The mode of transmission of Kobberling variety of familial partial lipodystrophy is not clear.  Loss of fat in the Kobberling variety is limited to the extremities with normal amounts of fat or even excess fat in the face, neck and trunk. So far, this variety has been reported only in women. These patients are predisposed to develop diabetes mellitus and high levels of serum triglycerides. Other clinical manifestations include acanthosis nigricans, coronary artery disease, hypertension and polycystic ovarian syndrome. Recently, Herbst et al. reported absence of LMNA or PPAR-γ gene mutations in 13 patients with the Kobberling variety. LMNA sequencing was done for exons 8-11 and PPARG sequencing was limited to exons 1-6 and 8.

Familial Partial Lipodystrophy- PPAR gamma (Peroxisome proliferator activated receptor-γ) gene mutations

We recently reported heterozygous mutation (Arg397Cys) of peroxisome proliferator-activated receptor gamma (PPARG) gene (involved in the differentiation of body fat) in a patient who did not appear to have Dunnigan variety of lipodystrophy. This patient had diabetes mellitus, high levels of serum triglycerides, hirsutism and had loss of fat from the extremities and face at the age of 50. The loss of fat was more prominent in the forearms and calves than in the upper arms and thighs. Thus, PPARG gene mutation could be the molecular basis for one of the variety of familial partial lipodystrophy. Since our report, two other groups have reported additional FPL families with PPARG missense mutations (pro467Leu, Val290Met and Phe388Leu).

PPAR-γ protein is a nuclear transcription factor and plays an important role in adipogenesis (generation of new fat cells from precursor cells). Thus, these dominant negative mutations may impair adipocyte  differentiation resulting in fat loss.

References

• Hegele RA.
  Lessons from human mutations in PPARgamma.
  Int J Obes Relat Metab Disord. 2005 Mar;29 Suppl 1:S31-5.
• Savage DB, Murgatroyd PR, Chatterjee VK, O'Rahilly S.
  Energy expenditure and adaptive responses to an acute hypercaloric fat load in humans with lipodystrophy.
  J Clin Endocrinol Metab. 2005 Mar;90(3):1446-52. Epub 2004 Dec 21.
• Herbst KL, Tannock LR, Deeb SS, Purnell JQ, Brunzell JD, Chait A.
  Kobberling type of familial partial lipodystrophy: an under recognized syndrome.
  Diabetes Care 2003; 26(6): 1819-24.
• Savage DB, Tan GD et al.
  Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma.
  Diabetes 2003; 52(4): 910-7.
• Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T.
  PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy.
  Diabetes 2002; 51(12): 3586-90.
• Agarwal AK, Garg A.
  A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy.
  J Clin Endocrinol Metab 2002; 87(1): 408-11.
• Kobberling J, Schwarck H, Cremer P, Fiechtl J, Seidel D, Creutzfeldt W.
  Partielle Lipodystrophie mit lipatrophischem Diabetes und Hyperlipoproteinamie.
  Verhandlungen der deutschen Gesellschaft fur Innere Medizin 1981; 87:958-961.
• Kobberling J, Willms B, Kattermann R, Creutzfeldt W.
  Lipodystrophy of the extremities. A dominantly inherited syndrome associated with lipoatrophic diabetes.
  Humangenetik 1975; 29:111-120.

Familial Partial Lipodystrophy due to v-AKT murine thymoma oncogene homolog 2 (AKT2) gene mutations

Recently, a heterozygous missense mutation, Arg274His, in AKT2 gene was reported in several members of a family who had insulin resistance and diabetes mellitus. One of them was a 35-year-old white female who developed diabetes mellitus at age 30 years, whereas her mother and grandmother harboring the same mutation developed diabetes during late thirties and a maternal uncle, a middle-aged person, had no diabetes but had hyperinsulinemia. Three of the four affected subjects had hypertension. The 35 year-old lady also had reduced body fat and partial lipodystrophy affecting mainly her extremities however, in depth evaluation of body fat distribution has not been conducted.

AKT2 belongs to the family of phosphoinositide-dependent serine/threonine kinases and is also known as protein kinase B (PKB)86. The three isoforms of AKT share more than 80% amino acid identity. Whereas, AKT1 is expressed almost everywhere, AKT2 is predominantly expressed in insulin sensitive tissues and AKT3 in the testes and brain. The mutant form of ATK2 has reduced lipid accumulating capacity. Previously, a knock-out mouse model has shown features of lipodystrophy, insulin resistance and diabetes with increasing age. Thus, lipodystrophy in patients with AKT2 mutations may be due to reduced adipocyte differentiation and deranged insulin action in cells.

References

• Al-Shali K, Cao H, Knoers N, Hermus AR, Tack CJ, Hegele RA. A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. J Clin Endocrinol Metab 2004;89:5655-60.
• George S, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 2004;304:1325-8