Endocrine Abstracts (2006) 11 S55

Specific metabolic features in Prader-Labhart-Willi syndome (PWS) as indicators of the underlying genetic defect

U Eiholzer

Institute Growth Puberty Adolescence, Zurich, Switzerland.

First described in 1956, Prader-Labhart-Willi syndome is a rare, complex neurodevelopmental disorder characterised by short stature, disturbed body composition with hyperphagia and hypoactivity, hypogonadism, cryptorchidism, oligophrenia, behaviour problems as well as extreme muscular hypotonia in the neonatal period. Its estimated prevalence ranges from 1:15,000–25,000 and it is caused by an absence of expression of paternally active genes in the PWS critical region on chromosome 15q11.2-q13. Despite in-depth knowledge of the genetic condition in PWS, the final link between the chromosomal disorder and the clinical symptoms remains unclear. Hypothalamic dysfunction appears to underlie many of the features of PWS, including short stature, hypogonadism, abnormal control of appetite and energy expenditure, high pain threshold, and sleep disorders, but no overt structural abnormalities of the hypothalamus have been found yet.

The increased fat accumulation in PWS is caused 1) by a reduction of acitivity-related energy expenditure, because PWS children engage less in physical activity, and 2) by a decrease in basal metabolic rate by 20–50%, reflecting the decrease in lean – mostly muscle – mass. Additionally, growth hormone deficiency contributes not only to the abnormal growth pattern and osteopenia, but also to the deficit of lean body mass and excess of body fat. Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (high FSH, low inhibin B) hypogonadism suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss.

Diabetes mellitus occurs in 17–40% of adults with PWS. During adolescence, insulin resistance and fasting insulin levels are still low, in parallell to the relatively low degree of visceral fat, but insulin secretion is delayed after glucose load. Later, a type 2-like diabetes is assumed to be precipitated by the addition of excessive obesity to impaired insulin secretion.

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