Lipodystrophy, Familial Partial, Type 7

A number sign (#) is used with this entry because of evidence that familial partial lipodystrophy type 7 (FPLD7) is caused by heterozygous mutation in the CAV1 gene (601047) on chromosome 7q31.

Homozygous mutation in the CAV1 gene can cause congenital generalized lipodystrophy-3 (CGL3; 612526).

Description

Lipodystrophies are rare disorders characterized by loss of body fat from various regions and predisposition to metabolic complications of insulin resistance and lipid abnormalities. FPLD7 is an autosomal dominant disorder with a highly variable phenotype. Additional features, including early-onset cataracts and later onset of spasticity of the lower limbs, have been noted in some patients (summary by Garg et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

Clinical Features

Berger et al. (2002) described familial lipodystrophy associated with congenital cataracts and cerebellar and spinal cord dysfunction. The proposita, a 28-year-old woman with congenital atypical partial lipodystrophy and cataracts, presented with a spastic-ataxic gait and lower extremity paresthesias at age 18 years. Laboratory investigation demonstrated a type V hyperlipidemia pattern, insulin resistance, and high alpha-tocopherol levels. Lack of fat in the face and upper body was noted at birth, and a small jaw necessitated multiple teeth extractions. In addition to congenital cataracts, she was said to have pigmentary retinopathy, lack of breast development, and pancreatitis complicating hyperlipidemia. She had symptomatic orthostatic hypotension and mild acanthosis nigricans. Her legs were spastic with spontaneous clonus, brisk reflexes, and bilateral Babinski signs. MRI of the cervical spine showed a signal abnormality in the spinal cord. Peroxisomal function panels were normal, and muscle biopsy showed no features suggestive of a mitochondrial disorder. Her father and his sister, 2 of 5 children, were similarly affected. The father had congenital cataracts, retinitis pigmentosa, and mild hyperlipidemia. Absence of facial, neck, and extremity fat was noted. Neurologic manifestations appeared to be minimal. The affected paternal aunt died from a neurologic condition at approximately age 40. The cause of death was attributed to multiple sclerosis. She had a fat distribution resembling that in the other 2 patients. Lower extremity weakness and ataxia started at the age of 18 to 20 years. Her condition deteriorated rapidly and she was wheelchair-bound within 2 years. Mutations were excluded in several genes, including the genes causing spinocerebellar ataxia 1 through 7 (see 164400).

Garg et al. (2015) reported 2 unrelated children, a 7-year-old boy and a 3-year-old girl, with a complex lipodystrophy syndrome apparent from birth. As infants, they presented with loss of subcutaneous fat, but not from the buttocks, and thin skin with prominent vessels suggestive of cutis marmorata. The patients had poor weight gain, increased bowel movements or cyclic vomiting, thin hair, and progeroid features, such as triangular face, sunken cheeks, and pinched nose. Both had poor overall weight gain, but normal cognitive development. The boy developed cataracts at age 30 months and the girl developed pulmonary arterial hypertension. Both patients had low levels of HDL cholesterol and 1 had increased serum cholesterol, but neither had glucose intolerance or hypertriglyceridemia.

Inheritance

The transmission pattern of FPLD7 in the family reported by Berger et al. (2002) was consistent with autosomal dominant inheritance.

Molecular Genetics

In the father and daughter with FPLD7 reported by Berger et al. (2002), Cao et al. (2008) identified a heterozygous truncating mutation in the CAV1 gene (601047.0004). The more severe neurologic phenotype in the daughter suggested that other factors, either genetic or nongenetic, can modulate the severity of the phenotype. Neither mutation was found in 1,063 controls. Functional studies of the variants were not performed. An unrelated patient with partial lipodystrophy without ocular or neurologic abnormalities was found to carry a heterozygous -88delC mutation in the 5-prime untranslated region of the CAV1 gene, with a potential effect on the reading frame. No coding sequence mutations were found in the LMNA (150330), PPARG (601487), BSCL2 (606158), or AGPAT2 (603100) genes. The 2 probands were ascertained from a cohort of 60 patients with partial lipodystrophy who were screened for CAV1 mutations. The CAV1 gene was chosen for study because mouse models deficient in Cav1 show some similar features (Razani et al., 2002).

In 2 unrelated patients with FPLD7, Garg et al. (2015) identified de novo heterozygous nonsense mutations in the CAV1 gene (Q142X, 601047.0005 and F160X, 601047.0006). Patient fibroblasts showed significantly reduced expression of CAV1 compared to controls, but there were no differences in the number or morphology of caveolae compared to controls.

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.