Generalized lipodystrophy is a disorder characterized by loss of adipose tissue and, usually, metabolic disturbance due to deficiency of hormones derived from these tissues, most importantly leptin. Generalized lipodystrophy (GL) may be divided in congenital GL, also known as Berardinelli-Seip syndrome and acquired GL, referred to as Lawrence syndrome.
Near-total lack of subcutaneous fat from birth is characteristic of congenital generalized lipodystrophy (CGL). One of the earliest symptoms of this condition is a well-defined musculature with prominent superficial veins. The infants and children show increased, insatiable appetite, often want to be breast-fed, or are looking for food. Tonsils and adenoids may be hyperplastic, hands and feet may be enlarged and umbilical hernias are common. Hepatomegaly and splenomegaly are frequently present from infancy leading to abdominal distention. Patients can also present with dermatological manifestations such as eruptive xanthomas, hirsutism and thick, curled scalp hair. Acanthosis nigricans occurs frequently in the adolescence. Children with CGL may attain more than 90% of adult growth within 10 years and an advanced bone age is detectable. Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients. Hypertriglyceridemia, liver cirrhosis, diabetes mellitus, as well as cardiovascular complications are frequently observed. Severe hypertriglyceridaemia may cause recurrent pancreatitis. Acquired generalized lipodystrophy (AGL) causes variable extent of fat loss and is usually accompanied by diabetes mellitus, hepatic steatosis and fibrosis and hypertriglyceridemia.
Diagnosis of this disease is mainly based on clinical features and generalized lipodystrophy should be included in the differential diagnosis of lean individuals presenting with early-onset diabetes mellitus, hypertriglyceridemia, nonalcoholic steatohepatitis (NASH), acanthosis nigricans and polycystic ovary syndrome. Laboratory studies are used to examine for associated conditions like metabolic disorders and autoimmune diseases. Fasting blood glucose, lipid profile, liver enzymes, uric acid, creatinine and urinalysis should be obtained. Tests may also be conducted for antinuclear antibodies, and anticardiolipin antibodies. For congenital lipodystrophy, genetic workup may be needed.
A general approach includes lifestyle modification like diet, exercise, and nutritional therapy. Patients with this disease are recommended to have 25% of daily calories from fat. 75% of the calories should be provided by protein and carbohydrates . Exercise may be helpful in improving the metabolic parameters. Resistance training is found to enhance total lean mass and to decrease total fat accumulation. Exercise is also helpful in increasing peripheral insulin sensitivity and HDL cholesterol levels. Patients with concurrent diabetes mellitus may be suggested oral anti-diabetic drugs such as metformin for managing this associated condition. Thiazolidinediones also may be helpful in improving insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Treatment guidelines for dyslipidemia in lipodystrophy are similar to that of coronary artery disease. Lifestyle modification is the first step in this regard. Statins are given for hypercholesterolemia. Fibrates and extended release niacin may be used for controlling hypertriglyceridemia. Ezetimibe may be opted for patients who cannot tolerate statins. In February 2014, the Food and Drug Administration (FDA) approved metreleptin (Myalept), a recombinant leptin analog, for the treatment of generalized forms of lipodystrophy in children and adults     .
Mortality and morbidity associated with the disease depend on the organs involved and the extent of involvement. In congenital forms most of the patients survive to young adulthood or early middle age.
Congenital generalized lipodystrophy is caused by an autosomal recessive mutation. There are four subtypes of CGL due to compound mutations in four genes, 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT2), Berardinelli-Seip congenital lipodystrophy 2 (BSCL2), caveolin 1 (CAV1), and polymerase I and transcript release factor (PTRF). In some patients one or more as-yet-unidentified genes cause the disorder. Acquired generalized lipodystrophy may be caused by medications, autoimmunity or may be idiopathic. Panniculitis-associated forms of AGL occur .
Both acquired and inherited types of this disease are rare. The incidence of CGL is 1:1.000,000 and found to be equal in male and female. The highest frequency of congenital generalized lipodystrophy is reported from Brazil . AGL is more common than the inherited form and the female to male ratio is 3:1.
Congenital generalized lipodystrophy is classified in type 1 to 4, depending on the clinical manifestations and the etiological mutations. Type 1 (CGL1) is caused by a mutation of 1-acylglycerol-3-phosphate-O-acyltransferase 2 gene (AGPAT2). AGPAT2 plays an important role in functioning of adipocyte tissue and also in the synthesis of triacylglycerol in adipose tissue . Mutation of this gene affects the metabolically important tissues like fat tissue in subcutaneous regions, bone marrow, intramuscular, intraabdominal and intrathoracic regions. Type 2 (CGL2) occurs due to mutations of Berardinelli-Seip Congenital Lipodystrophy 2 gene (BSCL2). BSCL2 is involved in the coding of the protein seipin, which is implicated in the differentiation of adipose tissue and lipid droplet formation . Caveolin 1 (CAV1) mutations, and Polymerase I and transcript release factor (PTRF) mutations are associated with CGL3, and CGL4, respectively. In some patients one or more as-yet-unidentified genes lead to CGL.
AGL may be caused by nucleoside reverse transcriptase inhibitors. It may result in abnormal proliferation of mitochondria, known as mitochondrial toxicity . Protease inhibitors are also implicated in the disruption of adipocyte differentiation and also in increased production of cytokines. Drug-induced lipodystrophy may also include increased lipolysis. Enhanced lipolysis along with deficiency of subcutaneous fat, indirectly lead to metabolic disturbances like insulin resistance and dyslipidemia.
There are no guidelines for prevention.
Generalized lipodystrophies are a group of disorders characterized by loss of adipose tissue and, usually, metabolic disturbance and may be divided in congenital GL, also known as Berardinelli-Seip syndrome and acquired GL, referred to as Lawrence syndrome. Congenital generalized lipodystrophy was first reported by Berardinelli in 1954 and Seip in 1959, and to date, approximately 300 cases have been described in the literature.
Lipodystrophy refers to a heterogeneous group of disorders that result in fat loss. Generalized lipodystrophy (GL) may be categorized as congenital GL, also known as Berardinelli-Seip syndrome and acquired GL, referred to as Lawrence syndrome. Loss of fat leads to metabolic complications, the severity of which depends on the extent of the loss. Location of fat loss may vary and patients usually have very little fat and appear muscular. In most of these patients the condition leads to serious problems like insulin resistance, high cholesterol, diabetes mellitus and fatty liver disease.
Clinical features with a family history of lipodystrophy and associated conditions are often used in diagnosis of the disease. Associated conditions may include diabetes mellitus, high levels of triglycerides or cholesterol, fatty liver, dark, velvety patches of skin and polycystic ovary syndrome. The treatment strategy includes alleviating the disturbances due to changes in fat distribution. Lifestyle modifications with diet, nutrition therapy and exercise are important steps in the treatment of the condition. Medications are given for controlling diabetes mellitus, high levels of cholesterol and triglycerides. Myalept is a recombinant leptin analog for the treatment of generalized forms of lipodystrophy in children and adults.