Congenital Generalized lipodystrophy Defination, Causes, Hiv, dunnigan: Congenital generalized lipodystrophy is a group of heterogeneous hereditary diseases that unite metabolic disturbances in adipose tissue up to its complete atrophy. The symptoms of this condition are the disappearance of the subcutaneous fat in most parts of the body, black acanthosis of skin folds, and diabetes. Some forms are also accompanied by varying degrees of oligophrenia, impaired functioning of the heart, liver, and skeletal muscles. Diagnosis of congenital generalized lipodystrophy is carried out on the basis of inspection data, family history, laboratory tests, and methods of genetic diagnosis. There is no specific treatment, diet therapy and symptomatic therapy are used.
- Causes of congenital generalized lipodystrophy
- Classification of congenital generalized lipodystrophy
- Symptoms of congenital generalized lipodystrophy
- Diagnosis of congenital generalized lipodystrophy
- Treatment, prognosis and prevention
Congenital generalized lipodystrophy (Berardinelli-Seyp syndrome) – several genetic conditions in which fatty tissue atrophy occurs with the development of some associated symptoms. Almost simultaneously, it was described by a Brazilian endocrinologistW. Berardinelli and Norwegian pediatrician M. Seip. Sometimes you can find another name for congenital generalized lipodystrophy – Seip-Lawrence syndrome. This disease is relatively rare, the incidence is about 1:10 000 000. Congenital generalized lipodystrophy with the same frequency affects both boys and girls and is detected in the first months of a child’s life. Data on mortality vary greatly, apparently, this is due to the variable severity of related disorders. Through the methods of modern genetics, several major types of congenital generalized lipodystrophy have been identified, differing in the genes in which mutations have occurred.
Causes of congenital generalized lipodystrophy
In general, the causes of the development of congenital generalized lipodystrophy are reduced to a violation of metabolism in adipose tissue (mainly subcutaneous tissue), due to genetic mutations. As a result, the atrophy of the largest fat depot in the body occurs, which, in turn, upsets the entire lipid metabolism as a whole; and since metabolism is a balanced system, disorders also affect the metabolism of carbohydrates and proteins. In case of congenital generalized lipodystrophy in patients, there is obstructed lipid absorption, therefore, their blood level rises and the load on the organs involved in their metabolism. First of all, it is the liver, in addition, there is an abnormal accumulation of fat in other organs – the kidneys, myocardium, skeletal muscles, which leads to a breakdown of their functions.
Congenital type 1 generalized lipodystrophy is caused by a mutation of the AGPAT2 gene located on chromosome 9. It encodes a special protein-enzyme 1-acylglycerol-3-phosphate-O-acyltransferase 2, which is responsible for an important step in the metabolism of fats (phosphorylation and the start of phospholipid formation). The decrease in enzyme activity as a result of the defective structure of the AGPAT2 gene leads to impaired lipid uptake by subcutaneous fatty tissue; in addition, this makes the adipocyte membranes unstable due to a deficiency of phospholipids. As a result of all this, atrophy of adipose tissue develops, triglycerides level in the blood rises, lipid deposition occurs in other organs, carbohydrate metabolism is disturbed with the development of type 2 diabetes. This is the clinical picture of congenital generalized lipodystrophy.
The form of the disease of the 2nd type develops as a result of the mutation of the gene BSCL2, which is located on the 11th chromosome. It encodes a protein called seipin, so the development mechanism of congenital generalized lipodystrophy in this case is quite different. Seipin controls the development and differentiation of adipocytes; therefore, defects in its structure due to the BSCL2 mutation result in the disruption of these processes. Because of this, the formation of subcutaneous fat is hampered at the earliest stages of development. Congenital type 3 generalized lipodystrophy is caused by a mutation of the CAV1 gene localized on chromosome 7. The product of its expression is the protein caveolin-1, which takes an active part in the formation of caveolae – membrane structures in the form of invaginations and vesicles, which contain many receptors and enzymes. Caveolae are involved in lipid uptake, the formation of intracellular lipid droplets and intercellular bonds between adipocytes. Violation of the structure of caveolin-1 leads to the difficulty of all these processes and the development of congenital generalized lipodystrophy.
Congenital type 4 generalized lipodystrophy is caused by a mutation of the PTRF gene located on the 17th chromosome. The product of this gene, the protein of the same name (polymerase and transcript release factor), is one of the translation termination factors controlling the formation of a number of other proteins, in particular, components of caveolae (caveolin proteins 1 and 3), therefore the mechanism of disorders in this form of pathology is similar to the disease 3rd type. A feature of the PTRF gene mutation is the fact that not only adipocytes, but also cells of the skeletal muscles and myocardium are affected, therefore this form of pathology is more often accompanied by muscular disorders.
Classification of congenital generalized lipodystrophy
All forms of congenital generalized lipodystrophy are autosomal recessive hereditary diseases, only the genetic and molecular mechanisms of the development of disorders are different. Small differences exist in the symptomatic picture of the pathology, but they are too blurred and inconstant to reliably separate the clinical forms of Berardinelli-Seip syndrome. Therefore, the genetic classification today remains the only true and accurate, according to it, there are 4 main types of this disease:
Congenital generalized lipodystrophy type 1 is caused by a mutation of the AGPAT2 gene located on the 9th chromosome. This leads to a defect in the structure of the enzyme 1-acylglycerol-3-phosphate-O-acyltransferase 2 adipocytes, which is the cause of the development of the disease.
Congenital generalized type 2 lipodystrophy – is caused by a mutation of the BSCL2 gene localized on chromosome 11. As a result, defects appear in the structure of Seipin protein, which is responsible for the processes of adipocyte differentiation and the development of fatty tissue.
Congenital type 3 generalized lipodystrophy – the cause of this pathology is the mutation of the CAV1 gene. It is located on the 7th chromosome and encodes the protein caveolin-1, which is responsible for the formation of specific formations on the surface of adipocytes – caveolae. Disruption of their structure leads to a breakdown of the metabolic activity of adipose tissue, not only in the subcutaneous tissue, but also in the bone marrow, which may have consequences for the hematopoietic system.
Congenital generalized lipodystrophy type 4 is caused by a mutation of the PTRF gene, the product of which is one of the proteins – translational regulators. This gene is located on the 17th chromosome and through the protein controls the synthesis of several other proteins – including caveolin 1 and 3.
Symptoms of congenital generalized lipodystrophy
The most characteristic and obvious symptom of congenital generalized lipodystrophy is the almost complete atrophy of subcutaneous fatty tissue, as a result of which the underlying structures are clearly contoured. The pediatrician can determine the disease immediately after the birth of the child or in the first months of his life. Further, in addition to thinning of the subcutaneous fat layer, increased appetite, rapid growth, larger relative sizes of the feet, hands, lower jaw join the symptoms, in some cases curly dark hair is also observed. After puberty, a larger size of the genital organs is often noted (the penis in boys and the clitoris in girls). Despite the lack of fatty tissue,
Mental retardation of a minor degree is a non-permanent symptom of congenital generalized lipodystrophy, most often it is observed in type 2 disease. On the skin in the neck and armpits is found black acanthosis. Symptoms of the liver – pain in the right hypochondrium, occasionally jaundice – are a sign of the progression of pathology and require symptomatic therapy. In addition, there may be manifestations of kidney damage – increased diuresis, back pain, until the development of chronic renal failure . Women may develop viral syndrome with menstrual disorders, hirsutism , the appearance of acne and infertility .
Cardiovascular disorders in congenital generalized lipodystrophy of different types are expressed differently. Symptoms of arterial hypertension (headaches, cardialgia, rapid heartbeat) are almost always observed , which can be caused by myocardial damage and kidney pathology. The fourth type of disease is characterized by the most frequent development of severe cardiomyopathy with the formation of heart failure . In such a situation, patients with congenital generalized lipodystrophy may be fatal due to sudden cardiac death. Sometimes there are a variety of arrhythmias , also caused by cardiomyopathy.
Diagnosis of congenital generalized lipodystrophy
Diagnosis of congenital generalized lipodystrophy is most often made by a pediatrician , since symptoms of the disease can be noticed at birth or in the first months of a child’s life. The main diagnostic methods are physical examination, laboratory tests of blood and urine, the study of the patient’s hereditary history and genetic tests. On examination, there is an almost complete absence of subcutaneous fatty tissue on the entire surface of the body, pronounced contouring of the muscles, which in most cases are quite developed. The characteristic appearance of the patient is a thin “skeletonized” face on the background of a developed figure, noticeable saphenous veins, curly dark hair, an increased size of the feet and hands ( acromegaly ), areas of black acanthosis in the skin folds area.
Palpation in congenital generalized lipodystrophy can reveal an enlarged liver and sometimes spleen, which is confirmed by ultrasound. In severe cases, cirrhosis of the liver occurs with its characteristic manifestations – jaundice, ascites.swelling. Biochemical analysis of blood reveals hypertriglyceridemia, hyperglycemia, elevated insulin levels, the glucose tolerance test shows a sharp decrease in carbohydrate absorption by the tissues. Also in the blood is determined by the overall increase in lipid levels (hyperlipidemia), mainly due to the fraction of very low density lipoproteins (VLDL). If the glucose level exceeds 10 mmol / l, then glucosuria and an increase in diuresis are associated with the manifestations of congenital generalized lipodystrophy. A study of the kidneys, including ultrasound, may reveal a violation of their functions, including chronic renal failure.
The study of the cardiovascular system in congenital generalized lipodystrophy includes electrocardiography , echocardiography , blood pressure determination. In some cases, an increase in the size of the heart (cardiomegaly) is observed, which can be replaced with age by dilated cardiomyopathywith the development of heart failure. The increase evenly affects all departments of the myocardium, which is easy to see during an ultrasound examination of the heart, the ECG will determine the expansion of the QRS complex and the violation of myocardial repolarization. Congenital generalized lipodystrophy may also be manifested by various types of arrhythmias, sudden cardiac death is possible.. Blood pressure is usually elevated, this may be due to myocardial damage, or kidney disease.
When studying the hereditary history of the patient, it is possible to identify cases of congenital generalized lipodystrophy among his relatives and determine the autosomal recessive pattern of inheritance. Genetic diagnosis by a geneticist is based on direct sequencing of disease-associated gene genes (AGPAT2, BSCL2, CAV1, and PTRF) to detect mutations. Differential diagnosis of congenital generalized lipodystrophy should be carried out with acquired varieties of this condition, anorexia , Itsenko-Cushing’s disease and thyrotoxicosis.
Treatment, prognosis and prevention
There is no specific treatment for this condition; only symptomatic therapy is possible to reduce the manifestations of the disease and prevent the development of complications. In order to reduce the load on the body with congenital generalized lipodystrophy, a special low-fat diet is being developed, which the patient must adhere to throughout his life. Traditional lipid-lowering drugs (for example, atorvastatin) are ineffective in some cases with this disease. Hepatoprotectors, hypoglycemic agents (meglitinides, biguanides), anti-arrhythmia drugs are also used in the treatment of this condition if indicated. When mental retardation is necessary to work with a psychologistand classes with a child on a special program. Some patients with congenital generalized lipodystrophy in adulthood are decided on a variety of cosmetic procedures and plastic surgery to correct an overly thin face.
The prognosis of the disease is often uncertain and largely depends on the involvement of the heart, liver and kidneys in the pathological process. In severe cases, heart failure (including sudden cardiac death), cirrhosis, and chronic renal failure may develop. Diabetic disorders are also possible – reduction of microcirculation in the limbs, retina, and longer wound healing. In women, in some cases, the ovaries are affected (for example, polycystic), leading to infertility. With slightly pronounced violations of the above organs, the prognosis for life is most often favorable.