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Congenital Generalized Lipodystrophy

What is Congenital Generalized Lipodystrophy?

Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare hereditary disorder that is characterized by a near total lack of body fat, known as adipose tissue, from birth or infancy. It belongs to a group of disorders called lipodystrophies, which are characterized by varying degrees of lack of fatty tissue and other symptoms. There are four main types of lipodystrophies; CGL is one of them. The lack of body fat means that fats must be stored in other areas of the body such as in the liver and muscles, which can lead to medical problems. Such problems can include metabolic issues, such as the inability to break down certain sugars (glucose intolerance), elevated levels of fats in the blood, and diabetes. The heart and liver can also be affected. There are several types of CGL, each caused by a mutation in a different gene.

 

Synonyms

  • Congenital Generalized Lipodystrophy
  • Congenital lipoatrophic diabetes
  • Berardinelli-Seip syndrome
  • Berardinell Seip congenital lipodystrophy

Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare hereditary disorder that is characterized by a near total lack of body fat, known as adipose tissue, from birth or infancy. It belongs to a group of disorders called lipodystrophies, which are characterized by varying degrees of lack of fatty tissue and other symptoms. There are four main types of lipodystrophies; CGL is one of them. The lack of body fat means that fats must be stored in other areas of the body such as in the liver and muscles, which can lead to medical problems. Such problems can include metabolic issues, such as the inability to break down certain sugars (glucose intolerance), elevated levels of fats in the blood, and diabetes. The heart and liver can also be affected. There are several types of CGL, each caused by a mutation in a different gene.

Acknowledgement of Congenital Generalized Lipodystrophy has not been added yet.

CGL is very rare and only around 300 individuals have been reported in medical literature. It is estimated that the worldwide prevalence is 1 in 10 million individuals. These numbers are not definitive because congenital generalized lipodystrophy can be underdiagnosed.

Name Abbreviation
Congenital Generalized Lipodystrophy CGL
Congenital lipoatrophic diabetes CGL
Berardinelli-Seip syndrome CGL
Berardinell Seip congenital lipodystrophy BSCL

Congenital generalized lipodystrophy is caused by mutations of specific genes. Four different genes are known to cause CGL. CGL type 1 is caused by mutations in the AGPAT2 gene, the BSCL2 gene in type 2, the CAV1 gene in type 3, and the PTRF gene in type 4. Some individuals do not have a mutation in any of these four genes, which suggests that additional undiscovered genes can cause CGL.  

Congenital generalized lipodystrophy is an autosomal recessive disorder. Both parents must have a mutation in at least one of two genes associated with CGL. The disorder can only be present if an individual has two copies of the mutation in the specific gene. This means that both parents are “carriers” of the gene. Some children are born with CGL and some can be a carrier. Some children will not have the disease and will not be a carrier.

The symptoms of CGL can be seen at birth or infancy.  Common features include insulin resistance, where the body is unable to recognize insulin, a hormone that helps to regulate blood sugar levels. Insulin resistance results in metabolic complications that can include the development of glucose intolerance, high levels of fats (triglycerides) in the bloodstream, and diabetes. These symptoms often develop anytime from childhood through adolescence and can be very difficult to control. Some individuals can experience episodes of pancreatitis (inflammation of the pancreas).

CGL can cause excessive accumulation of fat in the liver, heart, and other organs, which can cause a number of diseases.  In many cases, the liver can be double the normal size due to the accumulation of fat (fatty liver). This often causes an enlarged abdomen. Some individuals can eventually develop scarring and damage to the liver (cirrhosis). Eventually, liver failure can occur. Fat storage in the heart can lead to hypertrophic cardiomyopathy, a condition in which the heart muscle becomes abnormally thickened, which affects its ability to pump blood through the body.

There are distinctive physical features to this disorder. Individuals with CGL have a near total absence of body fat at birth and can have a very muscular appearance. Muscles can appear abnormally large (muscular hypertrophy). Affected children can also have a greatly increased appetite (severe hyperphagia). Some children have abnormally large hands, feet, and jaw. Umbilical hernia is also common.  

Many individuals develop acanthosis nigricans, a skin condition related to high amounts of insulin in the blood. This causes the skin, particularly in skin fold regions such as the neck, groin, and underarms, to become thick, dark and velvety.  

Intellectual disability can occur in some instances, particularly in individuals with a mutation in the BSCL2 gene (type 2). It is not a common finding in CGL caused by other mutations. Intellectual disability is usually mild to moderate.

After reaching puberty, some women may develop polycystic ovary syndrome. Additional symptoms have been reported to occur in association with CGL including mild intellectual disability, heart arrhythmias, muscle disease (myopathy), and bone cysts resulting in a predisposition to bone fractures. Some symptoms are more likely to only occur with a specific subtype of CGL. For example, mild intellectual disability has only been reported in CGL type 2.

CGL is diagnosed based on physical appearances, a detailed patient history, and a thorough clinical evaluation. At birth or within the first few years of life, it is easy to distinguish the muscular appearance, absence of body fat, and enlarged abdomen, which are the main symptoms of CGL.

Aside from recognition of physical appearance, there are a variety of tests that aid in the diagnosis. A blood chemical profile can be conducted to assess the levels of glucose, fats and other substances. The characteristic absence of adipose tissues can be found on magnetic resonance imaging (MRI) scans. Scans of the liver can also be used to diagnose the disease.  

Molecular genetic testing can confirm a diagnosis of CGL as it detects mutations in the specific genes that cause the disorder.

Congenital generalized lipodystrophy currently does not have a cure and the characteristic loss of adipose tissue is irreversible. The treatment is directed towards the specific symptoms that occur in each individual. People with CGL are encouraged to follow a high-carbohydrate and low-fat diet due to their limited ability to store fat. Regular exercise and maintaining a healthy weight are also recommended to decrease the chances of developing diabetes.

CGL is associated with leptin deficiency.  Leptin is a hormone found in fat cells (adipocytes).  Treatment of leptin injections has been found to greatly improve metabolic complications.  In 2014, the Food and Drug Administration approved the use of metreleptin, in addition to diet, for the treatment of the complications of leptin deficiency in individuals with CGL. Leptin is a hormone that helps to regulate food intake and specific hormones including insulin. Leptin is made by fat tissue and because individuals with CGL lack adipose tissue, they are deficient in leptin.

One option of treatment that is considered by some patients is cosmetic surgery. This can be used to treat the physical effects of the disorder, particularly in the face.

Additional treatment is based on the specific symptoms present in each individuals and will often follow existing standard guidelines.

The prognosis for CGL varies depending on the subtype and specific symptoms present. Most cases of CGL are quite severe and few patients are able to live normally without treatment. The life expectancy of individuals who are untreated tends to be around 20-30 years old.  With treatment, individuals can live relatively normal lives, although the lack of body fat can make strenuous activities more difficult to accomplish.

There is very little research on best practices to live with congenital generalized lipodystrophy as there are very few cases and little natural history of the disorder.

Nonetheless there are a few actions that can be taken. Individuals with CGL should monitor their diets as their large appetites may lead to overeating. Individuals should have four regular meals a day and avoid large meals due to their limited ability to store energy as fat.  

Families of people living with this condition are encouraged to look for counseling due to the psychological stress the diagnosis can cause. Support groups are strongly recommended for affected people and their families. For both children and adults, physical appearances can be very impactful to social image. Working with schools and counseling is recommended to deal with these issues. Genetic counseling will benefit affected individuals and families.

Berardinelli-Seip Congenital Lipodystrophy. Genetic Home Reference website. http://ghr.nlm.nih.gov/condition/berardinelli-seip-congenital-lipodystrophy.

Capeau J, Magre J, Caron-Debarle M, et al. Human lipodystrophies: genetic and acquired diseases of adipose tissue. Endocr Dev. 2010;19:1-20.

Congenital Generalized Lipodystrophy. National Organization for Rare Disorders website. http://rarediseases.org/rare-diseases/congenital-generalized-lipodystrophy/

Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96(11):3313-3325.

Lipodystrophy, Congenital Generalized, Type 1. Online Mendelian Inheritance in Man (OMIM) website. http://www.omim.org/entry/608594

Lipodystrophy, Congenital Generalized, Type 2. Online Mendelian Inheritance in Man (OMIM) website. www.omim.org/entry/269700

Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert Rev Clin Pharmacol. 2015;14:1-10.

Patni N, Garg A. Congenital generalized lipodystrophies – new insights into metabolic dysfunction. Nat Rev Endocrino. 2015;11(9)522-534.

van Maldergem L. Berardinelli-Seip Congenital Lipodystrophy. GeneReviews website. http://www.ncbi.nlm.nih.gov/books/NBK1212/.


van Maldergem L. Berardinelli-Seip Congenital Lipodystrophy. Orphanet website. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=528.

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