Congenital Generalised Lipodystrophy Berardinelli Seip Syndrome or Lipoatrophic Diabetes

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Congenital generalised lipodystrophy (CGLD) is an autosomal recessive, transmitted disease characterised by a pronounced loss of subcutaneous and visceral fat tissue manifested since birth. The condition is associated with acromegalic traits (Fig. 2), accelerated growth with normal hGH

Fig. 2. A patient with congenital lipodystrophy or lipoatrophic diabetes. There is evidence of a pronounced loss of subcutaneous fat, acromegaloid aspect, and phlebomegaly (for details, see Table 3, patient GF)

plasma levels, hypertrichosis, mild virilisation, liver enlargement, reduced glucose tolerance or overt diabetes, heat intolerance, and increased perspiration (Table 2) [21-23].

The loss of fat involves the mesenteric, perirenal, and paracardiac adipose tissue depots [24]. Orbital and perirenal fat depots are spared. Acanthosis nigricans and hyperinsulinaemia are the rule. Accelerated growth in early childhood and advanced bone development compared with age-matched controls have been reported, but adult body height is normal or only slightly increased. In one patient (e.g., DMM, Table 3) a defect in adipose tissue lipoprotein lipase in a small residual lobule of omental tissue obtained during surgery was observed [25]. In all four patients in our series, post-heparin plasma lipoprotein lipase activity was blunted or near absent. Elevated triglyceride and reduced HDL

cholesterol plasma levels are part of the syndrome. Total cholesterol levels are not constantly increased, but occasionally can be remarkably high [25] (Table 3). Muscle mass, evaluated by DEXA, is preserved on even increased compared with age-, sex- and BMI-matched subjects. The increase in resting energy expenditure is related to the higher fat-free mass/body mass ratio. Two subtypes of CGLD have been identified and are distinguished according to the mode of inheritance [26-29]. Type 1 CGLD is related to an autosomal recessive genetic defect in AGPAT2 isoform. This enzyme, involved in the biosynthesis of triglycerides and phospholipids, is expressed at high levels in adipose tissue. Thus, a defect in AGAPT function may reduce triglyceride synthesis in fat cells. Type 2 CGLD is related to an autosomal recessive involvement of seipin, a protein of unknown function [30]. Mutation of the seipin gene has been reported to cluster in a large consanguineous pedi-

Table 2. Clinical aspects of the most important lipodystrophies (LDs)

Generalised

Partial

Generalised

Partial

congenital

congenital

acquired

acquired

LD

LD

LD

LD

Eponym

Berardinelli

Dunningam

Lawrence

Barraquer Simons

Seip syndrome

syndrome

syndrome

syndrome

Inheritance

Autosomal recessive

Autosomal dominant

-

-

Gene involved

Type 1

AGPAT2

LMNA

Type 2

Seipin

PPARy

Age at onset

Birth

Puberty

Any age

Youth

Sex prevalence

=

Women

Women

Women

Insulin resistance

Usual

Usual

Frequent

Unusual

Glucose tolerance

Reduced

Reduced

Reduced

Normal

Acanthosis nigricans

Frequent

Frequent

Unusual

Absent

Hypertrichosis

Frequent

Frequent

Unusual

Absent

Genital hypertrophy

Frequent

Frequent

Unusual

Absent

Somatic growth

Precocious

Normal

Precocious

Normal

(if early manifestation)

Liver enlargement

Frequent

Frequent

Frequent

Absent

Hypertriglyceridaemia

Usual

Usual

Usual

Absent

Basal metabolic rate

Increased

Increased

Increased

Normal

Polycystic ovary syndrome

Frequent

Frequent

Frequent

Absent

C3 deficiency

Absent

Absent

Absent

Frequent

gree [31]. A high level of seipin RNA expression in the brain of affected subjects suggests an involvement of the cerebral nervous system. This hypothesis seems to be supported by the association of type 2 CGLD with mild mental retardation.

CGLD can manifest with different expression of signs and symptoms and with different degrees of severity of the metabolic abnormalities (Table 3). Insulin resistance usually evolves into overt diabetes. Micro- and macroangiopathies and keto-sis are unusual in lipoatrophic diabetes. An increased resting energy expenditure without abnormalities of thyroid function has been reported. Liver steatosis, liver fibrosis, portal hypertension, and oesophageal varices are late-onset complications, possibly leading to death.

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