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. It has been reported in various ethnic groups, but higher frequencies have been observed in certain regions of Lebanon, Brazil and Norway, possibly due to consanguinity (marriages between close relatives).

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

CGL is caused by mutations in specific genes that play a role in the development and function of adipose tissue. There are four main subtypes, each associated with mutations in different genes:

1. CGL1 - Caused by mutations in the AGPAT2 gene, involved in the biosynthesis of fat components called triglycerides and phospholipids.

2. CGL2 - Due to mutations in the BSCL2 gene, which encodes the protein seipin, essential for normal adipocyte (fat cell) differentiation.

3. CGL3 - Linked to mutations in the CAV1 gene, which codes for caveolin-1, involved in lipid droplet formation.

4. CGL4 - Caused by mutations in the PTRF gene, responsible for caveolae formation in adipocytes.

These genes play crucial roles in fat storage, lipid biosynthesis, fat cell differentiation and formation of lipid droplets. The condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of the mutated gene, one from each parent, to develop the disorder (see RareShare Guide on Genetic Inheritance). Some individuals do not have a mutation in any of these four genes, which suggests that additional undiscovered genes can cause CGL.  

Common symptoms of CGL include:

• Near-absence of subcutaneous fat: Visible from birth, resulting in muscular appearance and prominent veins.

• Insulin resistance: Leading to early-onset diabetes mellitus, typically during childhood.

• Hypertriglyceridemia: Elevated triglyceride levels can result in pancreatitis.

• Hepatomegaly: Due to fatty liver infiltration (hepatic steatosis).

• Acanthosis nigricans: Dark, velvety skin patches, usually in body folds.

• Increased appetite: Often seen in children due to the body's inability to store fat for energy.

• Enlarged organs: Including the liver, spleen, heart (cardiomegaly), and kidneys.

• Cognitive impairment:  In some cases associated with BSCL2 gene mutations.

Other abnormalities: Women may have enlarged genitalia (clitoromegaly), irregular menstrual periods and polycystic ovaries; men may show early-onset puberty.

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 diagnosis is based on clinical findings, family history, and genetic testing:

• Physical examination, including assessment of characteristic physical features and absence of subcutaneous fat.

• Blood tests for glucose, insulin, lipid profile, high triglyceride levels, low leptin levels and liver function.

• Imaging studies (MRI, DEXA) to assess body fat distribution.

Genetic testing to identify mutations in one of the genes associated with the disorder (AGPAT2, BSCL2, CAV1 or PTRF). Genetic testing confirms the subtype of CGL.

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.

There is no cure for CGL, so treatment focuses on managing symptoms and preventing complications:

1. Dietary management:

   • Low-fat, high-complex carbohydrate diet

   • Supplementation with essential fatty acids

2. Diabetes management:

   • Insulin therapy

   • Metformin and other insulin-sensitizing agents

3. Lipid-lowering medications:

   • Fibrates for hypertriglyceridemia

   • Statins for elevated LDL cholesterol

4. Leptin replacement therapy:

   • Metreleptin (recombinant human leptin) to improve metabolic abnormalities

5. Management of complications:

   • Regular cardiac evaluations and treatment of cardiomyopathy

   • Monitoring and management of hepatic steatosis

6. Cosmetic interventions:

   • Autologous fat transfer or synthetic fillers for facial fat loss (in adulthood)

7. Supportive care:

   • Physical therapy and exercise programs

   • Psychological support and counseling

The characteristic loss of adipose tissue in GCL is irreversible. 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, severity of metabolic complications and the effectiveness of treatment. 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. Life expectancy may be reduced due to complications such as:

• Cardiovascular disease

• Liver cirrhosis

• Acute pancreatitis

• Kidney disease

Early diagnosis and aggressive management of metabolic abnormalities are crucial for improving long-term outcomes. The introduction of leptin replacement therapy has significantly improved the metabolic control and quality of life for many patients with CGL.

 

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.

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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. 

Magre, J., et al. (2001). "Identification of the gene altered in congenital generalized lipodystrophy on chromosome 11q13." Nature Genetics, 28(4), 365-370.

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

Patni, N., & Garg, A. (2015). Congenital generalized lipodystrophies--new insights into metabolic dysfunction. Nature Reviews Endocrinology, 11(9), 522-534. ​​​​​​​

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

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