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Intro

Signs and symptoms

Congenital Generalized Lipodystrophy (The Berardinelli–Seip Syndrome) Clinical Picture

Congenital generalized lipodystrophy, a rare autosomal recessive disorder, originally described by Berardinelli[ 34] and Seip,[ 35] 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. The most characteristic clinical feature is nearly complete absence of adipose tissue and a consequently generalized muscular appearance recognized easily at birth ([Figure 2A] and [Figure 2B]).

Early childhood is marked by accelerated linear growth, an advanced bone age, and a voracious appetite. Later in childhood, marked acanthosis nigricans usually develops in the neck, axilla, groin, and trunk. 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. An acromegalic appearance with slight enlargement of the mandible, hands, and feet is common. After puberty, clitoromegaly and the polycystic ovary syndrome may develop in girls. Only a few affected women have had successful pregnancies, whereas affected men have normal fertility. Multiple focal lytic lesions develop in the appendicular bones after puberty.[ 36] A few patients have hypertrophic cardiomyopathy and mild mental retardation.[ 37][ 38]

Severe hyperinsulinemia and hypertriglyceridemia may be present, even during infancy. Extreme hypertriglyceridemia may result in recurrent acute pancreatitis. Ketosis-resistant diabetes mellitus usually develops during adolescence or thereafter, with attendant long-term complications.[ 38][ 39][ 40] Serum leptin and adiponectin levels are extremely low.[ 30]

Molecular Basis of Congenital Generalized Lipodystrophy Type 1

Two molecularly distinct forms of congenital generalized lipodystrophy have been defined — type 1 and type 2. Some patients have neither type, so that additional genes are most likely involved.

Positional cloning was used to identify the aberrant gene — 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) — in patients from several pedigrees in which the lipodystrophy was linked to chromosome 9q34.[ 39][41] Several homozygous or compound heterozygous mutations in the AGPAT2 gene were found in affected patients. Interestingly, almost all patients of African origin have a splice-site mutation (IVS4-2A>G) on the same haplotype, suggesting that the mutation has a common ancestral origin.

The five known isoforms of AGPAT catalyze an acylation reaction at the stereospecific number-2 position of glycerol-3-phosphate during the synthesis of triglycerides and phospholipids ([Figure 3]).[ 42][ 43] AGPAT2 mRNA expression is at least twice as high as that of AGPAT1 in human omental adipose tissue but is lower in the liver and far lower in the skeletal muscle.[ 39] These observations suggest that the aberrant AGPAT2 enzyme may cause lipodystrophy by reducing the synthesis of triglycerides in adipose tissue, thus leading to adipocytes that are depleted of triglycerides, or by reducing the bioavailability of phosphatidic acid and phospholipids that are important for intracellular signaling and membrane functions.[ 44] Affected patients lack metabolically active adipose tissue in most subcutaneous areas, intraabdominal and intrathoracic regions, and bone marrow, whereas mechanical adipose tissue, which fulfills a protective and cushioning function, such as in the joints, orbits, palms and soles, scalp, perineum, vulva, and pericalyceal regions of the kidneys, appears to be spared.[ 45][ 46][ 47] The preservation of mechanical adipose tissue in patients with AGPAT2 mutations may be due to the increased expression of other AGPAT isoforms in these adipose-tissue depots.

Molecular Basis of Congenital Generalized Lipodystrophy Type 2

Magre and colleagues[ 48] reported mutations in the seipin gene in patients from several large consanguineous pedigrees from Lebanon and Norway in which linkage to chromosome 11q13 had been noted. The seipin gene encodes a 398–amino-acid protein of unknown function; thus, the mechanisms causing lipodystrophy remain unclear. However, the fact that affected patients have high levels of expression of seipin mRNA in the brain yet weak expression in adipose tissue suggests that the central nervous system is involved. Patients with seipin mutations have a higher prevalence of mild mental retardation and hypertrophic cardiomyopathy than do those with AGPAT2 mutations.[ 38][ 39] Type 2 patients lack both metabolically active and mechanical adipose tissue.[ 47]

Other Types of Congenital Generalized Lipodystrophy Some patients with congenital generalized lipodystrophy (less than 20 percent) have neither mutations nor linkage to either the AGPAT2 or seipin gene, suggesting that additional loci[ 49][ 50][ 51] and other distinct pathways are involved.

http://www.sciencedirect.com/science/article/pii/S0009898109000096#bib4

Pathophysiology/Mechanism

The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.

http://www.utsouthwestern.edu/media/files/2400/Congenital-Generalized.pdf