Congenital generalized lipodystrophy, a rare autosomal recessive disorder of the adipose tissue, originally described by Berardinelli and Seip, has been reported in approximately 250 patients of various ethnic origins. Assuming that only 1 in 4 patients is reported, the estimated worldwide prevalence is about 1 in 10 million. In an autosomal recessive disorder, parents are carriers of the genes but are not affected. The risk increases with consanguinity (when parents are close relatives e.g. uncle-niece, cousins etc). There is a 25% chance of transmission of both defective genes to the affected children i.e the ratio of affected to unaffected children is 1:3.The lipodystrophy is characterized by near complete absence of body fat.

There are two types of congenital generalized lipodystrophy, CGL1 due to AGPAT2 gene mutations (alterations or abnormalities) and CGL2 due to BSCL2 gene alterations. Compared to CGL1, CGL2 patients have more severe lack of body fat. CGL1 patients have well preserved mechanical fat (the fat that serves supportive or protective functions and is located in the palms, soles, orbits, scalp and around the joints) and the metabolically active fat (fat that participates in the storage and release of energy and is located at most subcutaneous regions, intermuscular regions, bone marrow, intraabdominal and intrathoracic regions) is absent. CGL2 patients lack both the mechanical and metabolically active fat. The diagnosis thus is evident at birth or immediately afterwards. These infants look very muscular due to the absence of fat. This is an essential criterion for its diagnosis.

Patients also present with acanthosis nigricans (dark velvety pigmentation of the skin) in the axilla, neck or groin, severe insulin resistance, high levels of serum insulin and serum triglycerides and low levels of high-density lipoprotein (HDL) cholesterol. Extreme hypertriglyceridemia may result in recurrent pancreatitis. Patients with CGL2 have earlier onset of diabetes and have higher prevalence of mild mental retardation compared to CGL1. These patients also have accelerated linear growth and advanced bone age during their childhood, and have a voracious appetite. Basal metabolic rate of the body may be increased during the childhood. The onset of diabetes is usually during the pubertal years and requires high dose of insulin to control the blood glucose levels. Serum leptin and adiponectin levels are extremely low.

The other clinical features consist of enlarged hands, feet and prominent mandible (acromegaloid features), increased sweating, umbilical hernia and lytic lesions (bone appear to be eaten-up on X-rays) in long bones of the upper and lower extremities (arms, forearm, hands, thigh, calf, legs and feet) such as humerus, femur, etc. after puberty Hepatomegaly from fatty liver is almost universal and may ultimately lead to cirrhosis. Splenomegaly is common. Nearly all patients have a prominent umbilicus or frank umbilical hernia. Patients might also have hypertrophic cardiomyopathy (dysfunction of the heart). Females present with enlarged clitoris, increased body hair, absence of or irregular menstrual cycles, and polycystic ovaries (enlarged ovaries). Only a few affected women have had successful pregnancies, whereas affected men have normal fertility.

GENETIC BASIS

AGPAT2 Mutations

Recently, our group identified the gene on the long arm of chromosome 9 (9q34), which when mutated (altered gene) causes CGL1.This gene encodes for the enzyme AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2) that is responsible for the production of an important intermediate in the synthesis of triglycerides or fat. Mutations (alterations) in this gene may cause CGL by inhibiting the fat synthesis and storage in adipocytes (fat cells). Interestingly, almost all patients of African originhave a splice-site mutation (IVS4-2A>G) on the same haplotype, suggesting that the mutation has a common ancestral origin.

BSCL2 Mutations

Mutations in another gene located on the long arm of chromosome 11 (11q13) called BSCL2 (Berardinelli-Seip Congenital Lipodystrophy 2) also can cause CGL2. The gene product of BSCL2 is a protein, Seipin whose function remains unknown. Therefore how BSCL2 mutations cause CGL remains to be elucidated. Patients with seipin mutations have a higher prevalence of mild mental retardation and hypertrophic cardiomyopathy than do those with AGPAT2 mutations.

Other Types of Congenital Generalized Lipodystrophy

Some patients with congenital generalized lipodystrophy (less than 20 percent) have neither AGPAT2 or BSCL2 mutations, nor linkage to either gene locus, suggesting that additional loci and other distinct pathways are involved.

Novel Therapies

Our group has recently carried out a collaborative trial of leptin-replacement in patients with lipodystrophies. Leptin therapy markedly reduces the levels of blood glucose and lipids allowing discontinuation of several medications.We have also observed that leptin therapy decreases abnormal accumulation of fat in the muscle and liver. The efficacy of leptin therapy was also confirmed recently in a Japanese cohort of  7 patients with generalized lipodystrophy and a French cohort of 7 children with congenital generalized lipodystrophy who were treated with human recombinant leptin. However, leptin therapy is still investigational and we are enrolling patients for a randomized double-blind trial.

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