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.

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.

Minimal change disease has been called by many other names in the medical literature, including minimal change nephropathy, minimal change nephrosis, minimal change nephrotic syndrome, minimal change glomerulopathy, foot process disease (referring to the foot processes of the podocytes), nil disease (referring to the lack of pathologic findings on light microscopy), nil lesions, lipid nephrosis, and lipoid nephrosis.

Minimal change disease is most common in very young children but can occur in older children and adults. It is by far the most common cause of nephrotic syndrome in children between the ages of 1 and 7, accounting for the majority (about 90%) of these diagnoses. Among teenagers who develop nephrotic syndrome, it is caused by minimal change disease about half the time. It can also occur in adults but accounts for less than 20% of adults diagnosed with nephrotic syndrome. Among children less than 10 years of age, boys seem to be more likely to develop minimal change disease than girls. Minimal change disease is being seen with increasing frequency in adults over the age of 80.

People with one or more autoimmune disorders are at increased risk of developing minimal change disease. Having minimal change disease also increases the chances of developing other autoimmune disorders.

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.

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.

Management of sickle nephropathy is not separate from that of overall patient management. In addition, however, the use of ACE inhibitors has been associated with improvement of the hyperfiltration glomerulopathy. Three-year graft and patient survival in kidney transplant recipients with sickle nephropathy is lower when compared to those with other causes of end-stage kidney disease.

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction (papillary necrosis). Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

Also the sickle cell disease in young patients is characterized by renal hyperperfusion, glomerular hypertrophy, and glomerular hyperfiltration. Many of these individuals eventually develop a glomerulopathy leading to glomerular proteinuria (present in as many as 30%) and, in some, the nephrotic syndrome. Co-inheritance of microdeletions in the -globin gene (thalassemia) appear to protect against the development of nephropathy and are associated with lower mean arterial pressure and less protein in the urine.

Mild increases in the blood levels of nitrogen and uric acid can also develop. Advanced kidney failure and high blood urea levels occur in 10% of cases. Pathologic examination reveals the typical lesion of "hyperfiltration nephropathy" namely, focal segmental glomerular sclerosis. This finding has led to the suggestion that anemia-induced hyperfiltration in childhood is the principal cause of the adult glomerulopathy. Nephron loss secondary to ischemic injury also contributes to the development of azotemia in these patients.

In addition to the glomerulopathy described above, kidney complications of sickle cell disease include cortical infarcts leading to loss of function, persistent bloody urine, and perinephric hematomas. Papillary infarcts, demonstrable radiographically in 50% of patients with sickle trait, lead to an increased risk of bacterial infection in the scarred kidney tissues and functional tubule abnormalities. The presence of visible blood in the urine without pain occurs with a higher frequency in sickle trait than in sickle cell disease and likely results from infarctive episodes in the renal medulla. Functional tubule abnormalities such as nephrogenic diabetes insipidus result from marked reduction in vasa recta blood flow, combined with ischemic tubule injury. This concentrating defect places these patients at increased risk of dehydration and, hence, sickling crises. The concentrating defect also occurs in individuals with sickle trait. Other tubule defects involve potassium and hydrogen ion excretion, occasionally leading to high blood potassium, metabolic acidosis, and a defect in uric acid excretion which, combined with increased purine synthesis in the bone marrow, results in high blood uric acid levels.

About a third of untreated patients have spontaneous remission, another third progress to require dialysis and the last third continue to have proteinuria, without progression of renal failure.

Familial renal amyloidosis (or familial visceral amyloidosis, or hereditary amyloid nephropathy) is a form of amyloidosis primarily presenting in the kidney.

It is associated most commonly with congenital mutations in the fibrinogen alpha chain and classified as a dysfibrinogenemia (see Hereditary Fibrinogen Aα-Chain Amyloidosis). and, less commonly, with congenital mutations in apolipoprotein A1 and lysozyme.

It is also known as "Ostertag" type, after B. Ostertag, who characterized it in 1932 and 1950.

85% of MGN cases are classified as "primary membranous glomerulonephritis"—that is to say, the cause of the disease is idiopathic (of unknown origin or cause). This can also be referred to as "idiopathic membranous nephropathy". One study has identified antibodies to an M-type phospholipase A receptor in 70% (26 of 37) cases evaluated. Other studies have implicated neutral endopeptidase and cationic bovine serum albumin as antigens.

Membranoproliferative glomerulonephritis ("MPGN"), also known as mesangiocapillary glomerulonephritis, is a type of glomerulonephritis caused by deposits in the kidney glomerular mesangium and basement membrane (GBM) thickening, activating complement and damaging the glomeruli.

MPGN accounts for approximately 4% of primary renal causes of nephrotic syndrome in children and 7% in adults.

It should not be confused with membranous glomerulonephritis, a condition in which the basement membrane is thickened, but the mesangium is not.

HIV-associated nephropathy (HIVAN) refers to kidney disease developing in association with HIV infection. The most common, or "classical", type of HIV-associated nephropathy is a collapsing focal segmental glomerulosclerosis (FSGS), though other forms of kidney disease may also occur with HIV. Regardless of the underlying histology, renal disease in HIV-positive patients is associated with an increased risk of death.

HIVAN may be caused by direct infection of the renal cells with the HIV-1 virus, with resulting renal damage through the viral gene products. It could also be caused by changes in the release of cytokines during HIV infection. Usually occurs only in advanced disease and approximately 80% of patients with HIVAN have a CD4 count of less than 200. HIVAN presents with nephrotic syndrome and progressive kidney failure. Despite being a cause of chronic kidney failure, kidney sizes are usually normal or large.

Transplant glomerulopathy, abbreviated TG, is a disease of the glomeruli in transplanted kidneys. It is a type of renal injury often associated with chronic antibody-mediated rejection. However, transplant glomerulopathy is not specific for chronic antibody-mediated rejection; it may be the result of a number of disease processes affecting the glomerular endothelium.

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.

HIVAN is the third most common cause of ESRF among African Americans, and commonly seen in African-American patients with HIV compared with other ethnic groups. In the USA 12% of patients dying with AIDS have histologically proven HIVAN, the worldwide incidence amongst AIDS patients appears to be similar. A South African study at Tygerberg Hospital, Stellenbosch University, has shown HIVAN histology in 33/61(54%) biopsies performed in HIV positive patients.

Glomerulonephrosis is a non-inflammatory disease of the kidney (nephrosis) presenting primarily in the glomerulus (a glomerulopathy).

It can be contrasted to glomerulonephritis, which implies inflammation.

It can be caused by diethylnitrosamine.

Membranoproliferative glomerulonephritis involves deposits at the intraglomerular mesangium.

It is also the main hepatitis C associated nephropathy.

It also is related to a number of autoimmune diseases, prominently systemic lupus erythematosus (SLE). Also found with Sjögren syndrome, rheumatoid arthritis, inherited complement deficiencies (esp C2 deficiency), scleroderma, Celiac disease.

The histomorphologic differential diagnosis includes transplant glomerulopathy and thrombotic microangiopathies.

It is characterized by glomerular basement membrane thickening (referred to as "tram-tracking of the basement membrane"), increased mesangial matrix and segmental and global glomerulosclerosis.

The differential diagnosis of tram-tracking includes membranoproliferative glomerulonephritis (especially hepatitis C), and thrombotic microangiopathies.

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).

Glomerulopathy is a set of diseases affecting the glomeruli of the nephron.

Such diseases can include processes that are inflammatory or noninflammatory. Because the term "glomerulitis" exists for inflammatory conditions, "glomerulopathy" sometimes carries a noninflammatory implication.

Milroy's disease (MD) is a familial disease characterized by lymphedema, commonly in the legs, caused by congenital abnormalities in the lymphatic system. Disruption of the normal drainage of lymph leads to fluid accumulation and hypertrophy of soft tissues. It is also known as Milroy disease, Nonne-Milroy-Meige syndrome and hereditary lymphedema.

It was named by Sir William Osler for William Milroy, a Canadian physician, who described a case in 1892, though it was first described by Rudolf Virchow in 1863.

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

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.

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.