Congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) is a rare condition characterized by an almost total lack of fatty (adipose) tissue in the body and a very muscular appearance. Adipose tissue is found in many parts of the body, including beneath the skin and surrounding the internal organs. It stores fat for energy and also provides cushioning. Congenital generalized lipodystrophy is part of a group of related disorders known as lipodystrophies, which are all characterized by a loss of adipose tissue. A shortage of adipose tissue leads to the storage of fat elsewhere in the body, such as in the liver and muscles, which causes serious health problems.

The signs and symptoms of congenital generalized lipodystrophy are usually apparent from birth or early childhood. One of the most common features is insulin resistance, a condition in which the body's tissues are unable to recognize insulin, a hormone that normally helps to regulate levels of blood glucose, also called blood sugar. Insulin resistance may develop into a more serious disease called diabetes mellitus. Most affected individuals also have high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia), which can lead to the development of small yellow deposits of fat under the skin called eruptive xanthomas and inflammation of the pancreas (pancreatitis). Additionally, congenital generalized lipodystrophy causes an abnormal buildup of fats in the liver (hepatic steatosis), which can result in an enlarged liver (hepatomegaly) and liver failure. Some affected individuals develop a form of heart disease called hypertrophic cardiomyopathy, which can lead to heart failure and an abnormal heart rhythm (arrhythmia) that can cause sudden death.

People with congenital generalized lipodystrophy have a distinctive physical appearance. They appear very muscular because they have an almost complete absence of adipose tissue and an overgrowth of muscle tissue. A lack of adipose tissue under the skin also makes the veins appear prominent. Affected individuals tend to have prominent bones above the eyes (orbital ridges), large hands and feet, and a prominent belly button (umbilicus). Affected females may have an enlarged clitoris (clitoromegaly), an increased amount of body hair (hirsutism), irregular menstrual periods, and multiple cysts on the ovaries, which may be related to hormonal changes. Many people with this disorder develop acanthosis nigricans, a skin condition related to high levels of insulin in the bloodstream. Acanthosis nigricans causes the skin in body folds and creases to become thick, dark, and velvety.

Researchers have described four types of congenital generalized lipodystrophy, which are distinguished by their genetic cause. 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 generalized lipodystrophy type 1 develop cysts in the long bones of the arms and legs after puberty. Type 2 can be associated with intellectual disability, which is usually mild to moderate. Type 3 appears to cause poor growth and short stature, along with other health problems. Type 4 is associated with muscle weakness, delayed development, joint abnormalities, a narrowing of the lower part of the stomach (pyloric stenosis), and severe arrhythmia that can lead to sudden death.

Mutations in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes cause congenital generalized lipodystrophy types 1 through 4, respectively. The proteins produced from these genes play important roles in the development and function of adipocytes, which are the fat-storing cells in adipose tissue. Mutations in any of these genes reduce or eliminate the function of their respective proteins, which impairs the development, structure, or function of adipocytes and makes the body unable to store and use fats properly. These abnormalities of adipose tissue disrupt hormones and affect many of the body's organs, resulting in the varied signs and symptoms of congenital generalized lipodystrophy.

Some of the genes associated with congenital generalized lipodystrophy also play roles in other cells and tissues. For example, the protein produced from the BSCL2 gene is also present in the brain, although its function is unknown. A loss of this protein in the brain may help explain why congenital generalized lipodystrophy type 2 is sometimes associated with intellectual disability.

In some people with congenital generalized lipodystrophy, no mutations have been found in any of the genes listed above. Researchers are looking for additional genetic changes associated with this disorder.

Normal Function

The AGPAT2 gene provides instructions for making an enzyme that is found in many of the body's cells and tissues. It plays a critical role in the growth and development of adipocytes, which are cells that store fats for energy. Adipocytes are the major component of the body's fatty (adipose) tissue.

The AGPAT2 enzyme is part of a chemical pathway in many cells that produces two important types of fats (lipids): glycerophospholipids and triacylglycerols. Glycerophospholipids are the major component of cell membranes and are involved in chemical signaling within cells. Triacylglycerols (also known as triglycerides) are fat molecules that are stored in adipocytes for later conversion to energy.

The AGPAT2 enzyme is responsible for a particular chemical reaction in the production of these two types of lipids. Specifically, the enzyme helps convert a molecule called lysophosphatidic acid (LPA) to another molecule, phosphatidic acid (PA). Additional reactions convert phosphatidic acid to glycerophospholipids and triacylglycerols.

Health Conditions Related to Genetic Changes

Congenital generalized lipodystrophy

At least 26 mutations in the AGPAT2 gene have been identified in people with congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 1. This rare condition is characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus.

The AGPAT2 gene mutations that cause congenital generalized lipodystrophy type 1 greatly reduce or eliminate the activity of the AGPAT2 enzyme. Studies suggest that a loss of this enzyme's activity reduces the production and storage of triacylglycerols in adipocytes, which prevents these cells from storing fats. A lack of enzyme activity may also reduce the levels of glycerophospholipids in adipocytes, which changes the structure of the cell membrane and disrupts normal signaling within these cells. All of these abnormalities prevent the body from storing fats normally in adipose tissue. The resulting lack of body fat underlies the varied signs and symptoms of congenital generalized lipodystrophy type 1.

Other Names for This Gene

• 1-acyl-sn-glycerol-3-phosphate acyltransferase beta
• 1-acylglycerol-3-phosphate O-acyltransferase 2 (lysophosphatidic acid acyltransferase, beta)
• 1-AGP acyltransferase 2
• 1-AGPAT2
• BSCL1
• LPAAB
• LPAAT-beta
• lysophosphatidic acid acyltransferase-beta
• PLCB_HUMAN

Genomic Location

Normal Function

The BSCL2 gene provides instructions for making a protein called seipin, whose function is unknown. Within cells, seipin is located in the membrane of a structure called the endoplasmic reticulum. The endoplasmic reticulum modifies newly produced proteins and also helps transport proteins, fats, and other molecules to specific sites either inside or outside the cell.

The BSCL2 gene is active in cells and tissues throughout the body, particularly in nerve cells that control muscle movement (motor neurons) and in the brain. The gene is also active in fat-storing cells called adipocytes, which are the major component of fatty (adipose) tissue. Studies suggest that seipin plays a critical role in the development and function of adipocytes. In particular, seipin is involved in the development of lipid droplets, which are structures within these cells that store fat molecules.

Health Conditions Related to Genetic Changes

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Congenital generalized lipodystrophy

At least 25 mutations in the BSCL2 gene have been identified in people with congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 2. This rare condition is characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. In some cases, this form of the condition is also associated with intellectual disability, which is usually mild to moderate.

Most of the BSCL2 gene mutations that cause congenital generalized lipodystrophy type 2 lead to the production of a nonfunctional version of the seipin protein or prevent cells from making any of this protein. A loss of functional seipin disrupts the normal development and function of adipocytes, including lipid droplets, which prevents fats from being stored normally in adipose tissue. The resulting lack of body fat underlies most of the signs and symptoms of congenital generalized lipodystrophy type 2. A loss of seipin function in the brain may help explain why intellectual disability can occur with this form of the condition.

Distal hereditary motor neuropathy, type V

At least two BSCL2 gene mutations have been identified in people with distal hereditary motor neuropathy, type V, a progressive disorder that affects motor neurons in the spinal cord. It results in muscle weakness and affects movement of the hands and feet. The mutations that can cause this disorder each change a single protein building block (amino acid) in the seipin protein. In one mutation, the amino acid serine is replaced with the amino leucine at position 90 (written as Ser90Leu or S90L). In another, the amino acid asparagine is replaced with the amino acid serine at protein position 88 (written as Asn88Ser or N88S).

It is unclear how BSCL2 gene mutations cause distal hereditary motor neuropathy, type V. These genetic changes probably alter the structure of seipin, causing it to fold into an incorrect 3-dimensional shape. Research findings indicate that misfolded seipin proteins build up in the endoplasmic reticulum. This accumulation likely damages and kills motor neurons, which leads to muscle weakness.

Silver syndrome

At least two mutations in the BSCL2 gene, the N88S and S90L mutations described above, have been reported to cause Silver syndrome. This condition is characterized by muscle weakness and wasting in the hands and abnormal muscle stiffness (spasticity) in the legs. The mutations likely result in misfolded seipin proteins that accumulate within neurons, leading to cell damage and cell death. The loss of neurons causes muscle weakness and spasticity in people with Silver syndrome.

It is unclear how the same mutations in the BSCL2 gene can cause Silver syndrome; distal hereditary motor neuropathy, type V; or another disorder called Charcot-Marie-Tooth disease in different people. People with Silver syndrome sometimes have family members with the same BSCL2 gene mutation who have one of these other conditions.

Other Names for This Gene

• Berardinelli-Seip congenital lipodystrophy 2 (seipin)
• BSCL2_HUMAN
• GNG3LG
• seipin
• SPG17

Genomic Location

Normal Function

The CAV1 gene provides instructions for making a protein called caveolin-1. This protein appears to have diverse functions in cells and tissues throughout the body.

Caveolin-1 is the major component of caveolae, which are small pouches in the membrane that surrounds cells. Caveolae have multiple functions, some of which are not well understood. They are known to be involved in the transport of molecules from the cell membrane to the interior of the cell (endocytosis), processing of molecules on their way into the cell, maintaining the cell structure, and regulating chemical signaling pathways. Studies suggest that caveolae are particularly numerous in adipocytes, which are cells that store fats for energy. Adipocytes make up most of the body's fatty (adipose) tissue. In these cells, caveolae appear to be essential for the normal transport, processing, and storage of fats.

Caveolin-1 is also found in many other parts of cells, where it regulates various chemical signaling pathways. Through these pathways, caveolin-1 is involved in regulating cell growth and division (proliferation), the process by which cells mature to perform specific functions (differentiation), cell survival and the self-destruction of cells (apoptosis), and cell movement. The functions of caveolin-1 likely differ depending on the type of cell and the part of the cell where the protein is found.

Health Conditions Related to Genetic Changes

Congenital generalized lipodystrophy

At least one mutation in the CAV1 gene has been found to cause congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 3. This rare condition is characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. Additional features of congenital generalized lipodystrophy type 3 include poor growth and short stature.

The identified mutation replaces a single protein building block (amino acid) with a premature stop signal at position 38 of the caveolin-1 protein (written as Glu38Ter or E38X.) This mutation occurs in both copies of the CAV1 gene in each cell, and it prevents cells from producing any functional caveolin-1. It is unclear how a lack of this protein leads to the particular features of congenital generalized lipodystrophy type 3. However, the absence of caveolin-1 likely disrupts the normal development and function of adipocytes, which would prevent fats from being stored normally in adipose tissue. A lack of body fat underlies many of the signs and symptoms of this condition.

Pulmonary arterial hypertension

MedlinePlus Genetics provides information about Pulmonary arterial hypertension

Other disorders

In addition to congenital generalized lipodystrophy (described above), mutations in the CAV1 gene have been found to cause several other forms of lipodystrophy, which all involve a loss of adipose tissue. At least two mutations have been identified in people with atypical partial lipodystrophy, a condition characterized by the loss of fat under the skin of the face and upper body. Affected individuals also have hypertriglyceridemia and clouding of the lens of the eyes starting at birth (congenital cataracts). The CAV1 gene mutations that cause this condition are present in one copy of the gene in each cell. They reduce the amount of caveolin-1 that is produced within cells.

Two other mutations in the CAV1 gene have been found to cause neonatal-onset generalized lipodystrophy syndrome. The signs and symptoms of this condition include an overall loss of body fat except in the buttocks and on the palms of the hands and soles of the feet. Additional features include thin skin with visible blood vessels; a large, triangular head; and slow weight gain in childhood. The CAV1 gene mutations that cause this condition also occur in one copy of the gene in each cell and reduce the amount of caveolin-1 produced in cells.

Because CAV1 gene mutations can cause several different forms of lipodystrophy, it is clear that it plays an essential role in the development of adipose tissue. However, researchers are still working to determine how a shortage of caveolin-1 results in a loss of body fat and the associated features of these conditions.

Other Names for This Gene

• BSCL3
• CAV
• caveolin 1, caveolae protein, 22kDa
• caveolin-1 isoform alpha
• caveolin-1 isoform beta
• cell growth-inhibiting protein 32
• CGL3
• LCCNS
• MSTP085
• PPH3
• VIP21

Genomic Location

Normal Function

The CAVIN1 gene provides instructions for making a protein called cavin-1. This protein is found in cells and tissues throughout the body. It is most abundant in several types of cells: osteoblasts, which are cells that build bones; muscle cells; and adipocytes, which are cells that store fats for energy. Adipocytes make up most of the body's fatty (adipose) tissue.

Studies suggest that cavin-1 plays an essential role in forming and stabilizing caveolae, which are small pouches in the membrane that surrounds cells. Caveolae have multiple functions, some of which are not well understood. They are known to be involved in the transport of molecules from the cell membrane to the interior of the cell (endocytosis), processing of molecules on their way into the cell, maintaining the cell structure, and regulating chemical signaling pathways. Caveolae are particularly numerous in adipocytes, where they appear to be essential for the normal transport, processing, and storage of fats.

Within cells, cavin-1 is also found in the nucleus and in the fluid that surrounds the nucleus (the cytoplasm). In addition to its role in caveolae, studies suggest that this protein is involved in repairing damage to the outer cell membrane, cell growth and division (proliferation), cell movement, stopping cell division in older cells (senescence), and regulating various chemical signaling pathways. The functions of cavin-1 likely differ depending on the type of cell and the part of the cell where the protein is found.

Health Conditions Related to Genetic Changes

Congenital generalized lipodystrophy

More than 10 mutations in the CAVIN1 gene have been found to cause congenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 4. This rare condition is characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. Additional features of congenital generalized lipodystrophy type 4 include muscle weakness, delayed development, joint abnormalities, a narrowing of the lower part of the stomach (pyloric stenosis), and severe abnormalities of the heart rhythm (arrhythmias) that can lead to sudden death.

All of the identified CAVIN1 gene mutations prevent cells from producing any functional cavin-1. A lack of this protein probably impairs the formation of caveolae. Researchers suspect that a shortage of these important structures on the cell membrane disrupts many cell functions. However, it is unknown specifically how the absence of cavin-1 leads to a loss of body fat and the other health problems associated with congenital generalized lipodystrophy type 4.

Other Names for This Gene

• CAVIN
• cavin-1
• CGL4
• FKSG13
• polymerase I and transcript release factor
• PTRF
• RNA polymerase I and transcript release factor
• TTF-I interacting peptide 12

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Congenital generalized lipodystrophy has an estimated prevalence of 1 in 10 million people worldwide. Between 300 and 500 people with the condition have been described in the medical literature. Although this condition has been reported in populations around the world, it appears to be more common in certain regions of Lebanon and Brazil.