Hereditary amyloidosis is a health condition in which abnormal protein is produced due to an inherited gene mutation. The abnormal protein, called amyloid, deposits in organs and can lead to the disruption of the tissue and its function. Deposits mainly occur in the heart, nervous system, and kidneys. Symptoms widely vary according to the targeted tissue and gene mutation, and usually don't develop until adulthood.
There are two main types of hereditary amyloidosis - ATTR and non-ATTR, with more than 200 different gene variants. In ATTR, also called transthyretin amyloidosis, a mutation for the protein transthyretin is inherited. Transthyretin is a transport protein for thyroid hormones, which is manufactured in the liver. The mutation causes a misfolding of this protein, leading to the production of abnormal and insoluble amyloid and its subsequent deposition in tissues. Without early detection and treatment, ATTR is a progressive, multisystemic, life-threatening disease.
ATTR is currently considered a rare disease with a worldwide prevalence of 5 000 - 10 000 people.[1] It is believed that the real number might be way higher, with many cases being undiagnosed. The highest numbers of cases have been reported in so-called endemic countries - Portugal, Sweden, and Japan. The disease develops regardless of risk and protective factors since it's caused by a gene mutation that the person is already born with.
The most common form of hereditary amyloidosis is caused by a mutation in the gene TTR coding for protein transthyretin. Seldom, pathogenic changes are also found in other genes, such as fibrinogen A, apolipoprotein A1 and A2, or cystatin C. All types of hereditary amyloidosis have an autosomal dominant inheritance pattern (only one mutated allele of the gene can cause the disease).
More than 150 TTR pathogenic variants have been identified. Mutations in the TTR gene lead to the destabilization and misfolding of the transthyretin protein, thereby forming insoluble amyloid fibrils.[2]
Different TTR gene mutations are associated with different organs in the body. Nonetheless, the key factor in amyloid development is the stability of the TTR protein.[3]
Val30Met (reference amino acid valine is substituted by methionine at the amino acid position 30) is considered the most common variant among Caucasians.[4] In another study, it was observed that the most common genotype in China was Gly83Arg, followed by Val30Met and Val30Ala.[5]
Some mutations may induce cardiomyopathy (e.g. Val122Ile) while others are associated with neuropathy (e.g. Val30Met). Val122Ile is frequently found in African Americans with cardiac symptoms later in life.[6]
Due to the variable penetrance, carriers do not need to develop symptoms until advanced age, but their children may become affected. Interestingly, the largest cluster of people with the disease caused by the Val30Met mutation is to be found in northern Portugal, where the incidence is estimated to be 1 in 538 individuals.[7]
Knowing your genetic risk is important, and genetic testing is a convenient solution. It is possible to identify genetic variants and predict the probability of developing the disease in oneself or be aware of this during family planning.
Symptoms of amyloidosis vary in different genetic variants and are based on the affected tissue. Each patient might have unique and unexpected symptoms, which makes amyloidosis one of the hardest diseases to diagnose. Geographic location and other often unclear genetic and environmental factors also influence the clinical manifestation of the disease. Symptoms of different severities can develop in childhood but most patients don't experience any symptoms until adulthood. The mostly targeted tissues are the heart and nervous system, leading to diseases called cardiomyopathy and neuropathy. The GIT system, the kidneys, eyes, and carpal tunnel may also be affected.
The heart
Amyloid deposits into the heart tissue, causing its stiffening and a state called cardiomyopathy which leads to congestive heart failure or a change of its rhythm, known as arrhythmia. Patients experience nausea, shortness of breath, chest pain, the inability to sleep, or leg swelling. They're at a higher risk of a heart attack.
The nervous system
The abnormal protein deposits can lead to nerve damage, called neuropathy. Any nervous structure can be affected, peripheral, central, or autonomous. Therefore patients can experience burning, tingling, and pain in any part of their body. The autonomous nervous system controls inner organs and therefore amyloidosis can, for example, lead to vessel dysfunction and blood pressure problems.
The tongue
Macroglossia, which is a term for an elongated tongue.
The kidneys
Kidney dysfunction caused by the deposition of amyloid can result in the accumulation of water in tissues and body cavities. This can manifest as swelling of the lower limbs, abdominal distention, and breathing problems caused by the water in the lungs. The inability to filtrate blood can lead to kidney failure requiring replacement of the kidney function (e.g. hemodialysis).
Due to the wide variety of symptoms and their similarities to other disorders, diagnosis is usually very problematic. Steps leading to the diagnosis of amyloidosis involve blood and urine tests, which are also necessary for the assessment of which organs are affected and to what extent. A biopsy is performed to confirm the diagnosis and to specify the type of amyloidosis - a small piece of tissue is removed, colored (amyloidosis is identified by staining the tissue with Congo Red dye which will then produce an apple-green birefringence under polarized light), and observed under a microscope. Since the treatment plan differs between specific types of amyloidosis, an exact diagnosis is a must. Protein sequence analysis and DNA sequencing must be performed to obtain detailed information. Early and exact diagnosis is critical for the prognosis of the disease.
Treatment of hereditary amyloidosis is mainly focused on managing the symptoms of the disease and slowing down amyloid production. There is unfortunately no treatment that would reverse the damage and progression. Supportive treatment can help with pain, digestive problems (diarrhea, constipation, vomiting), nausea, or heart rate irregularities. Managing kidney and heart failure can significantly improve a patient’s quality of life. Sometimes kidney/heart transplant or carpal tunnel surgery may be performed. Liver transplant is the main treatment, with the goal to remove the main source of amyloid from the body. The outcome varies and depends on the gene variant and amyloid can build up nevertheless.
Since ATTR is a hereditary disease, there is unfortunately no way to prevent its development. It's only possible to apply changes that can protect targeted organs and decrease the risk of their failure. It may be necessary to adhere to a diet low in proteins and sodium if the kidneys are involved. Life changes, such as a nutritious and balanced diet combined with regular exercise are recommended. It may be beneficial to undergo genetic counseling to help the patient and his family to understand the disease, the mechanism behind it, and the possible impact on their future children.
The prognosis of the disease majorly depends on the genetic variant of hereditary amyloidosis and how early the patient is diagnosed and treated. Some patients can live only for a few years after the diagnosis, some may live for a longer period of time. Overall, people usually live 7-12 years after being diagnosed.[8]
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