Type 1 familial partial lipodystrophy: understanding the Köbberling syndrome

Abstract

Familial partial lipodystrophy are Mendelian disorders involving abnormal body fat distribution and insulin resistance. The current classification includes the Köbberling syndrome (type 1 familial partial lipodystrophy), characterized by fat loss in the lower limbs and abnormal fat accumulation in other areas. Type 1 familial partial lipodystrophy appears to be heritable, but little is known about it, including putative contributing mutations. We aimed to characterize this syndrome better by evaluating a group of women with phenotypic features of type 1 familial partial lipodystrophy. This is a case-controlled study in which 98 women with type 1 familial partial lipodystrophy that lacked classical mutations known to cause familial partial lipodystrophy were compared with 60 women without lipodystrophy and 25 patients with type 2 familial partial lipodystrophy (Dunnigan disease). Clinical course, body composition by dual-energy X-ray absorptiometry, HbA1c, lipid profile, insulin, leptin and family history were evaluated in all of the participants. Analyses of receiver-operating characteristic curve were performed for type 1 familial partial lipodystrophy diagnosis, comparing different truncal/limbs ratios. Among patients with type 1 familial partial lipodystrophy, 68 % developed recognizable lipodystrophy before adolescence, and most displayed an autosomal-dominant pattern (86 %). Women with type 1 familial partial lipodystrophy had less lower-limb adipose tissue than women without lipodystrophy, but significantly more than patients with Dunnigan disease. Moreover, metabolic disturbances occurred more frequently in the type 1 familial partial lipodystrophy group (81 %) than in the non-lipodystrophic group (30 %, p<0.05). The severity of metabolic disturbances was inversely proportional to the percentage of fat in the lower extremities and directly proportional to the amount of visceral adipose tissue. Metabolic profiles were worse in type 1 familial partial lipodystrophy than in Dunnigan disease. According to the receiver-operating characteristic curve analysis, the best ratio was subscapular/calf skinfolds (KöB index), with a cut-off value of 3.477 (sensitivity: 89 %; specificity: 84 %). Type 1 familial partial lipodystrophy was an early-onset, autosomal-dominant lipodystrophy, characterized by fat loss in the lower limbs and abnormal fat accumulation in the abdominal visceral region, associated to insulin resistance and metabolic disorders. A KöB index >3.477 is highly suggestive of this syndrome.

Severe insulin resistance: pathologies

“…The metabolic consequences are more marked than BMI matched controls including IR, NAFLD and hypertriglyceridaemia. Consequently, other features of hyperinsulinism are often present: acanthosis nigricans, acrochordons and hyperandrogenism . The remaining familial partial lipodystrophies are monogenic disorders.…”

Dunnigan-Type Familial Partial Lipodystrophy: Understanding and Treating the Syndrome

“…Clinically, there is progressive loss of subcutaneous adipose tissue in the limbs, trunk, and body and fat accumulation in the face and neck, which are associated with grave metabolic disorders including insulin resistance (with acanthosis nigricans in skin fold regions), glucose intolerance, diabetes mellitus, dyslipidemia, and hepatic steatosis [9]. The progressive loss of subcutaneous adipose tissue in the limbs and trunk is diagnosed via body composition analysis with dual energy X-ray densitometry, which demonstrates accentuated body fat reduction in affected patients [10].…”

Inflammatory myopathy in the context of an unusual overlapping laminopathy

“…Previous studies have described a LMNA-associated metabolic syndrome with a Köbberling-like fat distribution (3,4). EDMD2 is characterized as a progressive skeletal muscle weakness associated with early joint contractures.…”