Congenital generalized lipodystrophy (also known as Berardinelli–Seip lipodystrophy) is an extremely rare

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of

lipodystrophy Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissu ...

disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

Presentation

Congenital generalized lipodystrophy (CGL) is a rare

disorder which manifests with insulin resistance, absence of

subcutaneous fat The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, or superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and ...

and muscular hypertrophy. Homozygous or compound heterozygous mutations in four genes are associated with the four subtypes of CGL. The condition appears in early childhood with accelerated linear growth, quick aging of bones, and a large appetite. As the child grows up, acanthosis nigricans (

hyperpigmentation Hyperpigmentation, also known as the dark spots or circles on the skin, is the darkening of an area of Human skin, skin or nail (anatomy), nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or ...

and thickening of skin) will begin to present itself throughout the body – mainly in the neck, trunk, and groin. The disorder also has characteristic features like

hepatomegaly Hepatomegaly is enlargement of the liver. It is a non-specific sign (medicine), medical sign, having many causes, which can broadly be broken down into infection, hepatic tumours, and metabolic disorder. Often, hepatomegaly presents as an abdomin ...

or an enlarged liver which arises from fatty liver and may lead to

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

hypertrophy, lack of

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

, splenomegaly, hirsutism (excessive hairiness) and hypertriglyceridemia. Fatty liver and muscle hypertrophy arise from the fact that lipids are instead stored in these areas; whereas in a healthy individual, lipids are distributed more uniformly throughout the body subcutaneously. The absence of adipose tissue where they normally occur causes the body to store fat in the remaining areas. Common

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

problems related to this syndrome are cardiac hypertrophy and

arterial An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

(high

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

). This disorder can also cause

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...

. Most with the disorder also have a prominent umbilicus or umbilical

hernia A hernia (: hernias or herniae, from Latin, meaning 'rupture') is the abnormal exit of tissue or an organ (anatomy), organ, such as the bowel, through the wall of the cavity in which it normally resides. The term is also used for the normal Devel ...

. Commonly, patients will also have

acromegaly Acromegaly is a disorder that results in excess growth of certain parts of the human body. It is caused by excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There ...

with enlargement of the hands, feet, and jaw. After puberty, additional symptoms can develop. In women, clitoromegaly and

polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...

can develop. This impairs fertility for women, and only a few documented cases of successful pregnancies in women with CGL exist. However, the fertility of men with the disorder is unaffected.

Differences between type 1 and type 2

There are differences in how type 1 vs type 2 patients are affected by the disease. In type 1 patients, they still have mechanical adipose tissue, but type 2 patients do not have any adipose tissue, including mechanical. In type 2 patients, there is a greater likelihood of psychomotor retardation and

intellectual impairment Developmental disability is a diverse group of chronic conditions, comprising mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, espe ...

Genetics

Mechanism

Type 1

In individuals with Type 1 CGL, the disorder is caused by a mutation at the '' AGPAT2'' gene encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 and located at 9q34.3. This enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, which is important in the

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers specif ...

s. This enzyme is highly expressed in

, so it can be concluded that when the enzyme is defective in CGL, lipids cannot be stored in the adipose tissue.

Type 2

In those who have Type 2 CGL, a mutation in the '' BSCL2'' gene encoding the seipin protein and located at 11q13. This gene encodes a protein, Seipin, whose function is unknown. Expression of mRNA for the seipin protein is high in the brain, yet low in

s. Additionally, patients which have mutations in this protein have a higher incidence of

mental retardation Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

and lack mechanically active adipose tissue, which is present in those with AGPAT2 mutations.

Type 3

Type 3 CGL involves a mutation in the '' CAV1'' gene. This gene codes for the caveolin protein, which is a scaffolding membrane protein. This protein plays a role in lipid regulation. High levels of Cav1 are normally expressed in adipocytes. Thus, when the CAV1 gene mutates the adipocytes do not have Cav1 and are unable to properly regulate lipid levels.

Type 4

A mutation in the '' PTRF'' gene causes Type 4 CGL. This gene codes for a protein called polymerase I and transcript release factor. Some of the roles the PTRF product has are to stabilize and aid in formation of caveolae. Thus, the mechanism is similar to Type 3, in that the caveolae are unable to properly form and carry out their role in lipid regulation in both. Types 3 and 4 are two different mutations but they share a common defective pathway.

Diagnosis

Medical diagnosis of CGL can be made after observing the physical symptoms of the disease:

lipoatrophy Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone u ...

(loss of fat tissues) affecting the trunk, limbs, and face;

;

; insulin resistance; and high serum levels of

triglycerides A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and oth ...

Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

can also confirm the disease, as mutations in the '' AGPAT2'' gene is indicative of CGL1, a mutation in the '' BSCL2'' gene is indicative of CGL2, and mutations in the '' CAV1'' and '' PTRF'' genes are indicative of CGL3 and CGL4 respectively. Physical diagnosis of CGL is easier, as CGL patients are recognizable from birth, due to their extreme muscular appearance, which is caused by the absence of

. CGL3 patients have serum creatine kinase concentrations much higher than normal (2.5 to 10 times the normal limit). This can be used to diagnose type 3 patients and differentiate them from CGL 1 and 2 without mapping their genes. Additionally, CGL3 patients have low

muscle tone In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial contraction of the muscles, or the muscle's resistance to passive stretch during resting state.O’Sullivan, S. B. (2007) ...

when compared with other CGL patients.

Treatment

Metformin is the main drug used for treatment, as it is normally used for patients with

hyperglycemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...

. Metformin reduces appetite and improves symptoms of hepatic steatosis and

Leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...

can also be used to reverse insulin resistance and hepatic steatosis, to cause reduced food intake, and decrease blood glucose levels.

Diet

CGL patients have to maintain a strict diet for life, as their excess appetite will cause them to overeat. Carbohydrate intake should be restricted in these patients. To avoid chylomicronemia, CGL patients with hypertriglyceridemia need to have a diet very low in fat. CGL patients also need to avoid total

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, re ...

, trans fats, and eat high amounts of soluble fiber to avoid getting high levels of

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

in the blood.

History

Congenital generalized lipodystrophy, also known as Berardinelli–Seip lipodystrophy was first described in 1954 by Berardinelli and later by Seip in 1959. The gene for type 1 CGL was identified as '' AGPAT2'' at chromosome 9q34, and later the gene for type 2 CGL was identified as '' BSCL2'' at chromosome 11q13. More recently, type 3 CGL was identified as a separate type of CGL, which was identified as a mutation in the '' CAV1'' gene. Then, a separate type 4 CGL was identified as a mutation in the '' PTRF'' gene.

References

External links

{{Deficiencies of intracellular signaling peptides and proteins Conditions of the subcutaneous fat Rare syndromes