Primary Lipodystrophy

A heterogeneous group of very rare diseases characterized by a generalized or localized loss of body fat (lipoatrophy).

Epidemiology

Prevalence has been estimated at less than 1 case in 100 000.

Clinical description

In some forms, lipoatrophy is associated with selective hypertrophy of other fat deposits. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes, and hypertriglyceridemia leading to a risk of acute pancreatitis. The diabetes leads to chronic complications involving the retina, kidney, nerves and cardiovascular system, and to liver steatosis that could result in cirrhosis.

Etiology

Genetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome, see this term) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyltransferase involved in triglyceride synthesis. The origin of acquired generalized lipodystrophy (Lawrence syndrome, see this term) is unknown but the syndrome is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C, or in the PPARG gene encoding the adipogenic transcription factor PPARgamma. Some less typical forms of lipodystrophy, associated with signs of premature aging, have been linked to mutations in the LMNA gene or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome, see this term) is characterized by cephalothoracic fat loss. Its etiology is unknown but mutations in the LMNB2 gene, encoding the lamina protein lamin B2, may represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes.

Diagnostic methods

The genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis may be proposed.

Management and treatment

Treatment of diabetes, dyslipidemia and the resulting complications involves the classical intervention strategies. Insulin-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels have reported good results with respect to the metabolic and liver alterations.

Prognosis

The prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.