Amyloidosis transthyretin (ATTR Transthyretin amyloidosis type); Familial amyloid polyneuropathy (FAP Familial Amyloid Polyneuropathy); Cardiomyopathy familial amyloidotic (FAC: Familial Amyloid Cardiomiopathy); Family systemic amyloidosis (SFA: Systemic Amyloidosis Familial); Amiliodosis type 1 - Gen TTR

The term amyloidosis defines a group of disorders characterized by the accumulation of insoluble protein deposits in the form of fibers, in certain organs and tissues diseases. These protein deposits occur more frequently in the peripheral nervous system, causing peripheral neuropathy. The autonomic nervous system may also be affected by amyloidosis, and in some cases, central nervous system may also be affected. Other areas that may be affected include the heart, kidneys, eyes and gastrointestinal tract. The age at which symptoms begin to develop varies widely among affected individuals, being generally between 20 and 70 years old.

There are three main forms of transthyretin amyloidosis, which are distinguished by their symptoms and body systems that are affected:

  • The transthyretin amyloidosis neuropathic form, also known as familial amyloid polyneuropathy, primarily affects peripheral and autonomic nervous systems, which causes a peripheral neuropathy and difficulty controlling body functions. Deficiencies in bodily functions can include impotence, diarrhea, constipation, difficulty urinating and orthostatic hypotension. In addition, some people affected have heart and kidney problems. Eye problems may include vitreous opacity, dry eye and glaucoma. Some people with this form of transthyretin amyloidosis develop carpal tunnel syndrome.
  • The form of amyloidosis transthyretin leptomeningeal primarily affects the central nervous system. In people with this form, amyloidosis occurs in the leptomeningeal. Protein accumulation in this tissue can cause stroke and cerebral hemorrhage, hydrocephalus, ataxia, rigidity and spastic paralysis, seizures , and dementia. Similar to form neuropathic eye problems may also occur. When people with transthyretin amyloidosis leptomeningeal have eye problems, it is said to have the oculoleptomeningea form.
  • The cardiac form of transthyretin amyloidosis, familial amyloid cardiomyopathy known as affects the heart. People with cardiac amyloidosis may arrythmia, cardiomegaly, or orthostatic hypotension. These abnormalities can lead to progressive heart failure and death. Sometimes, people with heart form of transthyretin amyloidosis have mild peripheral neuropathy.

Transthyretin amyloidosis is due to mutations in the TTR gene, located on the long arm of chromosome 18 (18q12.1). This gene encodes the protein transthyretin (TTR). TTR protein of 127 amino acids and 14kDa, consists of four subunits, synthesized primarily in the liver, brain choroid plexus and retinal pigment epithelium of the eye. It is present in blood plasma and in cerebrospinal fluid and has, among other biological functions, bind and transport thyroxine (T4) in plasma (15%), but mainly in the cerebrospinal fluid, contributing to the transport of T4 through the blood brain barrier. Furthermore, it transports vitamin A in plasma. TTR variants bind with greater affinity and increased T4 concentrations of T4 and T3 in the blood, resulting in a process called hyperthyroxinemia family euthyroid, characterized by high concentration of T4 normal thyroid.

Mutations of TTR protein peripheral or autonomic neuropathies trigger and family cardiomyopathies. There are more than 100 genetic mutations in the transthyretin in inbred populations. These mutations induce conformational changes that destabilize the protein, causing aggregation in the form of amyloid fibrils, present both in hereditary forms of amyloidosis, and acquired. Growth would lead to amyloid material accumulating in tissues and organs, causing organ dysfunction , and ultimately death. These mutations could be considered transthyretin preclinical disease markers, as can be detected in patients with clinical manifestations associated with FAP, and in asymptomatic family at risk for the disease and / or transmitted to offspring. The most common mutations are: A109T, T119M, H90A, G6S, V30M, V122I, T60A and L58H, among others. These variants of TTR, causing ATTR family syndromes are rare, but some are common in some human populations. V30M (Portugal, Japan, Sweden, Balearic Islands), V122I (African Americans, and West Africa), T60A (Irish and Irish - Americans), L58H (US) or G6S (white Europeans) .

Early diagnosis is essential, because it is a neurodegenerative disease, the only treatment is liver transplantation, as the liver where 98% of TTR protein is synthesized, although when the SNC is affected transplantation not eliminate the disease.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In most cases, an affected person inherits the mutation from an affected parent. Rarely, cases are due to new mutations in the gene and occur in people with no history of disease in your family. Not all people who have a mutation in the TTR gene transthyretin amyloidosis develop.

Tests in IVAMI: in IVAMI perform detection of mutations associated with transthyretin amyloidosis, by complete PCR amplification of the exons of the TTR gene, and subsequent sequencing.  

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).