Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare genetic disorder characterized by the near total loss of body fat (adipose tissue) and extreme muscularity that is often present at birth or soon thereafter. CGL is associated with metabolic complications related to insulin resistance such as an inability to break down (metabolize) glucose (glucose intolerance), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), and diabetes. Diabetes associated with CGL is often very difficult to treat. Additional complications such as those affecting the liver and heart can also occur. The symptoms and severity of CGL can vary greatly from one person to another. There are four different subtypes of CGL each caused by mutations in different gene. All of the known types of CGL are inherited as autosomal recessive conditions.Introduction
Lipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to CGL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are not inherited, but acquired at some point during life (acquired lipodystrophy). The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. CGL was first described in the medical literature by Dr. Berardinelli in 1954 and reviewed by Dr. Seip in 1959.
Infants with all forms of CGL have a near total absence of body fat at birth or soon thereafter. They also have an extremely muscular appearance and may display prominent superficial veins. During early childhood, most children grow at an accelerated rate and have slightly enlarged hands, feet, and jaws (acromegaloid features). Infants and children have a markedly increased appetite and have been described as voracious eaters.
In individuals with CGL, fat deposits build up in areas of the body such as the muscles and liver. Consequently, affected individuals may develop abnormal enlargement of the muscles (muscular hypertrophy) or the liver (hepatomegaly). Some individuals may also have an abnormally enlarged spleen (splenomegaly). Hepatomegaly is often noticed during infancy. Fat accumulation in the liver (known as fatty liver or hepatic steatosis) may eventually cause scarring and damage to the liver (cirrhosis) and liver dysfunction. Ultimately, liver failure may develop in some patient, necessitating a liver transplant.
Individuals with CGL develop metabolic complications associated with insulin resistance. Some infants have a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Other complications of insulin resistance may occur at a young age (often between 15-20 years of age) including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Some individuals may experience extreme hypertriglyceridemia and chylomicronemia a condition characterized by the accumulation of chylomicrons (lipoprotein particles carrying fat) in the plasma. In some cases, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.
Intellectual disability can occur in CGL, especially in cases caused by mutations of the BSCL2 gene (CGL type 2). However, the presence and/or severity of intellectual disability can vary dramatically from one person to another, even among members of the same family. Most cases have been associated with mild or moderate intellectual disability. Intellectual disability is not common in other forms of CGL.
After puberty, some women with CGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of female sex hormones. Affected women may also have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, multiple cysts on the ovaries, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. Most women with CGL are unable to conceive. However, in a few reported cases, affected women have had successful pregnancies. Affected men usually have normal reproductive capabilities. Recently, morphological defects in sperms were reported in a 20-year-old male with CGL, type 2.
Heart irregularities may occur in some cases, especially abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy). This condition can obstruct the flow of blood in and out of the heart. Some individuals may have no associated symptoms; others may develop shortness of breath upon exertion, fatigue, and excessive sweating. As affected individuals age, they may experience chest pain or discomfort, irregular heartbeats, dizziness or fainting usually upon heavy exertion, and, eventually, life-threatening complications such as congestive heart failure. Hypertrophic cardiomyopathy is most common is individuals with CGL types 2 and 4. It often develops in individuals around the age of 30, but has been reported in infants as well.
Additional findings have been reported in individuals with CGL including excessive sweating (hyperhidrosis). Some findings are more likely to be associated with a specific subtype of CGL such as the formation of bone cysts after puberty (more common in types 1 and 2), which can cause individuals to be prone to spontaneous fractures; bone marrow fat loss (more common in types 1and 2); and problems with vitamin D, reported in a patient with CGL type 3. Muscular dystrophy, a general term for disorders that cause muscle weakness and loss of muscle tissue, and pyloric stenosis (constriction of the opening of stomach into duodenum) is seen in individuals with CGL type 4. Irregular heartbeats (cardiac arrhythmias) and sudden death have also been associated with CGL type 4.
Individuals with CGL type 1 lack metabolically active fat, which is the fat plays a role in the storage and release of energy and is located in subcutaneous regions, intermuscular regions, the bone marrow and areas with the abdomen and chest (thoracic cavity), but mechanical fat is well preserved. Mechanical fat is the fat that supports and protects regions subjected to mechanical insults and is located in the palms, soles, eye sockets (orbits), scalp, and around the joints. Individuals with CGL type 2 are prone to having a more severe form of lipodystrophy because they also experience the loss of mechanical fat.
CGL is caused by mutations of specific genes. Four genes that cause CGL have been identified including the AGPAT2 gene, which causes CGL type 1; the BSCL2 gene, which causes CGL type 2; the CAV1 gene, which causes CGL type 3; and the PTRF gene, which causes CGL type 4. Some individuals with CGL do not have a mutation in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.
CGL is inherited as an autosomal recessive condition. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the AGPAT2 gene is located on the long arm (q) of chromosome 9 (9q34). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q34” refers to band 34 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The AGPAT2 gene contains instructions for creating (encoding) the enzyme AGPAT2, which is involved in the creation (synthesis) of triglycerides and fatty substances called phospholipids.
The BSCL2 gene is located on the long arm of chromosome 11(11q12.3). This gene encodes a protein known as seipin. Recent data suggest a role of seipin in fusion of lipid droplets and in fat cell differentiation.
The CAV1 gene is located on the long arm of chromosome 7 (7q31). This gene encodes caveolin-1, which is expressed in caveolae, tiny structures on the surface of cells. Caveolae play a role in the formation of lipid droplets, most likely by transporting lipids and phospholipids from outside the cell to inside the cell. Lipid droplets are organelles, specialized subunits found within cells that have specific functions. One function of lipid droplets is the storage of lipids.
The PTRF gene is located on the chromosome 17 (17q21.2). This gene encodes cavin, an essential protein factor in the creation (biogenesis) of caveolae.
Researchers believe that various genes and gene products associated with CGL are involved with the proper creation, function, and/or health of lipid droplets within adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Mutations in the above mentioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissue of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with CGL such as cardiomyopathy is unknown. More research is necessary to understand the exact, underlying mechanisms that ultimately cause CGL and its associated symptoms.
Approximately 300 cases of CGL have been reported in the medical literature. The estimated worldwide prevalence is approximately 1 in 10 million individuals in the general population. The disorder has been reported in individuals of every ethnic group.
A diagnosis of CGL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A lipodystrophy diagnosis should be suspected in individuals who are lean or “non-obese” and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.
Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid.
The characteristic pattern of fat loss in CGL can be noted on magnetic resonance imaging (MRI). Radiographs can show the presence of lytic bones lesions that occur in some individuals with CGL.
Molecular genetic testing can confirm a diagnosis of CGL in most cases. Molecular genetic testing can detect mutations in specific genes that cause CGL and is available on a clinical basis or in some research laboratories.
Individuals with CGL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin. Although not a diagnostic test, determining leptin levels may help physicians predict a person’s response to leptin replacement therapy.
The treatment of CGL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Individuals with CGL and their families are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.
Despite the lack of clinical trial evaluation, individuals with CGL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. However, such diets may also raise very low density lipoprotein triglyceride concentration. It is important that children still consume sufficient energy for proper growth and development. Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes.
Leptin is a hormone found in adipocytes. Severe lipodystrophy is sometimes associated with leptin deficiency. On Feb. 24, 2014, the U.S. Food and Drug Administration approved Myalept (metreleptin for injection) as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. Myalept is a recombinant analogue (laboratory-created form) of human leptin and is taken once a day by subcutaneous (under the skin) injection. It has been found to be beneficial for improving metabolic complications, such as diabetes and hypertriglyceridemia. The most common side effects are low blood sugar (hypoglycemia), headache, decreased weight, and abdominal pain. Other side effects can be local reactions at injection site, possibility of developing leptin antibodies (which could result in severe infections or loss of treatment effectiveness) and rare cases of T- cell lymphoma. It is contraindicated in patients with general obesity not associated with congenital leptin deficiency and with prior severe hypersensitivity reactions to metreleptin or any of the product components. Myalept is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) which requires prescriber and pharmacy certification and special documentation. Detailed information about the medication for providers and patients can be found at http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm388903.pdf.
Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.
The characteristic loss of adipose tissue in individuals with CGL cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance. Individuals with severe facial lipodystrophy can undergo reconstructive facial surgery including fascial grafts from the thighs, free flaps from the anterolateral thigh, anterior abdomen, or temporalis muscle.
In some cases, liver disease can ultimately require a liver transplantation.
Additional therapies to treat individuals with CGL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with CGL and diabetes, although extremely high doses are often required. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications associated with CGL.
Special remedial education may be necessary for individuals with intellectual disability. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about acquired congenital generalized lipodystrophy:
Abhimanyu Garg, M.D.
Professor of Internal Medicine,
Chief, Division of Nutrition and Metabolic Diseases,
Distinguished Chair in Human Nutrition Research
UT Southwestern Medical Center at Dallas
5323 Harry Hines Boulevard, K5.214
Dallas, TX 75390-8537
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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