Berardinelli-Seip syndrome ...; Congenital lipodystrophy Berardinelli-Seip of; Congenital generalized lipodystrophy (Berardinelli-Seip syndrome, Seip congenital lipodystrophy Berardinelli-) - Genes AGPAT2, BSCL2, CAV1 and PTRF

Syndrome Berardinelli-Seip of, also known as congenital lipodystrophy Berardinelli-Seip or of congenital generalized lipodystrophy is a rare disease characterized by the lack of adipose tissue. This deficiency leads to having to store fat in other parts of the body such as the liver and the muscles, causing serious health problems. Signs and symptoms of congenital Berardinelli-Seip lipodystrophy are evident from birth or early childhood. Frequent features of this process include hypertriglyceridemia and insulin resistance. Insulin resistance in adolescence can become a diabetes mellitus. This syndrome also produces hepatic steatosis, which can damage the organ. The accumulation of fat in the heart can cause hypertrophic cardiomyopathy, which can lead to heart failure and arrhythmia, causing sudden death.

Likewise, individuals with this syndrome have a distinctive physical appearance, since the combination of almost complete absence of adipose tissue and muscle tissue overgrowth makes these individuals physically appear very muscular. They also tend to have a big chin, prominent orbital ridges and navel, and large hands and feet. Affected women may have clitoromegaly, hirsutism, irregular menstrual periods and ovarian cysts, which may be related to hormonal changes. Also we found individuals with acanthosis nigricans. Acanthosis nigricans causes the skin in body folds appear thickened, dark and velvety.

They described four forms of congenital lipodystrophy Berardinelli-Seip of which is primarily distinguished by their genetic cause, although the types also have some differences in their typical signs and symptoms. For example, in addition to the features described above, some people with congenital lipodystrophy Berardinelli-Seip of type 1 develop cysts in the long bones of the arms and legs after puberty. Type 2 may be associated with intellectual disability, usually mild to moderate. Type 3 seems to lead to poor growth and low stature along with other health problems. Type 4 is associated with muscle weakness, developmental delay, joint abnormalities, pyloric stenosis and severe arrhythmia that can cause sudden death.

Congenital lipodystrophy Berardinelli-Seip of is due to mutations in AGPAT2, BSCL2, CAV1 and PTRF genes, which are responsible for Type I, II, III and IV, respectively. The proteins encoded by these genes play important roles in the development and function of adipocytes, so that mutations in any of these genes or interrupt the normal function of adipocytes. As a result, the body is unable to use and store fats properly, so the almost total absence of body fat underlies the various signs and symptoms of the syndrome.

Mutations in the AGPAT2 (1-acylglycerol-3-phosphate O-acetyltransferase 2) gene, located on the long arm of chromosome 9 (9q34.3), are responsible for lipodystrophy Berardinelli-Seip type of I. This gene encodes the AGPAT2 enzyme that plays a critical role in the growth and development of adipocytes. This enzyme synthesizes two major types of lipids: glycerophospholipids and triacylglycerol converting lysophosphatidic acid (LPA) in phosphatidic acid (PA). They have identified at least 26 AGPAT2 gene mutations in people with this syndrome. AGPAT2 abnormal enzyme, can reduce the production and storage of triglycerides in adipocytes, which would make these cells can not store fat. The defective enzyme may also reduce concentrations of glycerophospholipids in adipocytes, modifying the structure of the cell membrane and interrupting the normal signaling within these cells.

The BSCL2 gene affected in lipodystrophy Berardinelli-Seip of type II. This gene is located on the long arm of chromosome 11 (11q13), and encodes the synthesis of seipina protein whose function is unknown. Within cells, seipina is located in the membrane of the endoplasmic reticulum. The BSCL2 gene is active in all cells, particularly in motor neurons and in brain cells. The gene is also present in adipocytes, and suggests that the protein seipina can play a critical role in the early development of these cells. The protein encoded from BSCL2 gene is also present in the brain and testis, although its function in these tissues is unknown. A loss of this protein in the brain may explain why many people with Berardinelli-Seip congenital type II syndrome have intellectual disabilities. They have been described at least 24 BSCL2 gene mutations as responsible for the type II congenital lipodystrophy. Most genetic changes result in the synthesis of a nonfunctional seipina that causes abnormal development of adipocytes.

Mutations in the gene CAV1, located on the long arm of chromosome 7 (7q31.1), are responsible for lipodystrophy Berardinelli-Seip type of III. This gene encodes caveolin-1 protein, which appears to have several functions in tissues throughout the body cells. Caveolin-1 is the major component of caveolae. Caveolae are involved in endocytosis, the processing of the molecules inside the cell, maintenance of cell structure, and in the regulation of chemical signaling pathways. Caveolae are particularly numerous in adipocytes, where it seems to be essential for proper transportation, processing and storage of fat. Caveolin-1 is also found in many other parts of the cells, where it regulates various routes of chemical signaling. Through these pathways, caveolin-1 is involved in growth regulation and cell proliferation, cell movement, cell differentiation, cell survival and apoptosis. The functions of caveolin-1 are likely to differ depending on the cell type and the part of the cell where the protein. Has identified at least one mutation in the CAV1 gene replacing an amino acid with a premature stop signal at the position 38 of the protein caveolin-1 (Glu38Ter or E38X.) This mutation inhibits the synthesis of any caveolin-1 functional. Although it is unclear how the absence of this protein leads to the particular characteristics of congenital lipodystrophy type III, its absence is likely alters the normal development and function of adipocytes.

Mutations in the gene PTRF, located on the long arm of chromosome 17 (17q21.2), are responsible for lipodystrophy Berardinelli-Seip type of IV. This gene encodes Cavina-1 protein, which is found in cells and tissues throughout the body, although it is more abundant in several cell types: osteoblasts, muscle cells and adipocytes. It is believed that Cavina-1 plays, like caveolin-1 (encoded by CAV1), an essential role in the formation and stabilization of caveolae. Furthermore, studies suggest that this protein is involved in repairing damage to the outer cell membrane, the cell growth and division, cell movement, cell senescence and regulation of several chemical signaling pathways. Functions Cavina-1 probably differ depending on the cell type and the part of the cell where the protein. They have identified at least ten mutations in the gene PTRF in individuals with type IV disease. These mutations inhibit any coding Cavina-1 functional, probably disrupts the formation of caveolae. Deficiency of these structures in the cell membrane alters many cellular functions. However, it not specifically knows how the absence of Cavina-1 results in a loss of body fat and other associated health problems.

This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with congenital lipodystrophy Berardinelli-Seip of, by complete PCR amplification of the exons of AGPAT2, BSCL2, CAV1 and PTRF, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).