Hereditary amyloidosis is a group of diseases characterized by the accumulation of insoluble protein complexes (amyloid) in various tissues – mainly in the nervous and digestive systems, kidneys and myocardium. Symptoms are neurological disorders, cardiac pathologies (cardiomyopathy), nephropathy and dyspeptic disorders. In various forms of hereditary amyloidosis, the defeat of a certain system prevails. The diagnosis is made on the basis of the clinical picture and histological examination of tissues, methods of molecular genetic determination have been developed for some forms. Treatment includes the use of immunosuppressive drugs, supportive and symptomatic therapy.
Hereditary or familial amyloidosis is a genetically determined disorder of protein metabolism, in which an abnormal protein is formed with its subsequent deposition as part of immune complexes in various tissues. As a nosological unit, amyloidosis has been known for a long time, but the genetic nature of some forms of this condition has been discovered only in recent decades. Differentiation of hereditary and non-hereditary forms is significantly complicated by the fact that a number of genetically determined pathologies (for example, periodic disease) are also characterized by amyloid deposition, but now it is considered that protein disorders in such diseases are secondary.
At the moment, primary hereditary amyloidosis reliably refers only to the types of pathology caused by a mutation of the TTR gene. A controversial issue is the classification of the so–called Finnish type of amyloidosis – it has been established that this disease is caused by a defect in the GSN gene, but it is still unclear whether amyloid deposits are a primary disorder or a consequence of any other processes. Some geneticists associate this type of disease with hereditary type 4 amyloidosis, but having a different genetic nature. The incidence of hereditary amyloidosis has not been determined due to the rarity of this condition.
The direct cause of primary hereditary amyloidosis is defects in the TTR gene, which is located on the 18th chromosome. Currently, more than 80 varieties of mutations of this gene have been identified, many of which lead to various pathologies – in addition to all forms of hereditary amyloidosis, they include distranstiretinemic hyperthyroxinemia and familial forms of carpal tunnel syndrome. Almost all TTR defects are inherited by an autosomal dominant mechanism, the expression product of this gene is the protein transtyretin, which functions as a transport protein for thyroxine and retinol. There are also other pathologies that are caused by various damage to the structure and formation of transthyretin – among them systemic senile amyloidosis and amyloid polyneuropathy.
The pathogenesis of hereditary amyloidosis is associated with a violation of the stability of transthyretin molecules – due to a mutation of the TTR gene, the structure of this protein molecule changes and it becomes unstable. In some cases, instability slightly affects its functions, but sometimes the conformation of the molecule changes so much that it acquires immunogenic properties. An abnormal protein causes a reaction similar to an allergic one (immunocomplex type), resulting in insoluble protein complexes that are prone to deposition in the extracellular space of tissues. The clinical manifestations of hereditary amyloidosis depend on where the deposition of protein complexes that cause organ dysfunction mainly occurs.
Classification and symptoms
Hereditary amyloidosis caused by mutations of the TTR gene can manifest itself as disorders of various organs and tissues – nerves, stomach and duodenum, kidneys, heart, eyes. At the same time, the clinical picture of the disease depends on the nature of the mutation, various forms differ among themselves by the predominant lesion of any organs, the severity of disorders and the duration of the course. To date, there are 6 main phenotypic forms of hereditary amyloidosis.
Type 1 (Andrade syndrome) is the most common variant of hereditary amyloidosis, was first described in 1952. It is most common in Portugal, as well as in the former Portuguese colonies (Latin America). The onset of this form of hereditary amyloidosis is most often recorded at the age of 30-40 years, the first symptom is a violation of sensitivity (pain, temperature, tactile) on the skin of the lower extremities. Polyneuropathy is gradually becoming more pronounced, in addition to the defeat of sensitive nerves, motor disorders of the muscles of the distal parts of the legs are joined over time. Due to a violation of innervation, hereditary amyloidosis often leads to trophic ulcers of the lower extremities. Pathology also affects the autonomic nervous system – patients have potency disorders and orthostatic hypotension. At the final stages of the development of hereditary amyloidosis type 1, protein deposits occur in the kidneys, heart and cornea, causing disorders in these organs and leading to death – most often, 10-13 years after the appearance of the first symptoms.
Type 2 (Rukavin syndrome) is a very rare type of hereditary amyloidosis, which was reliably described only in representatives of two families in the USA in 1956. It manifests itself at the age of 35-45 and begins with a pronounced carpal tunnel syndrome, to which, after a few years, damage to sensitive and autonomic nerves is added. This type of hereditary amyloidosis progresses very slowly, 15-20 years after the onset of the disease, deposits of amyloid in the intestine, heart, kidneys may be noted.
Type 3 (Van Allen syndrome) is a type of hereditary amyloidosis (hereditary amyloid neuropathy) characterized by a predominant lesion of nerves and intestines. The clinical manifestations of this disease are very similar to type 1, the main difference is the absence of significant damage to the autonomic nervous system. Also, patients with this form of hereditary amyloidosis often have gastritis and ulcers of the 12th duodenum.
Type 4 or hereditary amyloidosis of the Finnish type was first described in 1971, and, as already mentioned above, there is currently an active discussion about its genetic nature. Basically, with this form of the disease, the cranial nerves are affected, the sensitivity of the upper extremities is impaired. Over time, latticed corneal atrophy occurs and skin turgor decreases, at the final stages of pathology development, pronounced polyneuropathy and amyloid deposits in the heart occur. Unlike other forms of hereditary amyloidosis, this type can be inherited by an autosomal recessive mechanism (if the disease is caused by mutations of the GSN gene).
Hereditary cardiomyopathic amyloidosis or hereditary Danish-type amyloidosis is manifested by mild neurological disorders and significant myocardial damage (amyloidosis of the heart). Amyloid deposits lead to the rapid development of cardiomyopathy and heart failure, which causes death.
Nephropathic amyloidosis with deafness, urticaria and fever is a rare but rather severe form of hereditary amyloidosis, in which patients aged 20-30 years have fever of unknown genesis and frequent attacks of urticaria. Then these manifestations are joined by sensorineural hearing loss, which is subsequently complicated by complete deafness. Kidney damage (amyloidosis of the kidneys) often leads to chronic renal failure, which causes death from uremia in most patients.
Diagnosis and treatment
Diagnosis of hereditary amyloidosis is made on the basis of patient examination data, general clinical analyses, assessment of the condition of key organs (nervous system, heart, kidneys), histological examination of tissues, molecular genetic studies. During examination, signs of neurological lesions may be detected (impaired sensitivity and motor functions, hypo- or areflexia), in advanced cases, muscle atrophy due to lack of innervation is noted. Ophthalmological examination with hereditary amyloidosis often reveals signs of amyloid deposition in the vitreous body, corneal atrophy or ulceration is possible. In some cases, there may be violations from the skin – a decrease in turgor, urticaria, trophic ulcers.
Ultrasound examination of the heart and kidneys in hereditary amyloidosis also often gives a lot of information about this disease. In the case of amyloid deposition in the kidneys, their increase and compaction of the structure is observed, sometimes the presence of cysts is determined. At the final stages of the development of amyloidosis, a decrease in the kidneys may occur due to their atrophy. The amplitude and voltage of all teeth decreases on the ECG, the EchoCG detects a significant increase in the thickness of the myocardium and the size of the left ventricle. In some cases, ultrasound with hereditary amyloidosis can reveal deposits of amyloid in other organs – liver, spleen, large vessels. When biopsiing the affected organs of patients suffering from hereditary amyloidosis, a histological picture typical of this disease is noted – deposition of eosinophilic masses with a concentration around blood vessels. Modern genetics is able to detect mutations in the TTR gene by direct sequencing.
There is no specific treatment for hereditary amyloidosis, mainly symptomatic and supportive therapy is used. To slow down the course of the disease, immunosuppressive agents are used (in particular, corticosteroids), cytotoxic drugs are occasionally prescribed. In case of significant kidney damage due to hereditary amyloidosis, hemodialysis is indicated. Symptomatic treatment is also necessary for cardiomyopathy and heart failure. It is recommended to take increased dosages of B vitamins, as they slow down the development of neuropathy and contribute to improving the general condition of the patient.
In most cases, the prognosis of hereditary amyloidosis is unfavorable, since many forms of this disease lead to death 10-25 years after its onset. Symptomatic and supportive therapy, hemodialysis, and the use of immunosuppressants can slow down the development of this pathology. Taking into account the fact that most often the symptoms of hereditary amyloidosis appear in 30-40 years, timely diagnosis of the disease and reasonable supportive therapy can ensure the survival of patients to old age without a significant deterioration in the quality of life.