Diencephalic Involvement in Generalized Lipodystrophy: Rationale and Treatment With the Neuroleptic Agent, Pimozide

Abstract

Our results indicate that generalized lipodystrophy (GLD) possesses as one of its manifestations, diencephalic neuroendocrinopathy. It has been postulated that deranged hypothalamic catecholaminergic mechanisms lead to the hypersecretion of hypophysiotrophic hormones that are detectable in the peripheral circulation. Initial treatment of a pre-puberal GLD patient with chlorpromazine was unrewarding. Chronic treatment of the same patients with the selective dopaminergic blocking agent, pimozide, eliminated corticotrophin releasing factor and luteinizing hormone releasing factor activities from the general circulation. Pimozide treatment ameliorated most of the distorted blood chemistry profile, led to return of facial subcutaneous fat, and elimination of cutaneous hyperpigmentation, fever, abdominal pain, hypertrichosis, oilness of hair, scaliness of skin and to a state of general well-being.The results of these studies, structured within the framework of our present knowledge concerning hypothalamic neurotransmitter/releasing hormone physiology, support the concept of diencephalic involvement in GLD and may provide a guideline to effective therapy.

Congenital Generalized Lipodystrophy and Experimental Lipoatrophic Diabetes in Rabbits Treated Successfully With Fenfluramine

“…Furthermore the patient worsened during the 17 months of pimozide treatment. Contrary to what should be expected (Corbin et al 1974) the level of serum cortisol increased, and the serum concentrations of FSH and LH were un¬ changed. Corbin et al (1974) gave pimozide to a 7 year old girl with acquired gener¬ alized lipoatrophy with pigmentation, hyperlipaemia, insulin resistant hyper¬ glycaemia and hyperinsulinism, and they observed amelioration of the di¬ sturbed blood chemistry profile, and return of the facial subcutaneous fat.…”

“…The plasma lipids will vary with the total caloric intake, and the improvement of hyperinsulinaemia, hyperglycaemia and hypertriglyceridaemia was considered secondary to the reduced consumption of food. As observed by Corbin et al (1974) the initial treatment with chlorpromazine of our patient with congenital generalized lipodystrophy was unrewarding. Furthermore the patient worsened during the 17 months of pimozide treatment.…”

“…The failure of pimozide treatment in our patient can be due to the fact that he had a congenital generalized lipodystrophy, whereas the patient of Corbin et al (1974) had an acquired type. The pathogenesis may be different for the two types; clinically it has been observed that the acquired types have a more acute severe course (Seip 1971).…”

“…Upton 8c Corbin (1973) pursued this idea and proposed that a constant increased secretion of hypothalamic releasing hormones due to a disarrangement of hypothalamic transmitters with an excess of dopamine, and a lowered secretion of norepinephrine was of pathogenetic importance. Consequently they started to treat one patient with acquired generalized lipo¬ dystrophy with a selective dopamine receptor blocker, pimozide, and they ob¬ served a reverseal of all the abnormalities (Corbin et al 1974).…”

Enfin un gène pour la lipodystrophie congénitale de Berardinelli-Seip

“…de facteurs de libération hypothalamiques avait été décrite dans le plasma des patients [8,9]. Une fraction protéique isolée à partir de l'urine des patients Norvégiens (chez lesquels nous venons de détecter des mutations de la seipine) et injectée chez des animaux avait induit un syndrome anabolique associé à une lipoatrophie et à un diabète, ce phé-nomène n'apparaissant pas quand le patient donneur ou l'animal receveur étaient hypophysectomisés [10].…”