Congenital generalized lipodistrofiya
Congenital generalized lipodistrofiya – group of heterogeneous hereditary diseases which are united by violation of metabolism in fatty tissue up to its full atrophy. Symptoms of this state are disappearance of a hypodermic fatty layer on the most part of a body, black skin folds, diabetes. Some forms are also followed by different degree mental retardation, violation of work of heart, liver and skeletal muscles. Diagnostics of a congenital generalized lipodistrofiya is performed on the basis of data of survey, the family anamnesis, laboratory analyses, and also methods of genetic diagnostics. Specific treatment is absent, apply a dietotherapy and symptomatic therapy.
Congenital generalized lipodistrofiya
Congenital generalized lipodistrofiya (Berardinelli-Seyp's syndrome) – several genetic states at which there is an atrophy of fatty tissue to development of some accompanying symptoms. Practically it was at the same time described by the Brazilian doctor-endocrinologist U. Berardinelli and the Norwegian pediatrician M. Seyp. Sometimes it is possible to meet other name of a congenital generalized lipodistrofiya – Seypa-Lawrence's syndrome. This disease is rather rare, occurrence makes about 1:10 000 000. The congenital generalized lipodistrofiya with an identical frequency strikes both boys, and girls and comes to light on the first months of life of the child. Data on a lethality it is strong to be separated, most likely, it is caused by variable expressiveness of the accompanying violations. By means of methods of modern genetics it was defined several main types of a congenital generalized lipodistrofiya differing on genes in which there were mutations.
Reasons of a congenital generalized lipodistrofiya
In the general plan of the reason of development of a congenital generalized lipodistrofiya come down to the violation of metabolism in fatty tissue (generally to hypodermic cellulose) caused by genetic mutations. It is resulted by an atrophy of the largest fatty depot in an organism that, in turn, disturbs all lipidic exchange in general; and as metabolism represents the balanced system, violations affect also exchange of carbohydrates and proteins. At a congenital generalized lipodistrofiya at patients the complicated assimilation of lipids therefore their level in blood and load of the bodies participating in their metabolism increases is observed. First of all, the liver, besides, occurs abnormal accumulation of fat in other bodies – kidneys, a myocardium, skeletal muscles that leads to disorder of their functions.
The congenital generalized lipodistrofiya of type 1 is caused by a mutation of a gene of AGPAT2 located on the 9th chromosome. It codes the special protein-enzyme 1-atsilglitserol-3-fosfat-O-atsiltransferazu 2 which is responsible for an important stage of metabolism of fats (phosphorylation and start of formation of phospholipids). Decrease of the activity of enzyme as a result of defective structure of a gene of AGPAT2 leads to violation of assimilation of lipids hypodermic fatty cellulose, besides, it does membranes of adipocytes unstable because of deficiency of phospholipids. As a result of all this the atrophy of fatty tissue develops, there is an increase in level of triglycerides in blood, there is an adjournment of lipids in other bodies, carbohydrate exchange with development of diabetes of the 2nd type is broken. It also makes a clinical picture of a congenital generalized lipodistrofiya.
The form of a disease of the 2nd type develops as a result of a mutation of a gene of BSCL2 which is located on the 11th chromosome. It codes protein under the name therefore the mechanism of development of a congenital generalized lipodistrofiya in this case absolutely other. Seypin controls development and a differentiation of adipocytes therefore the defects of its structure caused by BSCL2 mutation lead to violation of these processes. Because of it formation of hypodermic fatty cellulose is at a loss at the earliest stages of development. The congenital generalized lipodistrofiya of type 3 is caused by a mutation of a gene of CAV1 localized on the 7th chromosome. A product of its expression is the protein kaveolin-1, taking active part in formation – membrane structures in the form of invagination and bubbles which contain on themselves a set of receptors and enzymes. Kaveola take part in absorption of lipids, formation of intracellular lipidic drops and intercellular communications between adipocytes. Violation of structure kaveolina-1 leads to difficulty of all these processes and development of a congenital generalized lipodistrofiya.
The congenital generalized lipodistrofiya of type 4 is caused by a mutation of a gene of PTRF located on the 17th chromosome. The product of this gene, the protein (polymerase and transcript release factor) of the same name, is one of the factors of termination of broadcasting controlling formation of some other proteins, in particular, of components (proteins 1 and 3) therefore the mechanism of violations at this form of pathology is similar to a disease of the 3rd type. Feature of a mutation of a gene of PTRF is the fact that not only adipocytes suffer, but also cells of skeletal muscles and a myocardium therefore this form of pathology is more often than others is followed by muscular violations.
Classification of a congenital generalized lipodistrofiya
All forms of a congenital generalized lipodistrofiya are autosomno-recessive hereditary diseases, only genetic and molecular mechanisms of development of violations differ. Small distinctions are available also in a symptomatic picture of pathology, however they too erased and changeable that on them it is reliable to divide clinical forms of a syndrome of Berardinelli-Seyp. Therefore genetic classification remains only true and exact today, according to it allocate 4 main types of this disease:
The congenital generalized lipodistrofiya type 1 – is caused by a mutation of a gene of AGPAT2 located on the 9th chromosome. It results in defect of structure of enzyme of 1-atsilglitserol-3-fosfat-O-atsiltransferazy of 2 adipocytes, as is the reason of development of a disease.
The congenital generalized lipodistrofiya of type 2 – is caused by a mutation of a gene of BSCL2 localized on the 11th chromosome. It is resulted by defects in structure of protein of the seypin who is responsible for processes of a differentiation of adipocytes and development of fatty cellulose.
The congenital generalized lipodistrofiya of type 3 – the reason of this pathology consists in CAV1 gene mutation. It is on the 7th chromosome and codes protein kaveolin-1, responsible for formation on the surfaces of adipocytes of special educations – . Violation of their structure leads to disorder of metabolic activity of fatty tissue, and not only in hypodermic cellulose, but also in marrow that can have consequences for system of a hematopoiesis.
The congenital generalized lipodistrofiya of type 4 – is caused by a mutation of a gene of PTRF which product is one of broadcasting proteins regulators. This gene is located on the 17th chromosome and by means of protein controls synthesis of several other proteins – including kaveolin 1 and 3.
Symptoms of a congenital generalized lipodistrofiya
The most characteristic and obvious symptom of a congenital generalized lipodistrofiya is almost full atrophy of hypodermic fatty cellulose therefore the subject structures konturirutsya rather accurately. The pediatrician right after the birth of the child or in the first months of his life can define a disease. Further, besides thinning of a hypodermic fatty layer, the increased appetite, rapid growth, larger relative sizes of feet, brushes, the lower jaw join symptoms, in some cases also curly dark hair are observed. After the pubertatny period larger size of genitals is quite often noted (a penis at boys and a clitoris at girls). Despite the lack of fatty cellulose, patients with a congenital generalized lipodistrofiya seldom look exhausted because of the expressed development of muscles (except for a disease of the 4th type).
Intellectual backwardness of insignificant degree is a changeable symptom of a congenital generalized lipodistrofiya, most often it is observed at the 2nd type of a disease. On skin in a neck and axillary hollows it is found black . Symptoms from a liver – pains in the right podreberye, occasionally jaundice – are a sign of progressing of pathology and demand symptomatic therapy. Besides, manifestations of damage of kidneys – the raised diuresis, waist pains are possible, up to development of a chronic renal failure. At women development of a virilny syndrome with violations of periods, a girsutizm, emergence by an acne and infertility is possible.
Cardiovascular violations at a congenital generalized lipodistrofiya of different types are expressed unequally. Practically symptoms of arterial hypertension (headaches, kardialgiya, tachycardia) which can be caused both by damage of a myocardium, and pathology of kidneys are always observed. The fourth type of a disease is characterized by the most frequent development of a heavy cardiomyopathy with formation of heart failure. In such situation patients with a congenital generalized lipodistrofiya can have a lethal outcome because of sudden warm death. The various arrhythmias which are also caused by a cardiomyopathy are sometimes possible.
Diagnostics of a congenital generalized lipodistrofiya
Diagnosing of a congenital generalized lipodistrofiya is most often made by the pediatrician as symptoms of a disease can be noticed at the birth or in the first months of life of the child. The main methods of diagnostics are fizikalny inspection, laboratory tests of blood and urine, studying of the hereditary anamnesis of the patient and genetic analyses. At survey almost total absence of hypodermic fatty cellulose on all surface of a body, the expressed konturirovaniye of muscles which are in most cases rather developed comes to light. Characteristic appearance of the patient – the thin "skeletirovanny" person against the background of the developed figure, noticeable hypodermic veins, curly dark hair, the increased size of feet and hands (akromegaliya), sites of a black akantoz in the field of skin folds.
The palpation at a congenital generalized lipodistrofiya can reveal increase in a liver and sometimes a spleen that is confirmed by ultrasonographies. In hard cases there is cirrhosis with its characteristic manifestations – jaundice, ascites, hypostases. Biochemical blood test reveals a gipertriglitseridemiya, a hyperglycemia, the increased insulin level, the glyukozotolerantny test shows sharp decrease in absorption of carbohydrates fabrics. Also in blood the general increase in level of lipids (giperlipidemiya), generally at the expense of fraction of lipoproteid of very low density (LPONP) is defined. If the level of glucose exceeds 10 mmol/l, then the glucosuria and increase in a diuresis join manifestations of a congenital generalized lipodistrofiya. A research of kidneys including ultrasonic, can reveal violation of their functions up to a chronic renal failure.
The research of cardiovascular system at a congenital generalized lipodistrofiya includes an electrocardiography, an echocardiography, determination of arterial pressure. In some cases increase in the sizes of heart (kardiomegaliya) which can be replaced over the years by a dilatatsionny cardiomyopathy with development of heart failure is observed. Increase evenly affects all departments of a myocardium that it is easy to see at ultrasound examination of heart, expansion of the QRS complex and violation of repolarization of a myocardium will be defined on the ECG. The congenital generalized lipodistrofiya can be also shown by arrhythmias of various type, sudden warm death is possible. Arterial pressure is usually increased, it can be caused by damage of a myocardium or pathology of kidneys.
When studying the hereditary anamnesis of the patient it is possible to reveal cases of a congenital generalized lipodistrofiya among his relatives and to define the autosomno-recessive nature of inheritance. The genetic diagnostics which is carried out by the doctor geneticist is based on a direct sekvenirovaniye of the sequences of the genes (AGPAT2, BSCL2, CAV1 and PTRF) associated with a disease for identification of mutations. Differential diagnostics of a congenital generalized lipodistrofiya should be carried out with the acquired kinds of this state, anorexia, Itsenko-Cushing's disease and a thyrotoxicosis.
Treatment, forecast and prevention
Specific treatment of this state does not exist, only symptomatic therapy for reduction of displays of a disease and the prevention of development of complications is possible. For the purpose of decrease in load of an organism at a congenital generalized lipodistrofiya the special diet with the lowered content of fats to which the patient has to adhere throughout all life is developed. Traditional gipolipidemichesky means (for example, ) at this disease in some cases are inefficient. Also in therapy of this state use gepatoprotektor, hypoglycemic means (meglitinida, biguanides), means against arrhythmia – in the presence of indications. At intellectual backwardness work with the psychologist and classes with the child in the special program is necessary. Some patients with a congenital generalized lipodistrofiya at adult age decide on various cosmetology procedures and plastic surgeries for correction of excessively thin person.
The forecast of a disease quite often uncertain and in many respects depends on an involvement of heart, a liver and kidneys into pathological process. In hard cases heart failure (including sudden warm death), cirrhosis, HPN can develop. Also diabetic violations – decrease in microcirculation in extremities, an eye retina, longer healing of wounds are possible. Women in some cases have a damage of ovaries (for example, ) leading to infertility. At slightly expressed violations of the above-stated bodies the forecast for life most often favorable.