Hereditary – group of diseases which are characterized by accumulation of insoluble proteinaceous complexes (amiloid) in various fabrics – mainly, in nervous and digestive systems, kidneys and a myocardium. Symptoms are neurologic violations, pathologies of heart (cardiomyopathy), nephropathy and dispepsichesky frustration. At various forms of a hereditary amiloidoz defeat of a certain system prevails. Diagnostics is made on the basis of a clinical picture and histologic studying of fabrics, methods of molecular and genetic definition are developed for some forms. Treatment includes use of immunosupressivny medicines, the supporting and symptomatic therapy.
Hereditary or family – genetically caused violation of exchange of proteins at which there is a formation of abnormal protein to its subsequent sedimentation as a part of immune complexes in various fabrics. As nosological unit it is known long ago, but the genetic nature of some forms of this state was found only in the last decades. The differentiation of hereditary and not hereditary forms considerably is complicated by the fact that a number of genetically caused pathologies (for example, a periodic disease) are also characterized by adjournment of an amiloid, but now is considered to be that proteinaceous violations at such diseases have secondary character.
At the moment authentically carry to primary hereditary amiloidoz only the pathology types caused by TTR gene mutation. A debatable question is classification of a so-called amiloidoz of the Finnish type – is established that this disease is caused by defect of a gene of GSN, however is still not clear whether deposits of an amiloid at the same time are primary violation or a consequence of any other processes. Some doctors geneticists associate this type of a disease with a hereditary amiloidoz of the 4th type, but having other genetic nature. Occurrence of a hereditary amiloidoz is not determined by the reason of a rarity of this state.
Reasons of a hereditary amiloidoz
Defects in a gene of TTR which settles down on the 18th chromosome are an immediate cause of primary hereditary amiloidoz. More than 80 kinds of mutations of this gene are at the moment identified, many of which lead to various pathologies – besides all forms of a hereditary amiloidoz, carry a distranstiretinemichesky gipertiroksinemiya and family forms of a carpal tunnel syndrome to them. Practically all defects of TTR are inherited on the autosomno-prepotent mechanism, a product of an expression of this gene is protein , performing functions of a transport protein for a tiroksin and Retinolum. Also other pathologies which are caused by various damages of structure and formation of a transtiretin – among them system senile and amyloid polyneuropathy are known.
The pathogenesis of a hereditary amiloidoz is connected with violation of stability of molecules of a transtiretin – because of a mutation of a gene of TTR the structure of this proteinaceous molecule changes and it becomes unstable. In some cases instability slightly influences its functions, but sometimes conformation of a molecule changes so that it gains immunogene properties. The abnormal protein causes the reaction similar with allergic (immunocomplex type) therefore there are insoluble proteinaceous complexes inclined to adjournment in ekstratsellyulyarny space of fabrics. Clinical manifestations of a hereditary amiloidoz depend on where mainly there is an adjournment of protein complexes which cause violations of functionality of bodies.
Classification and symptoms of a hereditary amiloidoz
Hereditary , caused by TTR gene mutations, it is capable to be shown by violations from different bodies and fabrics – nerves, a stomach and a 12-tiperstny gut, kidneys, heart, eyes. At the same time the clinical picture of a disease depends on character of a mutation, various forms differ among themselves in the prevailing defeat of any bodies, expressiveness of violations and duration of a current. Today allocate 6 main phenotypical forms of a hereditary amiloidoz.
Type 1 (Andrade's syndrome) – is the most widespread option of a hereditary amiloidoz, was for the first time described in the 1952nd year. It is most widespread in Portugal, and also in the former Portuguese colonies (Latin America). The beginning of this form of a hereditary amiloidoz most often is registered at the age of 30-40 years, the first symptom is sensitivity violation (painful, temperature, tactile) on skin of the lower extremities. The polyneuropathy gradually becomes more and more expressed, besides damage of sensitive nerves motive disorders of muscles of disteel departments of legs join over time. Because of violation of an innervation hereditary often leads to trophic ulcers of the lower extremities. Pathology affects also the autonomic nervous system – at patients violations of a potentiality and orthostatic hypotonia are observed. At final stages of development of a hereditary amiloidoz of the 1st type of adjournment of protein arise in kidneys, heart and a cornea, causing violations in these bodies and leading to a lethal outcome – most often, in 10-13 years after emergence of the first symptoms.
Type 2 (Rukavin's syndrome) – very rare type of a hereditary amiloidoz which authentically was described only at representatives of two families in the USA in the 1956th year. It is shown in 35-45 years and begins with the expressed tunnel syndrome of a carpal tunnel which in several years join damage of sensitive and vegetative nerves. This type of a hereditary amiloidoz progresses very slowly, in 15-20 years after the beginning of a disease deposits of an amiloid in intestines, heart, kidneys can be noted.
Type 3 (Van Allen's syndrome) – the kind of a hereditary amiloidoz (a hereditary amyloid neuropathy) which is characterized by the prevailing damage of nerves and intestines. Clinical displays of this disease are very similar to the 1st type, the main difference consists in lack of considerable damage of the autonomic nervous system. Also at patients with this form of a hereditary amiloidoz gastritises and ulcers of a 12-tiperstny gut are often noted.
Type 4 or hereditary the Finnish type was for the first time described in the 1971st year, concerning its genetic nature as it was already told above, the active discussion is at the moment conducted. Generally at this form of a disease craniocereberal nerves are surprised, sensitivity of the top extremities is broken. Over time there is a trellised atrophy of a cornea and turgor of skin decreases, at the final stages of development of pathology there are expressed polyneuropathy and deposits of an amiloid in heart. Unlike other forms of a hereditary amiloidoz, this type can be inherited on the autosomno-recessive mechanism (in case the disease is caused by GSN gene mutations).
Hereditary kardiomiopatichesky or hereditary the Danish type it is shown by poorly expressed neurologic violations and considerable damage of a myocardium ( hearts). Deposits of an amiloid lead to bystry development of a cardiomyopathy and heart failure that becomes the reason of a lethal outcome.
Nefropatichesky with deafness, urticaria and fever – rare, but rather severe form of a hereditary amiloidoz at whom patients at the age of 20-30 years have a fever of unspecified genesis and frequent attacks of urticaria. Then neurotouch relative deafness which in the subsequent is complicated by full deafness joins these manifestations. Damage of kidneys ( kidneys) quite often leads to a chronic renal failure, as becomes a cause of death from uraemia of most of patients.
Diagnostics and treatment of a hereditary amiloidoz
Diagnostics of a hereditary amiloidoz is made on the basis of the given survey of the patient, all-clinical analyses, assessment of a condition of key bodies (nervous system, heart, kidneys), histologic studying of fabrics, molecular and genetic researches. At survey signs of neurologic defeats (violation of sensitivity and motive functions, hypo can come to light - or the arefleksiya), in the started cases is noted the atrophy of muscles caused by lack of an innervation. Ophthalmologic inspection at a hereditary amiloidoz quite often finds signs of adjournment of an amiloid in a vitreous body, the atrophy or an ulceration of a cornea is possible. In some cases violations from integuments can be noted – decrease in turgor, urticaria, trophic ulcers.
Ultrasound examination of heart and kidneys at a hereditary amiloidoz also quite often gives a lot of information on this disease. In case of adjournment of an amiloid in kidneys their increase and consolidation of structure is observed, existence of cysts sometimes is defined. At final stages of development of an amiloidoz there can be a reduction of kidneys because of their atrophy. Amplitude and a voltage of all teeth decreases by the ECG, EhoKG finds significant increase in thickness of a myocardium and the sizes of the left ventricle. In some cases by ultrasonography method at a hereditary amiloidoz it is possible to reveal deposits of an amiloid and in other bodies – a liver, a spleen, large vessels. At a biopsy of the struck bodies of the patients suffering from a hereditary amiloidoz the histologic picture, typical for this disease, – adjournment of eozinofilny masses with concentration around blood vessels is noted. The modern genetics is capable to reveal mutations in a gene by TTR method of a direct sekvenirovaniye.
Specific treatment of a hereditary amiloidoz does not exist, the symptomatic and supporting therapy is generally applied. For delay of a course of a disease use immunosuppressants (in particular – corticosteroids) occasionally appoint cytotoxic medicines. In case of considerable damage of kidneys because of a hereditary amiloidoz the hemodialysis is shown. Symptomatic treatment is also necessary at a cardiomyopathy and heart failure. It is recommended to accept the raised dosages of vitamins of group B as they slow down development of neuropathy and promote improvement of the general condition of the patient.
Forecast of a hereditary amiloidoz
In most cases the forecast of a hereditary amiloidoz adverse as many forms of this disease lead to a lethal outcome in 10-25 years after its beginning. The symptomatic and supporting therapy, a hemodialysis, application of immunosupressor are capable to slow down development of this pathology. Taking into account that most often symptoms of a hereditary amiloidoz are shown in 30-40 years, timely diagnosis of a disease and the reasonable supporting therapy are capable to provide survival of patients till an old age without considerable deterioration of life.