Lipodystrophy, Congenital Generalized, Type 3

A number sign (#) is used with this entry because of evidence that congenital generalized lipodystrophy type 3 (CGL3) is caused by homozygous mutation in the CAV1 gene (601047) on chromosome 7q31. One such family has been reported.

Heterozygous mutation in the CAV1 gene can cause familial partial lipodystrophy-7 (FPLD7; 606721).

Description

Congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, and early onset of diabetes (Garg, 2004).

For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Clinical Features

Kim et al. (2008) described a 20-year-old woman, born of consanguineous Brazilian parents, with congenital generalized lipodystrophy. Facial lipoatrophy was noted at 3 months, but development was otherwise normal except for recurrent pneumonia, chronic diarrhea, and poor growth. The patient had normal cognitive development. At age 8 years, she had generalized lipoatrophy with muscular hypertrophy, organomegaly, and features of severe insulin resistance, including acanthosis nigricans and hirsutism. She had severe hepatosplenomegaly and hepatic steatosis. Laboratory studies were consistent with diabetes mellitus, hypertriglyceridemia, and hypercholesterolemia. In addition, she had mild hypocalcemia, which was likely due to vitamin D resistance. At age 20, she had primary amenorrhea, acanthosis nigricans particularly on the neck and axillae, protruding abdomen, thick curly hair, and prominent peripheral veins in the limbs. Detailed magnetic resonance imaging of the proband confirmed near total absence of both subcutaneous and visceral adipose tissue, with only vestigial amounts in the dorsal subcutaneous regions. In contrast, bone marrow fat was well preserved. So-called mechanical adipose deposits were less severely affected, being reduced in scalp but preserved in the retroorbital region. In the extremities, adipose tissue was preserved in the fingers and the plantar region with some loss of signal intensity.

Inheritance

The transmission pattern of CGL3 in the family reported by Kim et al. (2008) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient, born of consanguineous Brazilian parents, with CGL3, Kim et al. (2008) identified homozygosity for a premature termination mutation in exon 2 of the CAV1 gene (601047.0001). A sister of the proband, who carried the mutation in heterozygosity, was morbidly obese, suggesting that haploinsufficiency for CAV1 does not lead to globally impaired accumulation of adipose tissue. The proband's father had hypercholesterolemia and hypertension, with death at age 53 due to myocardial infarction; the heterozygous mother had both hypertension and type 2 diabetes diagnosed in her 40s. However, both heterozygous sibs examined at 18 and 23 years of age had normal metabolic parameters and blood pressure. That the sequence of CAV1 was normal in 3 other CGL patients without mutation in seipin (606158) or AGPAT2 (603100) suggested that alterations in another gene were responsible for the phenotype in these patients.

Animal Model

Razani et al. (2002) found that older Cav1-null mice had lower body weights and were resistant to diet-induced obesity compared to wildtype. Adipocytes from Cav1-null mice lacked caveolae membranes. Early on, a lack of Cav1 selectively affected only the female mammary gland fat pad and resulted in a nearly complete ablation of the hypodermal fat layer. With age, there was a systemic decompensation in lipid accumulation, resulting in smaller fat pads, reduced adipocyte cell diameter, and poorly differentiated/hypercellular white adipose parenchyma. Laboratory studies showed that Cav1-null mice had severely elevated triglyceride and free fatty acid levels, although insulin, glucose, and cholesterol levels were normal. The lean body phenotype and metabolic defects observed in these mice suggested a role for CAV1 in systemic lipid homeostasis in vivo.