The familial amyloid neuropathies (or familial amyloidotic neuropathies, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy) are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.

Cerebral amyloid angiopathy (CAA), also known as congophilic angiopathy, is a form of angiopathy in which amyloid deposits form in the walls of the blood vessels of the central nervous system. The term "congophilic" is used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after application of a special stain called Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis.

Since this can be caused by the same amyloid protein that is associated with Alzheimer's dementia, brain bleeds are more common in people who have a diagnosis of Alzheimer's Disease, however they can also occur in those who have no history of dementia. The bleeding within the brain is usually confined to a particular lobe and this is slightly different compared to brain bleeds which occur as a consequence of high blood pressure (hypertension) - a more common cause of a hemorrhagic stroke (or bleeding in the brain).

Usually manifesting itself between 20 and 40 years of age, it is characterized by pain, paresthesia, muscular weakness and autonomic dysfunction. In its terminal state, the kidneys and the heart are affected. FAP is characterized by the systemic deposition of amyloidogenic variants of the transthyretin protein, especially in the peripheral nervous system, causing a progressive sensory and motor polyneuropathy.

The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. These proteins include: transthyretin (ATTR, the most commonly implicated protein), apolipoprotein A1, and gelsolin.

Due to the rareness of the other types of familial neuropathies, transthyretin amyloidogenesis-associated polyneuropathy should probably be considered first.

"FAP-I" and "FAP-II" are associated with transthyretin. (Senile systemic amyloidosis [abbreviated "SSA"] is also associated with transthyretin aggregation.)

"FAP-III" is also known as "Iowa-type", and involves apolipoprotein A1.

"FAP-IV" is also known as "Finnish-type", and involves gelsolin.

Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis.

Familial amyloid polyneuropathy (FAP), also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR (hereditary form), or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied.

FAP can be ameliorated by liver transplantation.

Tauopathy belongs to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as paired helical filaments). The precise mechanism of tangle formation is not completely understood, and it is still controversial as to whether tangles are a primary causative factor in the disease or play a more peripheral role. Primary tauopathies, i.e., conditions in which neurofibrillary tangles (NFT) are predominantly observed, include:

- Primary age-related tauopathy (PART)/Neurofibrillary tangle-predominant senile dementia, with NFTs similar to AD, but without plaques.

- Chronic traumatic encephalopathy, including dementia pugilistica

- Progressive supranuclear palsy

- Corticobasal degeneration

- Frontotemporal dementia and parkinsonism linked to chromosome 17

- Lytico-Bodig disease (Parkinson-dementia complex of Guam)

- Ganglioglioma and gangliocytoma

- Meningioangiomatosis

- Postencephalitic parkinsonism

- Subacute sclerosing panencephalitis

- As well as lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis

Neurofibrillary tangles were first described by Alois Alzheimer in one of his patients suffering from Alzheimer's disease (AD), which is considered a secondary tauopathy. AD is also classified as an amyloidosis because of the presence of senile plaques.

The degree of NFT involvement in AD is defined by Braak stages. Braak stages I and II are used when NFT involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there's also involvement of limbic regions such as the hippocampus, and V and VI when there's extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.

In both Pick's disease and corticobasal degeneration, tau proteins are deposited as inclusion bodies within swollen or "ballooned" neurons.

Argyrophilic grain disease (AGD), another type of dementia, is marked by an abundance of argyrophilic grains and coiled bodies upon microscopic examination of brain tissue. Some consider it to be a type of Alzheimer's disease. It may co-exist with other tauopathies such as progressive supranuclear palsy and corticobasal degeneration, and also Pick's disease.

Huntington's disease (HD): a neurodegenerative disease caused by a CAG tripled expansion in the Huntington gene is the most recently described tauopathy (Fernandez-Nogales et al. Nat Med 2014). JJ Lucas and co-workers demonstrate that, in brains with HD, tau levels are increased and the 4R/3R balance is altered. In addition, the Lucas study shows intranuclear insoluble deposits of tau; these "Lucas' rods" were also found in brains with Alzheimer's disease.

Tauopathies are often overlapped with synucleinopathies, possibly due to interaction between the synuclein and tau proteins.

The non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex" due to their association with frontotemporal dementia, or frontotemporal lobar degeneration.

Wild-type transthyretin amyloid accumulates mainly in the heart, where it causes stiffness and often thickening of its walls, leading consequently to shortness of breath and intolerance to exercise, called diastolic dysfunction. Excessively slow heart rate can also occur, such as in sick sinus syndrome, with ensuing fatigue and dizziness. Wild-type transthyretin deposition is also a common cause of carpal tunnel syndrome in elderly men, which may cause pain, tingling and loss of sensation in the hands. Some patients may develop carpal tunnel syndrome as an initial symptom of wild-type transthyretin amyloid.

There appears to be an increase in the risk for developing hematuria or blood in the urine due to urological lesions.

AL amyloidosis can affect a wide range of organs, and consequently present with a range of symptoms. The kidneys are the most commonly affected organ in AL amyloidosis. Symptoms of kidney disease and renal failure can include fluid retention, swelling, and shortness of breath.

In addition to kidneys, AL amyloidosis may affect the heart, peripheral nervous system, gastrointestinal tract, blood, lungs and skin. Heart complications, which affect more than a third of AL patients, include heart failure and irregular heart beat. Other symptoms can include stroke, gastrointestinal disorders, enlarged liver, diminished spleen function, diminished function of the adrenal and other endocrine glands, skin color change or growths, lung problems, bleeding and bruising problems, fatigue and weight loss.

AL amyloidosis can occur spontaneously. It is, however, often associated with other blood disorders, such as multiple myeloma and Waldenström's macroglobulinemia. About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis.

In medicine, proteopathy (Proteo- ["pref". protein]; -pathy ["suff". disease]; proteopathies "pl".; proteopathic "adj".) refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a gain of toxic function) or they can lose their normal function. The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases) include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, and a wide range of other disorders (see List of Proteopathies).

The concept of proteopathy can trace its origins to the mid-19th century, when, in 1854, Rudolf Virchow coined the term amyloid ("starch-like") to describe a substance in cerebral corpora amylacea that exhibited a chemical reaction resembling that of cellulose. In 1859, Friedreich and Kekulé demonstrated that, rather than consisting of cellulose, "amyloid" actually is rich in protein. Subsequent research has shown that many different proteins can form amyloid, and that all amyloids have in common birefringence in cross-polarized light after staining with the dye Congo Red, as well as a fibrillar ultrastructure when viewed with an electron microscope. However, some proteinaceous lesions lack birefringence and contain few or no classical amyloid fibrils, such as the diffuse deposits of Aβ protein in the brains of Alzheimer patients. Furthermore, evidence has emerged that small, non-fibrillar protein aggregates known as oligomers are toxic to the cells of an affected organ, and that amyloidogenic proteins in their fibrillar form may be relatively benign.

The syndromes within CAPS overlap clinically, and patients may have features of more than one disorder. In a retrospective cohort of 136 CAPS patients from 16 countries, the most prevalent clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either urticarial or maculopapular rash; 97% of cases) especially after cold exposure, and musculoskeletal involvement (myalgia, arthralgia, and/or arthritis, or less commonly joint contracture, patellar overgrowth, bone deformity, bone erosion and/or osteolytic lesion; 86% of cases). Less common features included ophthalmological involvement (conjunctivitis and/or uveitis, or less commonly optic nerve atrophy, cataract, glaucoma or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning headache, papilloedema, and/or meningitis, or less commonly seizure, hydrocephalus or mental retardation; 40% of cases), and AA amyloidosis (4% of cases). Age of onset is typically in infancy or early childhood. In 57% of cases, CAPS had a chronic phenotype with symptoms present almost daily, whereas the remaining 43% of patients experienced only acute episodes. Up to 56% of patients reported a family history of CAPS. Previous studies confirm these symptoms, although the exact reported rates vary.

The mean age at presentation is thirty-seven years with a reported range of nineteen to sixty-four years. The mean age of onset since diagnosis of diabetes is fifteen years. The female:male ratio is 1.3:1. Other diabetic complications such as nephropathy, neuropathy, retinopathy and hypertension are usually present. Its major symptom is the acute onset muscle pain, usually in the thigh, in the absence of trauma. Signs include exquisite muscle tenderness and swelling.

Most individuals diagnosed with LECT2 amyloidosis in the United States (88%) are of Mexican descent and reside in Southwest region of the United States (New Mexico, Arizona, far Western Texas). Other groups with higher incidence rates of the disorder include First Nation Peoples in Canada, Punjabis, South Asians, Sudanese, Native Americans, and Egyptians. In Egyptians, for example, LECT2 is second most common cause of renal amyloidosis, accounting for nearly 31% of all cases.

ALECT2 amyloidosis is generally diagnosed in individuals between the ages 40 and 90, with a mean age of 67 years old. The disorder commonly presents with renal disease that in general is advanced or at an end stage. Associated signs and symptoms of their renal disease may include fatigue, dehydration, blood in urine, and/or other evidence for the presence of the nephrotic syndrome or renal failure. Further studies may find that these individuals have histological or other evidence of LECT2 amyloid deposition in the liver, lung, spleen, kidney, and/or adrenal glands but nonetheless they rarely show any symptoms or signs attributable to dysfunction in these organs. Unlike many other forms of systemic amyloidosis, LECT2 deposition has not been reported to be deposited in the myocardium or brain of affected individuals. Thus, LECT2 amyloidosis, while classified as a form of systemic amyloidosis, almost exclusively manifests clinically as renal amyloidosis. No familial link has been found in the disorder although there have been several cases described among siblings.

RS3PE is a constellation of symptoms that can be caused by many other conditions. Since there is no definitive diagnostic test, other conditions have to be ruled out before this rare condition can be diagnosed.

The main differential diagnosis is polymyalgia rheumatica (PMR), although pain, stiffness and weakness at the level of the shoulders and pelvic girdle with associated systemic symptoms (fever, malaise, fatigue, weight loss) is more typical of PMR. Prospective studies have found a subgroup of PMR patients with hand edema, as well as other similarities. Thus, RS3PE has been proposed as a condition related to PMR or even that they are both part of the same disorder. However, PMR typically requires protracted courses of steroids, whereas corticosteroids can be tapered more quickly with persisting remission in RS3PE.

Other rheumatological disorders that can cause the features typical for RS3PE include late onset (seronegative) rheumatoid arthritis, acute sarcoidosis, ankylosing spondylitis and other spondyloarthropathies such as psoriatic arthropathy, mixed connective tissue disease, chondrocalcinosis and arthropathy due to amyloidosis.

RS3PE has been documented in patients with cancers (Non-Hodgkin's lymphoma, gastric cancer, pancreatic cancer, lung cancer, breast cancer, colon cancer, prostate cancer and bladder cancer, among others), in whom it might represent a paraneoplastic manifestation.

Other underlying disorders include vasculitides such as polyarteritis nodosa.

Other causes of edema include heart failure, hypoalbuminemia, nephrotic syndrome and venous stasis. The key distinguishing feature is that these conditions don't tend to manifest with pitting edema at the back of the hands.

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).

Amyloidosis is a group of diseases in which abnormal protein, known as amyloid fibrils, builds up in tissue. Symptoms depend on the type and are often variable. They may include diarrhea, weight loss, feeling tired, enlargement of the tongue, bleeding, numbness, feeling faint with standing, swelling of the legs, or enlargement of the spleen.

There are about 30 different types of amyloidosis, each due to a specific protein misfolding. Some are genetic while others are acquired. They are grouped into localized and systemic forms. The four most common types of systemic disease are light chain (AL), inflammation (AA), dialysis (AβM), and hereditary and old age (ATTR).

Diagnosis may be suspected when protein is found in the urine, organ enlargement is present, or problems are found with multiple peripheral nerves and it is unclear why. Diagnosis is confirmed by tissue biopsy. Due to the variable presentation, a diagnosis can often take some time to reach.

Treatment is geared towards decreasing the amount of the involved protein. This may sometimes be achieved by determining and treating the underlying cause. AL amyloidosis occurs in about 3–13 per million people per year and AA amyloidosis in about 2 per million people per year. The usual age of onset of these two types is 55 to 60 years old. Without treatment, life expectancy is between six months and four years. In the developed world about 1 per 1,000 people die from amyloidosis. Amyloidosis has been described since at least 1639.

AA amyloidosis is a form of amyloidosis, a disease characterized by the abnormal deposition of fibers of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A protein (SAA), an acute-phase protein which is normally soluble and whose plasma concentration is highest during inflammation.

Wild-type transthyretin amyloid (WTTA), also known as senile systemic amyloidosis (SSA) and abbreviated as ATTR, is a disease that typically affects the heart and tendons of elderly people. It is caused by accumulation of a wild-type (that is to say a normal) protein called transthyretin. This is in contrast to a related condition called transthyretin-related hereditary amyloidosis where a genetically mutated transthyretin protein tends to deposit at a much earlier age than in WTTA, due to abnormal conformation and bioprocessing.

It belongs to a group of diseases called amyloidosis, chronic progressive conditions linked to abnormal deposition of normal or abnormal proteins, because these proteins are misshapen and cannot be properly degraded and eliminated by the cell metabolism.

LECT2 Amyloidosis is a form of amyloidosis caused by the LECT2 protein. It was found to be the third most common (~3% of total) cause of amyloidosis in a set of more than 4,000 individuals studied at the Mayo Clinic; the first and second most common forms the disorder were AL amyloidosis and AA amyloidosis, respectively. Amyloidosis is a disorder in which the abnormal deposition of a protein in organs and/or tissues gradually leads to organ failure and/or tissue injury.

Although more than 30 different proteins can cause amyloidosis, the disorder caused by LECT2 is distinctive in three ways. First, it has an unusually high incidence in certain ethnic populations. Second, it is a systemic form of amyloidosis (i.e. amyloid deposited in multiple organs), as opposed to a localized form (amyloid deposits limited to a single organ) but nonetheless injures the kidney without or rarely injuring the other organs in which it is deposited. Third, LECT2 amyloidosis is diagnosed almost exclusively in elderly individuals.

Given its relatively recent discovery, exceptionally strong ethnic bias, limitation to causing kidney disease, and restriction to elderly individuals, LECT2 amyloidosis appears at present to be an under-recognized cause of chronic kidney disease particularly in the ethnic groups that exhibit a high incidence of the disorer.

The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved.

Amyloid deposition in the kidneys can cause nephrotic syndrome, which results from a reduction in the kidney's ability to filter and hold on to proteins. The nephrotic syndrome occurs with or without elevations in creatinine and blood urea concentration, two biochemical markers of kidney injury. In AA amyloidosis, the kidneys are involved in 91–96% of people, symptoms ranging from protein in the urine to nephrotic syndrome and rarely renal insufficiency.

Amyloid deposition in the heart can cause both diastolic and systolic heart failure. EKG changes may be present, showing low voltage and conduction abnormalities like atrioventricular block or sinus node dysfunction. On echocardiography, the heart shows a restrictive filling pattern, with normal to mildly reduced systolic function. AA amyloidosis usually spares the heart.

People with amyloidosis do not get central nervous system involvement but can develop sensory and autonomic neuropathies. Sensory neuropathy develops in a symmetrical pattern and progresses in a distal to proximal manner. Autonomic neuropathy can present as orthostatic hypotension but may manifest more gradually with nonspecific gastrointestinal symptoms like constipation, nausea, or early satiety.

Accumulation of amyloids in the liver can lead to elevations in serum aminotransferases and alkaline phosphatase, two biomarkers of liver injury, which is seen in about one third of people. Liver enlargement is common. In contrast, spleen enlargement is rare, occurring in 5% of people. Splenic dysfunction, leading to the presence of Howell-Jolly bodies on blood smear, occurs in 24% of people with amyloidosis. Malabsorption is seen in 8.5% of AL amyloidosis and 2.4% of AA amyloidosis. One suggested mechanism for the observed malabsorption is that amyloid deposits in the tips of intestinal villi (fingerlike projections that increase the intestinal area available for absorption of food), begin to erode the functionality of the villi, presenting a sprue-like picture.

A rare development is a susceptibility to bleeding with bruising around the eyes, termed "raccoon-eyes," caused by amyloid deposition in the blood vessels and a reduced activity of thrombin and factor X, two clotting proteins that lose their function after binding with amyloid.

Amyloid deposits in tissue and causes enlargement of structures. Twenty percent of people with AL amyloidosis have an enlarged tongue, that can lead to obstructive sleep apnea, difficulty swallowing, and altered taste. Tongue enlargement does not occur in ATTR or AA amyloidosis. Enlarged shoulders, "shoulder pad sign," results from amyloid deposition in synovial space. Deposition of amyloid in the throat can cause hoarseness. Aβ2MG amyloidosis (Hemodialysis associated amyloidosis) likes to deposit in synovial tissue, causing chronic synovitis, which can lead to repeated carpal tunnel syndrome.

Both the thyroid and adrenal gland can be infiltrated. It is estimated that 10–20% of individuals with amyloidosis have hypothyroidism. Adrenal infiltration may be harder to appreciate given that its symptoms of orthostatic hypotension and low blood sodium concentration may be attributed to autonomic neuropathy and heart failure.

"Amyloid deposits occur in the pancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or 'amylin.' This is stored with insulin in secretory granules in B cells and is co secreted with insulin." (Rang and Dale's Pharmacology, 2015.)

Individuals affected by RS3PE typically have repeated episodes of inflammation of the lining of their synovial joints and swelling of the end portion of the limbs. The arms and hands are more commonly affected than the legs and feet. Both sides are usually involved though RS3PE can affect only one side in certain cases.

Affected males develop generalized reticular hyper pigmentation in early childhood.

Hair often looks bedraggled or brushed backwards, hanging low on the forehead.

Among the associated extracutaneous manifestations are described:

- Respiratory infections

- Dyskeratosis corneal photophobia

- Hypohidrosis with large deficit of thermoregulation

- Growth retardation

- Gastrointestinal disorders

- Kidney disease

- Kidney stones

- Urinary infections

- Webbed feet or hands

- Electrolyte imbalance

- Retinitis pigmentosa

- Lymphoedema

- Thyroid abnormalities

Each patient shows some of the symptoms listed above. Not every sick person will show all of the listed symptoms.

In females the disease is characterized by skin rashes linear hyper pigmentation following the Blaschko's lines, morphologically similar to stage 3 pigment incontinence. There are no systemic manifestations associated with XLPDR in females.

People with monoclonal gammopathy generally do not experience signs or symptoms. Some people may experience a rash or nerve problems, such as numbness or tingling. Severe renal disease has also been found in a subset of those with monoclonal gammopathy. MGUS is usually detected by chance when the patient has a blood test for another condition or as part of standard screening.

Diabetic myonecrosis is a complication of diabetes. It is caused by infarcted muscle tissue, usually in the thigh.