Familial amyloidosis (also known as hereditary amyloidosis) is a type of systemic amyloidosis caused by the gene mutation.
Amyloidosis is a rare disorder characterized by the deposition of abnormal protein called amyloid in the body. Amyloid is an abnormal protein built up of fibril proteins (95%), the P component and several glycoproteins. In the microscope amyloid is seen as an extracellular eosynophilic hyaline substance.
Familial amyloidosis is caused by the various genetic mutations. A type of mutation defines the organ involvement and features of the disorder. The symptoms of the disease typically are not seen until the adulthood (the onset of the disease typically takes place at the age between 25 and >50 years). However, sometimes the disorder develops during childhood. Affected individuals usually die in 5-15 years after the disease manifestation.
Familial amyloidosis develops due to gene mutation which leads to the production and deposition of amyloid in various organs. About 179 mutations are known to cause amyloidosis, each of them defines specific organ involvement. Usually familial amyloidosis affects the heart, nervous system and kidneys and is inherited as an autosomal dominant pattern.
Transthyretin amyloidosis (ATTR) is the most common form of familial amyloidosis. The most common mutation which results in ATTR is a replacement of valine by methionine at position 30 on chromosome 18 (where the TTR gene is found). Transthyretin is produced by the liver. Normally transthyretin carries thyroxine (T4, the thyroid hormone) and binds vitamin A (retinol A). The mutations in the TTR gene result in the misfolding of the protein and its deposition in various organs and tissues.
Non-ATTR amyloidosis may be represented as the following conditions:
- apolipoprotein AI amyloidosis (A ApoAI);
- gelsolin amyloidosis (A Gel);
- lysozyme amyloidosis (A Lys);
- cystatin C amyloidosis (A Cys);
- fibrinogen Aα-chain amyloidosis (A Fib);
- apolipoprotein AII amyloidosis (A ApoAII).
As long as familial amyloidosis is a hereditary condition anyone with a family history of the disease is at risk. The disease in inherited in an autosomal dominant manner.
Symptoms of ATTR
Transthyretin amyloidosis commonly affects the heart, leading to familial amyloid cardiomyopathy, and the nervous system, causing familial amyloid polyneuropathy also known as Corino de Andrade’s disease. Sometimes amyloid may be stored in the kidneys or the gastrointestinal tract, depending on the type of genetic mutation.
- Familial amyloid polyneuropathy develops as a result of nerve damage due to amyloid deposition. Both peripheral nervous system and autonomic nervous system (the one that controls the functioning of the internal organs) may be affected. Peripheral neuropathy is characterized by the sensorimotor impairment. A person experiences numbness, tingling and burning pain along with a loss of sensation in the limbs. Usually the first symptoms occur on the distal parts of the lower extremities. Later the upper extremities also become involved and the motor function is disturbed.
Autonomic neuropathy in FAP leads to the impairment of blood pressure and heart rate regulation, digestion, perspiration, reproductive system dysfunction. The involvement of the nerves of the digestive tract results in nausea, diarrhea or constipation, weight loss and loss of appetite. Bladder control problems may also arise.
- Familial amyloid cardiomyopathy is associated with the mutation Val122Ile (replacement of valine by isoleucine at position 122 on chromosome 18) and is common for native African males. FAC is characterized by the deposition of amyloid in the tissues of the heart (mainly the myocardium) that interferes with the conduction of the stimuli and results in the heart block and heart insufficiency. The heart muscle becomes stiff and thick and therefore develops diastolic dysfunction. This means that the cardiomyopathy is of restrictive type. Common signs of cardiomyopathy include arrhythmia and palpitations, chest pain (angina pectoris), fatigue, shortness of breath, episodes of unconsciousness (syncope), swellings of the legs (peripheral edema), nausea and weight loss.
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Symptoms of Non-ATTR
Non-ATTR is known to affect various organs depending on the type of the mutation. Amyloid deposits may be found in the kidneys, heart, liver, brain, the eyes and peripheral nerves.
If the mutation is located in the Apolyprotein AI gene several organs appear affected: the kidneys, liver, heart, peripheral nerves, the skin, and larynx.
Mutations in Fibrinogen Aa and Apolyprotein AII result in the kidney damage.
Lysozyme mutation results in involvement of the kidney, liver and possibly the digestive system.
Gelsolin mutation is known to lead to peripheral neuropathy, the eye may be affected as well.
Cystatin C mutation is associated with cerebral hemorrhage.
To verify the diagnosis blood and urine test along with biopsies are performed. The tissue samples are later processed with the Congo red stain. Genome sequencing is recommended to detect the type of mutation and make an accurate diagnosis.
Treatment of ATTR
It is recommended to follow the diet with restrictions of salt consumption and intake of water up to 1.5 liters per day.
ATTR requires liver transplantation to reduce the production of amyloid. In cases of FAC the transplantation of both the liver and the heart was reported as an effective measure.
Pacemakers are used to control the heartbeat when the conduction system of the heart is damaged.
The treatment of Non-ATTR is based on the organ involvement and may include transplantations of the liver, kidney, cornea or the heart. However, this method appears less effective in case of Non-ATTR as opposite to ATTR.
A brand new drug Tafamidis meglumine (Vyndaqel®, Pfizer) was developed to slow down the progression of ATTR and has been reported to show clinical efficacy in FAP administered at a dosage of 20 mg once per day.
A nonsteroidal anti-inflammatory drug Diflunisal at a dosage of 250 mg twice per day is able to inhibit the release of TTR and reduce the progression of neurologic symptoms.
A wide range of medications may be used as a supportive treatment. Diuretics (Furosemide) , antiarrhytmic drugs, calcium channel blockers, digoxin, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and beta blockers are prescribed to support the heart functioning.