abnormal thickening of the palms and soles.

Autosomal recessive and dominant, X-linked, and acquired forms have all been described.

Hereditary pyropoikilocytosis (HPP) is an autosomal recessive form of hemolytic anemia characterized by an abnormal sensitivity of red blood cells to heat and erythrocyte morphology similar to that seen in thermal burns. Patients with HPP tend to experience severe haemolysis and anaemia in infancy that gradually improves, evolving toward typical elliptocytosis later in life. However, the hemolysis can lead to rapid sequestration and destruction of red cells. Splenectomy is curative when this occurs.

HPP has been associated with a defect of the erythrocyte membrane protein spectrin and with spectrin deficiency.It was characterized in 1975.It is considered a severe form of hereditary elliptocytosis.

The median age at diagnosis is 38 years. Women are at higher risk for developing breast cancer.

This disease is more common in women and an association with the gene FLT4 has been described. FLT4 codes for VEGFR-3, which is implicated in development of the lymphatic system.

Milroy's disease is also known as primary or hereditary lymphedema type 1A or early onset lymphedema.

It is a very rare disease with only about 200 cases reported in the medical literature. Milroy's disease is an autosomal dominant condition caused by a mutation in the FLT4 gene which encodes of the vascular endothelial growth factor receptor 3 (VEGFR-3) gene located on the long arm (q) on chromosome 5 (5q35.3).

In contrast to Milroy's disease (early onset lymphedema type 1A,) which typically has its onset of swelling and edema at birth or during early infancy, hereditary lymphedema type II, known as Meige disease, has its onset around the time of puberty. Meige disease is also an autosomal dominant disease. It has been linked to a mutations in the ‘forkhead’ family transcription factor (FOXC2) gene located on the long arm of chromosome 16 (16q24.3). About 2000 cases have been identified. A third type of hereditary lymphedema, that has an onset after the age of 35 is known as lymph-edema tarda.

Mutations of the alphaspectrin gene causes this disease.

HPP can be considered as a subset of hereditary elliptocytosis to homozygous and it leads to severe disruption.

Meige lymphedema, also known as Meige disease, Late-onset lymphedema, and Lymphedema hereditary type 2, is an inherited disease in which patients develop lymphedema. The onset is between the ages of 1 and 35. Other causes of primary lympoedema include Milroy's disease which occurs before the age of 1, and lymphoedema tarda which occurs after the age of 35.

Meige disease,(Hereditary lymphedema type II), has its onset around the time of puberty. It is an autosomal dominant disease. It has been linked to a mutations in the ‘forkhead’ family transcription factor (FOXC2) gene located on the long arm of chromosome 16 (16q24.3). It is the most common form of primary lymphedema, and about 2000 cases have been identified. Meige disease usually causes lymphedema of the legs, however, other areas of the body may be affected, including the arms, face and larynx. Yellow toe nails occur in some individuals.

Surgical removal of the stomach (gastrectomy) is typically recommended after for people after 20 years of age, and before 40 years of age.