Familial amyloid polyneuropathy, also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis (ATTR) (hereditary form).
Transthyretin (TTR) amyloidosis (ATTR) is a progressive, multiorgan, multigenotypic disease caused by TTR amyloid fibril deposition in various tissues.
It is caused by extracellular deposits, in organs and tissues of misfolded transthyretin variant and wild-type transthyretin protein.
Common clinical manifestations include peripheral and autonomic neuropathy and cardiomyopathy, with substantial morbidity and a poor prognosis.
With amyloid neuropathy, serial nerve conduction studies can be useful for objectively monitoring the course of disease and for assessing response to treatment such as liver transplantation.
An autosomal dominant neurodegenerative disease.
A slowly progressive condition characterized by the buildup of abnormal deposits of amyloid in the body’s organs and tissues.
Mutations in the TTR gene cause transthyretin amyloidosis.
TTR mutations accelerate the process of TTR amyloid formation.
TTR mutations are the most important risk factor for the development of clinically significant ATTR.
More than 100 amyloidogenic TTR variants cause systemic familial amyloidosis, with age at symptom onset, pattern of organ involvement, and disease course variation.
Genetic studies to look for a TTR variant can be helpful in many patients performing polymerase chain reaction (PCR) testing to look for known, common TTR variants.
If a TTR variant is suspected but initial screening results are negative, more comprehensive analysis for a TTR variant can be performed: electrospray ionization mass spectrometry (ESIMS) or the gene can be studied by PCR and such methods as single-strand conformation polymorphism analysis and/or direct sequencing.
Most TTR mutations are associated with cardiac and/or nerve involvement.
The most common ATTR mutations are:
Thr60Ala (24%)
Val30Met (15%)
Val122Ile (10%)
Ser77Tyr (5%)
ATTR is caused by a single-point mutation, that promotes destabilization of the native quarternary structure into beta-pleated sheet predominant, insoluble and inactive form.
Tetramer dissociation is a required step in amyloid fibril formation.
Amyloidogenic mutations destabilize the native quaternary and tertiary structures of TTR, thereby inducing conformational changes that lead to dissociation of the tetramers into partially unfolded species, which can subsequently self-assemble into amyloid fibrils.
Clinically the GI tract, vitreous, lungs, and carpal ligament are also frequently affected.
It 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.
There are three stages of ATTR-FAP:
Stage 0: Asymptomatic carrier of a known ATTR mutation
Stage I: Sensory polyneuropathy; preserved walking capacity without the need for a walking stick
Stage II: Progressive walking disability; ambulatory, but requires assistance, one to two walking sticks or crutches required
Stage III: Wheelchair bound or bedridden
FAP can be ameliorated by liver transplantation.
Liver transplant remains the gold standard.
Liver transplantation is the only effective therapy for familial amyloid polyneuropathy, as it removes the source of mutant TTR.
Familial amyloid polyneuropathy has an autosomal dominant pattern of inheritance.
Usually manifesting itself between 20 and 40 years of age, it is characterized by pain, paresthesia, muscular weakness and autonomic dysfunction.
The TTR gene provides instructions for producing a protein called transthyretin.
Transthyretin transports vitamin A and thyroxine throughout the body.
To transport retinol and thyroxine, four transthyretin proteins must be bound to form a four-protein unit.
Transthyretin protein is produced primarily in the liver, and a small amount of this protein is produced in the choroid plexus and in the retina.
Transthyretin (TTR) amyloidosis (ATTR) is a progressive, multiorgan, multigenotypic disease caused by TTR amyloid fibril deposition in various tissues.
TTR gene mutations are thought to alter the structure of transthyretin, impairing its ability to bind to other transthyretin proteins and altering its normal function.
TTR mutations accelerate the process of TTR amyloid formation.
TTR mutations are the most important risk factor for the development of clinically significant ATTR.
More than 100 amyloidogenic TTR variants cause systemic familial amyloidosis, with age at symptom onset, pattern of organ involvement, and disease course variation.
Most TTR mutations are associated with cardiac and/or nerve involvement.
Clinically the GI tract, vitreous, lungs, and carpal ligament are also frequently affected.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Rarely, it results from new mutations in the gene and occur in people with no history of the disorder in their family.
Not all people who have a TTR gene mutation will develop transthyretin amyloidosis.
Such protein deposits most frequently occur in the peripheral nervous system, and sensory cells that detect sensations such as touch, pain, heat, and sound.
Nervous system protein deposits result in a loss of sensation in the extremities, known as peripheral neuropathy.
The autonomic nervous system may be effected by amyloid deposits.
The brain and spinal cord may be affected.
Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract.
The age at which symptoms begin to develop varies widely.
Onset is typically between ages 20 and 70.
There are three major forms of transthyretin amyloidosis.
The forms of transthyretin amyloidosis are distinguished by their symptoms and the body systems they affect.
Common physical findings in advanced disease:
Cachexia
Peripheral edema
Hepatomegaly
Purpura
Orthostatic hypotension
Impaired sensation and/or strength in the upper and/or lower extremities
Carpal tunnel syndrome
Cardiac involvement:
Diastolic dysfunction
Chronic heart failure
Arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias.
Typical neurological findings include symmetric sensory impairment and weakness.
The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions.
Bodily dysfunctions include sexual impotence, diarrhea, constipation, problems with urination, and orthostatic hypotension.
Patients may experience heart and kidney problems.
Eye problems may include cloudiness of vitreous opacity, dry eyes, glaucoma, or pupils with an irregular appearance.
Some patients with transthyretin amyloidosis develop carpal tunnel syndrome, which is characterized by numbness, tingling, and weakness in the hands and fingers.
The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system.
In leptomeningeal form of transthyretin amyloidosis occurs in the leptomeninges
Accumulation of amyloid protein can cause stroke and bleeding in the brain, hydrocephalus, ataxia, spastic paralysis, seizures, and loss of intellectual function.
Eye problems may be associated with leptomeningeal transthyretin amyloidosis, and are said to have the oculoleptomeningeal form.
Transthyretin cardiac amyloidosis may have an arrhythmia, cardiomegaly, or orthostatic hypotension.
These abnormalities can lead to progressive heart failure and death.
Occasionally, people with the cardiac form of transthyretin amyloidosis have mild peripheral neuropathy.
In northern Portugal, the incidence of this condition is thought to be one in 538 people.
This disease is endemic in Portuguese locations, with more than 1000 affected people, coming from about 500 families, where 70% of the people develop the illness.
In northern Sweden, more specifically Skellefteå, 1.5% of the population has the mutated gene.
It is less common among Americans of European descent, where it is estimated to affect one in 100,000 people.
The cardiac form of transthyretin amyloidosis is more common among people with African ancestry, and affects between 3 percent and 3.9 percent of African Americans and approximately 5 percent of people in some areas of West Africa.
In its terminal state, the kidneys and the heart are affected.
It 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.
It is caused by a mutation of the TTR gene, located on human chromosome 18q12.1-11.2.
A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly found in transthyretin amyloidosis.
The transthyretin protein is a tetramer.
To aggregate the tetramer has to dissociate into misfolded monomers resulting in a variety of structures including amyloid fibrils.
Most patients are heterozygotes, and they deposit both mutant and wild type TTR subnits.
The defective gene responsible for the disorder is located on an autosome 18, and only one copy of the defective gene is sufficient to cause the disorder.
Drugs targeting hepatic messenger RNA can slow the progression of ATTRv poly neuropathy, because the liver produces 90% of the amyloidogenic protein.
TTR silencer drugs, and the TTR mRNA lead to the breakdown of mRNA, preventing the production of transthyretin proteins, and are therapeutic tools for ATTRv polyneuropathy.
The medication tafamidis is used for the treatment of transthyretin familial amyloid polyneuropathy
Tafamidis delays neurological problems when started early.
[[Tafamidis]] selectively binds to TTR and kinetically stabilizes wild-type native TTR and mutant TTR.
Tafamidis has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation.
Early intervention with tafamidis led to minimal disease progression over 5.5 years in patients with mild ATTR-FAP.
A tafamidis trial in patients with stage I neuropathic ATTR failed to achieve statistical significance for its primary endpoints of neurological deterioration and quality of life.
Tafamidis (20 mg once daily) slows the progression of the disease over a 36-month period and importantly reversed the weight loss and muscle wasting associated with disease progression.
All measured endpoints indicated that Tafamidis decreased the rate of disease progression.
In August 2018, the FDA approved patisiran, an siRNA-based treatment, at an expected cost of up to $450,000 per year.
Patisiran and inotersen are approved by the US Food and Drug Administration (FDA) for treatment of polyneuropathy caused by hereditary transthyretin-related amyloidosis (hATTR) in adults.
Liver transplantation remains the gold standard for therapy.
Results in more aggressive disease with a poor prognosis and other types of breast cancer.
Therapeutic strategies rely on reducing ongoing amyloid formation through stabilization of the tetrameric form of TTR with diflunisal for tafamidis or through innovation of the TTR protein synthesis with inotetsen or a patisiran by means of degradation of the TTR messenger RNA.
Patisiran utilizes RNA interference, by mediating the cleavage of specific messenger RNAs (mRNAs).
Administration is via intravenous infusion every 3 weeks.
Patients taking patisiran showed significantly improved scores on the Neuropathy Impairment Score.
Inotersen is indicated for polyneuropathy of hATTR in adults.
Inotersen is given as a once-weekly subcutaneous injection.
Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin mRNA by binding TTR mRNA.
In the absence of a liver transplant, FAP is invariably fatal, usually within a decade.
Approximately 10% of the subjects die from liver transplant procedure or complications resulting from the procedure, which is a form of gene therapy wherein the liver expressing wild type and mutant TTR is replaced by a liver only expressing wild type TTR.