Generalized Lipodystrophy Research Articles

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.

Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.

Mutations in the seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil.

Berardinelli-Seip congenital lipodystrophy (BSCL) is characterized by a near total congenital absence of fat and predisposition to develop diabetes mellitus. In this study, we investigated the presence of mutations in the Seipin and 1-acylglycerol phosphate acyltransferase 2 (AGPAT2) genes in 32 affected subjects with BSCL from 17 consanguineous pedigrees living in two separate geographical regions, the northeastern and southeastern regions, of Brazil. All, except one, of the 22 BSCL subjects from 15 families living in the northeastern region were found to have a homozygous 669insA mutation in the Seipin gene. In contrast, all 10 BSCL subjects from two families living in the southeastern region were found to a have a homozygous 1036-bp deletion including exons 3 and 4 of AGPAT2. These results support genetic heterogeneity among BSCL patients in Brazil. Our finding of a single mutation in the Seipin and AGPAT2 genes in the pedigrees from the northeastern and southeastern regions, respectively, will be useful in genetic counseling of subjects from these large pedigrees from Brazil.

Genetic basis of congenital generalized lipodystrophy

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by extreme lack of body fat and severe insulin resistance since birth. Recently, mutations have been reported in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin) genes in affected subjects from pedigrees linked to chromosomes 9q34 and 11q13, respectively. The AGPAT2 catalyses the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. High expression of AGPAT2 mRNA in adipose tissue compared to other isoforms suggests that the mutations might affect the adipose tissue the most. The function of BSCL2 remains unknown. Several CGL pedigrees reveal no mutation in either of the above genes and are not linked to these loci, suggesting additional genetic loci for CGL. Thus, several distinct mechanisms can lead to extreme lack of adipose tissue in humans and cause CGL.

Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

Prevalence of mutations in AGPAT2 among human lipodystrophies.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.

Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman.

Seventeen children with congenital generalized lipodystrophy or Berardinelli-Seip Congenital Lipodystrophy (BSCL) from 12 consanguineous sibships were observed in Oman. All children had widespread absence of adipose tissue from infancy together with apparent muscle hypertrophy and hepatomegaly. They did not appear to represent a single homogenous entity, and it was possible to subclassify the cases into two distinct groups. In the first group of seven cases, the features were similar to other published cases with acanthosis nigricans, raised insulin levels, and insulin resistance. In this group, there was an association between the degree of acanthosis nigricans and the severity of the disorder. Molecular analysis of these cases showed homozygosity at the BSCL2 locus on chromosome 11q13 in four of the seven cases. In the second group of ten cases, there were striking abnormalities in both skeletal and nonskeletal muscle. Reduced exercise tolerance and percussion myoxedema were observed in skeletal muscle, while infantile hypertrophic pyloric stenosis, prominent veins (phlebomegaly), disturbance of cardiac rhythm, and cardiomyopathy were observed in nonskeletal muscle. There was evidence against homozygosity in some cases for the known loci for BSCL, and this group may represent a new clinical syndrome with lipodystrophy at a different genetic location.

Serum adiponectin and leptin levels in patients with lipodystrophies.

Lipodystrophies are characterized by selective but variable loss of body fat and metabolic complications of insulin resistance. We hypothesized that reduced synthesis and secretion of adipocyte-specific proteins may be related to the metabolic complications of lipodystrophy. Therefore, we compared fasting serum concentrations of adiponectin and leptin, in 18 patients with congenital generalized lipodystrophy (CGL), 11 with acquired generalized lipodystrophy (AGL), 46 with familial partial lipodystrophy-Dunnigan variety (FPLD) and 18 with acquired partial lipodystrophy (APL) and studied their relationship to metabolic parameters. Patients with CGL and AGL had markedly reduced serum adiponectin levels compared to those with FPLD and APL (median [range]: 1.5 [0.4-7.5], 3.2 [0.6-7.7], 6.9 [1.9-23.2] and 7.9 [3.1-13.3] microg/mL, respectively, p < 0.0001); the same trend was noted for serum leptin levels (0.63 [0.05-3.7], 2.18 [0.05-11.30], 2.86 [0.23-9.00] and 6.24 [1.21-10.4] ng/mL, respectively, p < 0.0001). Serum adiponectin levels correlated negatively with fasting serum triglycerides (r = -0.6, p < 0.001) and insulin levels (r = -0.5, p < 0.0001) and positively with serum high-density lipoprotein cholesterol levels (r = 0.5, p < 0.001). Serum adiponectin levels were lower in patients with diabetes compared to non-diabetic subjects (3.0 vs. 7.1 microg/mL, p < 0.001). Our results indicate that serum adiponectin and leptin levels are extremely low in patients with generalized lipodystrophies and may be related to severe insulin resistance and its metabolic complications in lipodystrophies.

Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci.

Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the absence of body fat and insulin resistance and accompanied by other features, including acanthosis nigricans, organomegaly, hyperandrogenism, and diabetes. We have examined case subjects from 11 families in Oman with CGL. All subjects were the progeny of consanguineous marriages; therefore, a homozygosity mapping strategy was used to investigate the reported loci, 11q13 and 9q34. Three subjects could be linked to 11q13, and mutations were found within the seipin gene. An additional eight subjects were linked to 9q34, but the locus was in a 9-cM interval with no known microsatellites, so further fine mapping was not possible. However, two sibships (four subjects) did not map to either locus, raising the possibility of more than two lipodystrophy loci within the Oman population.

Localization, cDNA sequence and genomic organization of the rat seipin gene (Bscl2) and sequence analysis in inbred rat models of Type 2 diabetes mellitus

Mutations in the gene encoding seipin cause Berardinelli-Seip congenital lipodystrophy 2, with symptoms including near-absence of adipose tissue and altered glucose tolerance. Radiation hybrid analysis localized the seipin gene (Bscl2) in rat to a major quantitative trait locus in rat chromosome 1 linked to glucose intolerance in the Goto-Kakizaki (GK) rat model of Type 2 diabetes. We determined the genomic organization of Bscl2 and screened coding exons and flanking intron sequences for mutations in GK, Wistar and Brown Norway rats, as well as in the Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rat. Two silent single nucleotide polymorphisms that were identified also were found in non-diabetic rat strains. We conclude that mutations in the gene for seipin are unlikely to contribute to diabetes in GK and OLETF rats.

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Single nucleotide polymorphisms of RXRA encoding retinoid X receptor alpha.

Retinoic X receptor alpha (RXRA), encoded by RXRA, plays a key role in development and metabolism, specifically in adipocyte biology, glucose homeostasis, and intestinal cholesterol balance. RXRA is also a positional candidate gene for Berardinelli-Seip congenital lipodystrophy. We report the systematic screening of RXRA coding regions by genomic DNA sequencing, which has resulted in the identification of three novel single-nucleotide polymorphisms.

Discovery of a lipodystrophy gene: one answer, one hundred questions.

Lipodystrophy is a rare and heterogenous disorder characterized by absence or loss of adipose tissue from different parts of the body. Classification of the different lipodystrophy syndromes is based mainly on whether the disease is congenital/familial or acquired, and whether the fat loss is generalized or partial. Since the first patient with lipodystrophy was described 115 years ago (1) much has been learned about the clinical features of this condition. However, until recently, little was known about the etiology and pathogenesis of these syndromes. Two groups have now identified the gene mutations responsible for familial partial lipodystrophy. Surprisingly, all the mutations were found in lamin A/C, a gene on human chromosome 1q21‐22 encoding a nuclear envelope protein (2, 3). The gene for congenital generalized lipodystrophy was mapped to human chromosome 9q34 (4). While these findings provide some insight into the genetic causes of familial lipodystrophy, they also raise many new questions. In order to better understand these recent discoveries and their implications, it is helpful to review briefly what is known about lipodystrophies (5) and lamins (6‐9) and about their potential relationship. Lipodystrophies are divided into familial and acquired categories. Familial lipodystrophies can further be subdivided into two major groups: congenital generalized lipodystrophy (Berardinelli‐Seip syndrome) and familial partial lipodystrophy (Dunnigan variety) (Table 1). Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by almost complete absence of adipose tissue from birth. All metabolically active fat (subcutaneous, intra-abdominal, intrathoracic, bone marrow, parathyroid glands) is missing whereas mechanical fat (palms, soles, orbits, buccal region, tongue) is preserved. Familial partial lipodystrophy (FPLD) has an autosomal dominant inheritance, but the onset of symptoms occurs in puberty when patients start losing subcutaneous fat from the extremities, and typically accumulate fat in the neck and face. The rest of the metabolically active adipose tissue remains normal. The two main syndromes of acquired lipodystrophy are acquired generalized lipodystrophy (Lawrence syndrome) and acquired partial lipodystrophy (Barraquer‐ Simons syndrome). Acquired generalized lipodystrophy is characterized by an onset in childhood or adolescence. Patients lose subcutaneous fat from the extremities, the trunk, the neck and face as well as from palms and soles. Concomitant autoimmune disease is common in these patients. Acquired partial lipodystrophy begins also in childhood and affects primarily the face spreading then down to the neck, shoulders, upper extremities and trunk. There also is an association with autoimmune diseases, especially mesangiocapillary glomerulonephritis that typically develops years after the onset of the lipodystrophy. All the lipodystrophies share a characteristic phenotype of increased muscular appearance in the areas of fat loss. This may explain why women are more frequently diagnosed with the disease than men, who may not seek medical attention, as their findings may not be as noticeable. Metabolically, the lipodystrophy syndromes are accompanied by severe disturbances of glucose and lipid metabolism with the exception of acquired partial lipodystrophy, which only rarely shows metabolic complications. A hallmark of lipodystrophy is

Skeletal muscle morphology and exercise response in congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive genetic disorder characterized by almost complete absence of adipose tissue, muscular appearance, and severe insulin resistance since birth. We investigated whether insulin resistance in CGL patients is associated with abnormal muscle morphology and whether increased muscularity imparts increased muscle strength and exercise capacity We obtained quadriceps muscle biopsies to study muscle fiber types and capillary density in three African-American women (aged 17-20 years) with CGL. We also assessed quadriceps muscle strength, muscle metabolism, and maximal O2 consumption in the patients. Quadriceps muscle biopsies revealed a markedly higher percentage of type II (fast-twitch glycolytic) muscle fibers in patients with CGL versus sedentary young women (75-78 vs. 47-57%, respectively). The capillary-to-fiber ratio (2.7-3.0), however, was normal. Cross-sectional areas of type I (slow-twitch oxidative) (1,262-2,685 microm2) and type II (2,304-3,594 microm2) fibers were far below the normal values (3,811-4,310 and 3,115-4,193 microm2, respectively), suggesting muscle hyperplasia but not hypertrophy The quadriceps muscle strength, as measured by Cybex, was below average; the maximal O2 consumption (23-32 ml x kg(-1) x min(-1)) was also below average. 31P nuclear magnetic resonance spectroscopy of the forearm muscles revealed normal pH and metabolic responses to static and dynamic exercises. We conclude that insulin resistance in patients with CGL is associated with an increased proportion of type II muscle fibers but not reduced capillary density. Increased muscularity in CGL is due to muscle hyperplasia and is not associated with increased muscle strength.

Leptin is a potent anti-diabetic in mice with lipodystrophy and insulin resistance.

Obesity is associated with insulin resistance. However, insulin sensitivity can be even more attenuated in individuals with hardly any fat cells at all. Patients with Berardinelli-Seip congenital lipodystrophy (BSCL) have insulin resistance with secondary hyperinsulinaemia, and insulin-resistant diabetes mellitus (1). They may also have hyperlipidaemia, hepatomegaly, hypertrophic cardiomyopathy, acanthosis nigricans, elevated basal metabolic rate and an excessive food intake. The syndrome is thought to be autosomal recessive, and linkage studies have indicated a locus at chromosome 9q34 (2), whereas 1q21‐22 is the locus in a similar syndrome with partial lipodystrophy (3). The region on chromosome 9 harbours the retinoid X receptor a gene (RXRA), which is a potential candidate gene and important for adipocyte differentiation. Recently, three transgenic mouse models of generalised lipodystrophy have been developed. In all of them the expression of specific genes was directed to white and brown fat cells through use of a vector with a regulatory sequence found in the aP2 gene, which is adipocyte-specific. A delayed-onset form of lipodystrophy was induced in mice by Burant et al. (4), who used the aP2 enhancer/ promoter to target the expression of the diphtheria toxin A gene to adipocytes. These mice gradually lost their fat, but did not show any sign of lipodystrophy until 5‐6 months of age. At 8‐10 months no white adipose tissue was visible, and they developed insulin resistance, diabetes, fatty liver and hypertriglyceridaemia. A mouse model developed by Moitra et al. (5) was lipodystrophic from birth. They directed the expression of an artificial transcription factor designated A-ZIP/F to white and brown fat cells. The transcription factor was constructed so that it made stable promiscuous dimerisation with all members of the Jun and CCAAT/ enhancer-binding protein (C/EBP) family and attenuated their activity. Previous studies have shown that these proteins are essential for terminal adipocyte differentiation. The mice had no fat tissue at birth and developed diabetes with increased serum glucose and insulin levels. The liver was filled with lipid and the internal organs were enlarged as in humans with BSCL.

Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver. We have developed a mouse model that mimics these features of CGL: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under the control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in messenger RNAs encoding several fat-specific proteins, including leptin, a fat-derived hormone that regulates food intake and energy metabolism. Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.

Congenital total lipodystrophy and peripheral pulmonary artery stenosis

Multiple peripheral pulmonary artery stenoses were detected in three patients with congenital generalised lipodystrophy. This association, which has not been described before, may be clinically important in patients with lipodystrophy...

Genetics of the Berardinelli-Seip syndrome (congenital generalized lipodystrophy) in Norway: epidemiology and gene mapping. Berardinelli-Seip Study Group.

Five of the six families with the Berardinelli-Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum lod score + 1.3). None of the last showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A heterochromatic 9qh + segregated from one parent in two families.

BEHAVIOR SYNDROME IN FEMALE LIPODYSTROPHY PATIENTS RECEIVING NEUROLEPTIC DRUGS

Pimozide, an antipsychotic neuroleptic drug, administered to a young girl with generalized lipodystrophy (GLD) Induced a beneficial effect (Pediat.Res.8:435, 1974). When we administered pimozide to other lipodystrophy patients, the drug produced in affected females beyond puberty a mood change which prevented its continued use.Pimozide in low dose (1-4 mg/day) to 5 postpubescent females (3 GLD, 2 atypical lipodystrophy) produced an immediate disabling mood change characterized by catalepsy, anxiety, and sedation. These changes were not the extrapyramidal side effects produced by pimozide in high dose (>40 mg/day). In one GLD patient, the neuroleptic agents trifluropromazine and haloperidol were administered separately in low dose with effects like that of pimozide. Continued use of pimozide in the original prepubescent GLD patient has shown limited beneficial effect; now that she is entering puberty, the behavior syndrome is developing. Two males with GLD (2 and 56 years) and one prepubescent female with partial lipodystrophy, have not developed the behavior syndrome on pimozide.These observations indicate an aberrant neurohumoral etiologic mechanism in lipodystrophy and support the theory of defective hypothalmic dopamine metabolism. Absence of the behavior syndrome in a pre- and postpubescent male suggests a sex difference in hypothalamic dopamine metabolism. The findings are analogous to the induced behavior in rats injected intracerebrally with β-endorphin, a fragment of the pituitary hormone, β-lipotrophin.

CONGENITAL GENERALIZED LIPODYSTROPHY:

Generalized lipodystrophy (Berardinelli-Seip's syndrome) was diagnosied in a boy at the age of 8-1/2 months. Ten months later he died because of aspiration of food. Necropsy with special reference to the CNS revealed hypothalamic lesions, probably of a malformative or hamartomatous nature. The findings lend additional support to the view that hypothalamic dysfunction is responsible for the signs and symptoms of generalized lipodystrophy.

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.