Congenital Generalised Lipodystrophy
Congenital generalised lipodystrophy is a rare inherited condition where a child is born with almost no body fat. This severe lack of fat tissue causes the body to store fat in places it shouldn’t, leading to serious health problems including diabetes, liver disease, and heart complications.
Berardinelli-Seip congenital lipodystrophy, Berardinelli-Seip syndrome, BSCL, CGL
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LD27.60
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10053547
Table of contents
- What is congenital generalised lipodystrophy?
- How common is this condition?
- Signs and symptoms
- Four types of the condition
- Genetic causes
- How the disease develops
- Diagnosis
- Treatment and management
What is congenital generalised lipodystrophy?
Congenital generalised lipodystrophy is a rare inherited disorder where a person is born with an almost complete absence of fatty tissue, also called adipose tissue, throughout their body[1]. This condition is part of a larger group of disorders known as lipodystrophies, which are all characterised by a loss of adipose tissue[1].
Adipose tissue is found in many parts of the body, including beneath the skin and surrounding the internal organs. It serves crucial functions: it stores fat for energy, provides cushioning for various body parts, helps keep the body warm, and releases important hormones[1]. When the body lacks sufficient adipose tissue, fat must be stored elsewhere, particularly in the liver and muscles, which causes serious health problems[1].
The condition is inherited in an autosomal recessive pattern, meaning both parents must carry a changed gene for their child to develop the disorder. Couples where each member carries at least one changed gene should be informed that the risk of passing the disease to their offspring is 25%[5].
How common is this condition?
Congenital generalised lipodystrophy is extremely rare, with an estimated occurrence of 1 in 10 million people worldwide[1]. Between 300 and 500 people with the condition have been described in medical literature[1]. Although this condition has been reported in populations around the world, it appears to be more common in certain regions of Lebanon and Brazil[1]. In Brazil, particularly in the State of Rio Grande do Norte, the prevalence appears to be much higher than reported in other locations[4].
Signs and symptoms
The signs and symptoms of congenital generalised lipodystrophy are usually apparent from birth or early childhood[1]. Babies born with this condition have almost no body fat and instead appear very muscular because of an overgrowth of muscle tissue[1]. The lack of adipose tissue under the skin also makes the veins appear prominent[1].
The condition typically presents in the first months of life with failure to thrive, an enlarged liver (called hepatomegaly), generalised lack of fat tissue, prominent musculature, and a prominent belly button[5]. The disorder also has characteristic physical features like prominent bones above the eyes, large hands and feet, and a prominent belly button[1].
One of the most common features is insulin resistance, a condition in which the body’s tissues are unable to recognise insulin, a hormone that normally helps to regulate levels of blood sugar[1]. Insulin resistance may develop into a more serious disease called diabetes mellitus[1]. The condition appears in early childhood with accelerated growth, quick aging of bones, and a large appetite[3].
Most affected individuals also have high levels of fats called triglycerides circulating in the bloodstream, a condition known as hypertriglyceridaemia, which can lead to the development of small yellow deposits of fat under the skin called eruptive xanthomas and inflammation of the pancreas called pancreatitis[1].
Additionally, congenital generalised lipodystrophy causes an abnormal buildup of fats in the liver, called hepatic steatosis or fatty liver, which can result in an enlarged liver and even liver failure[1]. Some affected individuals develop a form of heart disease called hypertrophic cardiomyopathy, which can lead to heart failure and an abnormal heart rhythm that can cause sudden death[1].
Many people with this disorder develop acanthosis nigricans, a skin condition related to high levels of insulin in the bloodstream. This causes the skin in body folds and creases to become thick, dark, and velvety[1]. As the child grows up, this hyperpigmentation and thickening of skin will begin to present itself throughout the body, mainly in the neck, trunk, and groin[3].
After puberty, additional symptoms can develop. In women, an enlarged clitoris, an increased amount of body hair (called hirsutism), irregular menstrual periods, and multiple cysts on the ovaries may occur, which may be related to hormonal changes[1]. This impairs fertility for women, and only a few documented cases of successful pregnancies in women with the condition exist. However, the fertility of men with the disorder is unaffected[3].
High blood pressure and bone cysts are frequent complications[5]. Accelerated growth in infancy and precocious puberty have been reported in some cases[5].
Four types of the condition
Researchers have described four types of congenital generalised lipodystrophy, which are distinguished by their genetic cause[1]. The types also have some differences in their typical signs and symptoms.
In addition to the features described above, some people with type 1 develop cysts in the long bones of the arms and legs after puberty[1]. In type 1 patients, they still have some mechanical adipose tissue, but type 2 patients do not have any adipose tissue, including mechanical[3].
Type 2 can be associated with intellectual disability, which is usually mild to moderate[1]. In type 2 patients, there is a greater likelihood of developmental delays and intellectual impairment[3]. Mild intellectual disability can be present, mainly in cases related to changes in the BSCL2 gene[5].
Type 3 appears to cause poor growth and short stature, along with other health problems[1].
Type 4 is associated with muscle weakness, delayed development, joint abnormalities, a narrowing of the lower part of the stomach (called pyloric stenosis), and severe abnormal heart rhythm that can lead to sudden death[1]. Muscular dystrophy and cardiac abnormal rhythm are reported in cases related to changes in the CAVIN1 gene[5].
Genetic causes
Four distinct types of congenital generalised lipodystrophy exist: type 1 is associated with changes in the AGPAT2 gene; type 2 is associated with changes in the BSCL2 gene; type 3 is associated with changes in the CAV1 gene; and type 4 is associated with changes in genes called PTRF or CAVIN1[2][5].
The AGPAT2 gene is located at position 9q34.3 and encodes a key enzyme in triglyceride production called 1-acylglycerol-3-phosphate O-acyltransferase 2[3][5]. The BSCL2 gene is located at position 11q13 and encodes a protein called seipin[5]. The CAV1 gene is located at position 7q31.2 and the CAVIN1 gene is at position 17q21.2; these encode caveolin-1 and cavin-1 respectively, which are major components of specialised plasma membrane structures called caveolae[5].
The products of these genes have crucial roles in the production of phospholipids and triglycerides, as well as in the formation of lipid droplets and caveolae within fat cells[2]. Generalised lipodystrophy is described in rare patients with changes in the genes PPARG or LMNA, for which changes in one copy of the gene are associated with familial partial lipodystrophy[5].
How the disease develops
The predominant cause of health complications in congenital generalised lipodystrophy is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue[2]. When a person has almost no body fat, excess calories must be diverted to the liver, skeletal muscle, and pancreas, impairing insulin action[6].
The production of triglycerides and phospholipids starts with an enzyme called glycerol-3-phosphate acyltransferase adding a fatty acid to glycerol-3-phosphate. This is followed by another step performed by the enzyme AGPAT (1-Acylglycerol-3-phosphate acyltransferase), which creates a key intermediate in the production pathway of both triglycerides and phospholipids[4]. AGPAT2 is abundant in fatty tissue[4].
The product of the BSCL2 gene is a protein called seipin that causes the fusion of small lipid droplets, creating large lipid droplets. Seipin resides in the structure within cells called the endoplasmic reticulum and concentrates at the junction with developing lipid droplets[4].
Caveolin-1 and cavin-1 are required for the formation and stabilisation of caveolae, which are specialised structures in the cell membrane. Changes in the CAV1 gene (type 3) or CAVIN1 gene (type 4) can cause loss of caveolae in the membrane[4].
Profound lack of the hormone leptin (called hypoleptinaemia) further worsens metabolic problems by inducing a very strong appetite[2]. The severity of the metabolic complications is generally proportional to the extent of body fat loss[2].
Diagnosis
Diagnosis of congenital generalised lipodystrophy is based on recognition of the clinical picture and associated metabolic disturbances including low levels of leptin in the blood[5]. The identification of each form of the disease requires genetic testing[5].
A detailed medical history and a thorough clinical examination to evaluate body fat loss are essential. Tools used to help measure the loss of body fat include skin fold measurements, a scanning technique called dual-energy X-ray absorptiometry (DEXA), and whole-body MRI[8]. A variety of other tests including genetic testing, leptin levels and a full metabolic panel can be helpful for the patient and family members who may be at risk for genetic forms[8].
Conditions that must be distinguished from congenital generalised lipodystrophy include acquired generalised lipodystrophy (which occurs mainly in the context of autoimmune diseases), other genetic syndromes of insulin resistance, autoinflammatory diseases, partial forms of lipodystrophy and premature ageing syndromes[5].
Prenatal diagnosis can be discussed in families with a known disease-causing gene change[5]. A positive genetic test in an adult patient may lead to testing whether their partner carries a changed gene[5].
Treatment and management
Patients require psychological support, a low-fat diet, increased physical activity and sometimes cosmetic surgery[2]. Effective management includes lifestyle changes and aggressive, evidence-based treatment of associated health conditions[8].
Aside from conventional therapy for high lipid levels and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with congenital generalised lipodystrophy[2]. Metreleptin is a replacement therapy for the hormone leptin. In Japan, clinical trials on leptin therapy in patients with congenital generalised lipodystrophy started in 2002, and metreleptin replacement therapy was approved in 2013[9]. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalised lipodystrophy[8].
Metreleptin therapy has been shown to improve markedly the metabolism of fats and sugars in studies from the United States and Europe[9]. Comprehensive management with metreleptin therapy, dietary control with additional medication, and psychological counselling in line with the patients’ stages of growth and development were important in achieving long-term metabolic control of this condition[9].
Diet should be carefully managed[5]. Patients are defective in the storage of body fat and, consequently, they deposit fat in tissues where it shouldn’t be stored, mainly liver, and can develop cirrhosis. Insulin resistance is a typical finding, causing diabetes that requires high daily doses of insulin[4].
Patients with congenital generalised lipodystrophy have considerably high risks of diabetic complications and cardiovascular events from early childhood. Thus, early intervention is essential for preventing early complications[9].
