Congenital generalized lipodystrophy is a group of heterogeneous hereditary diseases that combine metabolic disorders in adipose tissue up to its complete atrophy. Symptoms of this condition are the disappearance of the subcutaneous fat layer on most of the body, black acanthosis of the skin folds, diabetes mellitus. 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 examination data, family history, laboratory tests, as well as methods of genetic diagnosis. There is no specific treatment, dietary therapy and symptomatic therapy are used.
Congenital generalized lipodystrophy (Berardinelli-Seip syndrome) is several genetic conditions in which adipose tissue atrophy occurs with the development of some concomitant symptoms. It was described almost simultaneously by the Brazilian endocrinologist U. Berardinelli and the Norwegian pediatrician M. Seip. Sometimes you can find another name for congenital generalized lipodystrophy – Seip-Lawrence syndrome.
This disease is relatively rare, the occurrence is about 1:10 000 000. Congenital generalized lipodystrophy affects both boys and girls with the same frequency 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 concomitant disorders. Using the methods of modern genetics, several main types of congenital generalized lipodystrophy have been identified, differing in the genes in which mutations occurred.
In general, the causes of the development of congenital generalized lipodystrophy are reduced to a violation of metabolism in adipose tissue (mainly subcutaneous tissue) caused by genetic mutations. As a result, 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, violations also affect the exchange of carbohydrates and proteins. With congenital generalized lipodystrophy, patients have difficulty assimilating lipids, so their blood levels and the load on the organs involved in their metabolism increases. First of all, it is the liver, in addition, there is an abnormal accumulation of fat in other organs – kidneys, myocardium, skeletal muscles, which leads to a disorder of their functions.
Congenital generalized lipodystrophy type 1 is caused by a mutation of the AGPAT2 gene located on the 9th chromosome. It encodes a special protein-the enzyme 1-acylglycerol-3-phosphate-O-acyltransferase 2, which is responsible for an important stage of fat metabolism (phosphorylation and the start of phospholipid formation). A decrease in the activity of the enzyme as a result of a defective structure of the AGPAT2 gene leads to a violation of the absorption of lipids by subcutaneous fat, in addition, it makes the membranes of adipocytes unstable due to a deficiency of phospholipids. As a result of all this, adipose tissue atrophy develops, the level of triglycerides in the blood increases, lipids are deposited in other organs, carbohydrate metabolism is disrupted with the development of type 2 diabetes mellitus. This is the clinical picture of congenital generalized lipodystrophy.
The type 2 form of the disease develops as a result of a mutation of the BSCL2 gene, which is located on the 11th chromosome. It encodes a protein called seipin, so the mechanism of development of congenital generalized lipodystrophy in this case is completely different. Seipin controls the development and differentiation of adipocytes, therefore, defects in its structure caused by the BSCL2 mutation lead to a violation of these processes. Because of this, the formation of subcutaneous fat is difficult at the earliest stages of development.
Congenital generalized lipodystrophy type 3 is caused by a mutation of the CAV1 gene localized on the 7th chromosome. The product of its expression is the protein caveolin-1, which takes an active part in the formation of caveol membrane structures in the form of invaginations and vesicles, which contain many receptors and enzymes. Caveoles are involved in the absorption of lipids, the formation of intracellular lipid droplets and intercellular connections 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 generalized lipodystrophy type 4 is caused by a mutation of the PTRF gene located on chromosome 17. 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, the components of caveol (proteins caveolin 1 and 3), therefore, the mechanism of disorders in this form of pathology is similar to type 3 disease. A feature of the mutation of the PTRF gene is the fact that not only adipocytes suffer, but also skeletal muscle and myocardial cells, therefore this form of pathology is more often accompanied by muscle disorders.
All forms of congenital generalized lipodystrophy are autosomal recessive hereditary diseases, only the genetic and molecular mechanisms of the development of disorders differ. There are small differences in the symptomatic picture of pathology, but they are too erased and unstable to reliably divide the clinical forms of Berardinelli-Seip syndrome according to them. 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 of adipocytes, which is the cause of the development of the disease.
- Congenital generalized lipodystrophy type 2 is caused by a mutation of the BSCL2 gene localized on the 11th chromosome. As a result, defects occur in the structure of the protein seipin, which is responsible for the processes of differentiation of adipocytes and the development of adipose tissue.
- Congenital generalized lipodystrophy type 3 – the cause of this pathology is a 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 special formations on the surface of adipocytes – caveoles. Violation of their structure leads to a disorder of the metabolic activity of adipose tissue, not only in subcutaneous tissue, but also in the bone marrow, which can have consequences for the hematopoiesis system.
- Congenital generalized lipodystrophy type 4 is caused by a mutation of the PTRF gene, the product of which is one of the translation regulatory proteins. This gene is located on the 17th chromosome and controls the synthesis of several other proteins through protein, including caveolins 1 and 3.
The most characteristic and obvious symptom of congenital generalized lipodystrophy is almost complete atrophy of subcutaneous fat, as a result of which the underlying structures are quite clearly contoured. A pediatrician can determine the disease immediately after the birth of a child or in the first months of his life. In the future, in addition to thinning of the subcutaneous fat layer, the symptoms are joined by increased appetite, rapid growth, larger relative sizes of feet, hands, lower jaw, in some cases curly dark hair is also observed.
After puberty, there is often a larger size of the genitals (penis in boys and clitoris in girls). Despite the absence of fatty tissue, patients with congenital generalized lipodystrophy rarely look exhausted due to the pronounced development of musculature (with the exception of type 4 disease).
Mental retardation of a minor degree is a non-permanent symptom of congenital generalized lipodystrophy, most often it is observed in type 2 of the disease. Black acanthosis is found on the skin in the neck and armpits. Symptoms from 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, lower back pain, up to the development of chronic renal failure. Women may develop virile syndrome with menstrual disorders, hirsutism, acne and infertility.
Cardiovascular disorders in congenital generalized lipodystrophy of different types are expressed differently. Almost always there are symptoms of arterial hypertension (headaches, cardialgia, palpitations), which can be caused by both myocardial damage and kidney pathology.
The fourth type of the 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 have a fatal outcome due to sudden cardiac death. Sometimes various arrhythmias are possible, also caused by cardiomyopathy.
Diagnosis of congenital generalized lipodystrophy is most often performed by a pediatrician, since the 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 analyses. The examination reveals an almost complete absence of subcutaneous fat on the entire surface of the body, pronounced contouring of muscles, which in most cases are sufficiently developed. The characteristic appearance of the patient is a thin “skeletonized” face against a developed figure, noticeable subcutaneous veins, curly dark hair, increased size of the feet and hands (acromegaly), areas of black acanthosis in the area of skin folds.
Palpation in congenital generalized lipodystrophy can reveal an increase in the liver and sometimes the spleen, which is confirmed by ultrasound studies. In severe cases, cirrhosis of the liver occurs with its characteristic manifestations – jaundice, ascites, edema. A biochemical blood test reveals hypertriglyceridemia, hyperglycemia, elevated insulin levels, a glucose tolerance test shows a sharp decrease in the absorption of carbohydrates by tissues. Also, a general increase in the level of lipids (hyperlipidemia) is determined in the blood, mainly due to the fraction of very low density lipoproteins (VLDL). If the glucose level exceeds 10 mmol / l, then the manifestations of congenital generalized lipodystrophy are joined by glucosuria and increased diuresis. Examination of the kidneys, including ultrasound, can reveal a violation of their functions up to chronic renal failure.
The study of the cardiovascular system in congenital generalized lipodystrophy includes electrocardiography, echocardiography, determination of blood pressure. In some cases, there is an increase in the size of the heart (cardiomegaly), which can be replaced over the years by dilated cardiomyopathy with the development of heart failure. The increase evenly affects all parts of the myocardium, which is easy to see with an ultrasound examination of the heart, an ECG will determine the expansion of the QRS complex and a violation of myocardial repolarization. Congenital generalized lipodystrophy can also be manifested by arrhythmias of various types, sudden cardiac death is possible. Blood pressure is usually elevated, this may be due to myocardial damage or kidney pathology.
When studying the hereditary history of a patient, it is possible to identify cases of congenital generalized lipodystrophy among his relatives and determine the autosomal recessive nature of inheritance. Genetic diagnostics performed by a geneticist is based on direct sequencing of sequences of genes associated with the disease (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.
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 diet with a reduced fat content is being developed, which the patient should adhere to throughout his life.
Traditional hypolipidemic agents (for example, atorvastatin) are ineffective in this disease in some cases. Also, hepatoprotectors, hypoglycemic agents (meglitinides, biguanides), anti–arrhythmia agents are used in the treatment of this condition, if there are indications. With mental retardation, it is necessary to work with a psychologist and classes with a child according to a special program. Some patients with congenital generalized lipodystrophy in adulthood decide on a variety of cosmetic procedures and plastic surgery to correct an excessively thin face.
Prognosis and prevention
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 of the liver, CRF may develop. Diabetic disorders are also possible – a decrease in microcirculation in the extremities, the retina of the eye, longer wound healing. In women, in some cases, ovarian damage occurs (for example, polycystic), leading to infertility. With slightly pronounced violations of the above organs, the prognosis for life is most often favorable.