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PubMed1995

An unusual type of familial lipodystrophy.

A mother and her daughter with a novel type of familial partial lipodystrophy were studied. Both had atrophy of fat in the face, chest, and upper and lower limbs and abdominal obesity caused by intraabdominal fat accumulation. The mother had severe insulin resistance and impaired glucose tolerance, whereas the daughter had normal glucose tolerance and normal insulin sensitivity. Both had metabolic rates about 30% above normal levels, but normal thyroid function and plasma lipids.

Abdomen↗
PubMed1999

Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety).

Familial partial lipodystrophy, Dunnigan type (FPLD), is a rare autosomal dominant genetic disorder characterized by gradual loss of sc fat from the extremities, commencing at the time of puberty. Excess fat deposition may occur in the face and neck area. Limited information is available about adipose tissue distribution in patients with FPLD. To investigate whether there is a unique pattern of fat distribution in both affected men and women with FPLD, we performed whole-body magnetic resonance imaging in one male and three female patients from two pedigrees. Magnetic resonance imaging studies confirmed the clinical findings of near-total absence of sc fat from all extremities. Reduction in sc adipose tissue from the truncal area was more prominent anteriorly than posteriorly. Increased fat stores were observed in the neck and face. Intermuscular adipose tissue in the extremities and pelvic area were subjectively increased. Intraabdominal and intrathoracic adipose tissue was not reduced. Bone marrow fat, as well as mechanical adipose tissue, was present in normal amounts. The pattern of fat distribution in the male and females was similar. We conclude that FPLD results in a characteristic absence of sc fat from the extremities, with preservation of intermuscular fat stores.

Adipose Tissue↗
PubMed1999

A gene for congenital generalized lipodystrophy maps to human chromosome 9q34.

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.

Acanthosis Nigricans↗
PubMed2000

Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety).

Familial partial lipodystrophy, Dunnigan type (FPLD; Mendelian Inheritance in Man #151660), is an autosomal dominant disorder characterized by loss of s.c. fat from the extremities and trunk since puberty and predisposition to insulin resistance and its complications. However, for lack of recognition of affected men, previous studies could not ascertain any gender differences in phenotypic expression. Therefore, anthropometric variables and prevalence of diabetes mellitus, dyslipidemia, hypertension, and atherosclerotic vascular disease were compared among 17 postpubertal men and 22 women with FPLD from eight pedigrees. All individuals completed a questionnaire, and fasting blood was analyzed for glucose, insulin, and lipoprotein concentrations. Both affected men and women had similar patterns of fat loss. Compared with the affected men, women had higher prevalence of diabetes (18% and 50%, respectively; P = 0.05) and atherosclerotic vascular disease (12% and 45%, respectively; P = 0.04) and had higher serum triglycerides (median values, 2.27 and 4.25 mmol/L, respectively; P = 0.02) and lower high-density lipoprotein cholesterol concentrations (age-adjusted means, 0.94 and 0.70 mmol/L, respectively; P = 0.04). The prevalence of hypertension and fasting serum insulin concentrations were similar. In conclusion, women with FPLD are more severely affected with metabolic complications of insulin resistance than men. These observations raise the possibility that women with generalized and regional obesity may also have more severe metabolic sequelae of insulin resistance.

Adult↗
PubMed2000

LMNA R482Q mutation in partial lipodystrophy associated with reduced plasma leptin concentration.

Mutations in LMNA, which encodes lamins A and C, have been found in patients with autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). We analyzed the relationship between plasma leptin and the rare LMNA R482Q mutation in 23 adult FPLD subjects compared with 25 adult family controls with normal LMNA in an extended Canadian FPLD kindred. We found that the LMNA Q482/R482 genotype was a significant determinant of plasma leptin, the ratio of plasma leptin to body mass index (BMI), plasma insulin, and plasma C peptide (P= 0.015, P = 0.0007, P = 0.0004, and P < 0.0001, respectively), but not BMI (P = 0.67). Family members who were heterozygous for LMNA Q482/R482 had significantly lower plasma leptin and leptin:BMI ratio than unaffected R482/R482 homozygotes. Fasting plasma concentrations of insulin and C peptide were both significantly higher in LMNA Q482/R482 heterozygotes than in R482/R482 homozygotes. Multivariate regression analysis revealed that the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%, respectively, of the attributable variation in log leptin, leptin:BMI ratio, log insulin, and log C peptide (P = 0.013, P = 0.0007, P = 0.0002 and P < 0.0001, respectively). The results indicate that a rare FPLD mutation in LMNA determines the plasma leptin concentration. It remains to be established whether the reduction in leptin results from the reduced adipose tissue mass in FPLD or from another subcellular effect of mutant LMNA. It also remains to be established whether the insulin resistance in FPLD is a consequence of the reduced plasma leptin or of another functional change resulting from mutant LMNA.

Adult↗
PubMed2001

Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene.

The lamin A/C (LMNA) gene has recently been reported to be mutated in familial partial lipodystrophy, Dunnigan variety (FPLD). We found mutations within exon 8 of LMNA (R482Q, R482W, and G465D) in 12 families with typical FPLD and in exon 11 (R582H) in 1 atypical family. To investigate phenotypic heterogeneity, we compared body fat distribution, using anthropometry and whole body magnetic resonance imaging, and metabolic parameters in women with atypical and typical FPLD. Compared with women with typical FPLD, the two sisters with atypical FPLD had less severe loss of sc fat from all the extremities and trunk and particularly from the gluteal region and medial parts of proximal thighs. Both types had similar excess of fat deposition in the neck, face, intraabdominal, and intermuscular regions. Women with atypical FPLD tended to have lower serum triglyceride and higher high density lipoprotein cholesterol concentrations. As exon 11 of LMNA does not comprise part of the lamin C-coding region, the R582H mutation affects only lamin A protein. Therefore, a unique phenotype of atypical FPLD may result from disrupted interaction of lamin A with other proteins and chromatin compared with typical FPLD, in which interaction of both lamins A and C may be disrupted.

Adipose Tissue↗
PubMed2002

Induction of adipocyte differentiation by a thiazolidinedione in cultured, subepidermal, fibroblast-like cells of an infant with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is characterized by the absence of adipose tissue from birth due to a hypothetical differentiation block. The genetic causes of CGL are still not completely understood. Subepidermal, fibroblast-like cells were prepared from the sc tissue of an infant with CGL. Preadipocytes from sc adipose tissue and foreskin fibroblasts from three healthy patients, respectively, were used as controls. Adipose differentiation was induced in cultured cells by exposure to 10 nM insulin, 200 pM T(3), 1 microM cortisol, and 2 microM rosiglitazone. Under these conditions 42% of the subepidermal, fibroblast-like CGL cells developed into mature adipocytes. Adipogenic differentiation was dependent on rosiglitazone. The differentiation rate was comparable in cultures of preadipocytes from control patients maintained under the same conditions (53%, 38%, and 20%). In contrast, foreskin fibroblasts did not differentiate into adipocytes. Morphological changes in CGL cells during differentiation were associated with the expression of fat cell-specific mRNAs (PPARgamma, leptin, and glut-4). In addition, these cells revealed characteristic features of mature adipocytes, such as lipogenesis or leptin secretion. Taken together, we show that adipocyte precursor cells were present in subepidermal tissue of a patient with CGL and were able to differentiate into adipocytes in the presence of a thiazolidinedione. These findings strongly support clinical trials with thiazolidinediones in patients with CGL.

Adipocytes↗
PubMed2001

CT appearances of HIV-related lipodystrophy syndrome.

Highly active antiretroviral therapy in HIV-1 infected patients is associated with a lipodystrophy syndrome, characterized by wasting of peripheral fat, central adiposity, hyperlipidaemia and insulin resistance. The CT findings are presented and the differential diagnosis is discussed.

Adult↗
PubMedDate not supplied

HIV lipodystrophy: a review.

The dramatic clinical benefit of highly active antiretroviral therapy has been offset, to an extent, by the development of unforeseen long-term toxicities. Of these, the HIV lipodystrophy syndrome is most prominent. The array of related but possibly separate manifestations includes fat deposition and atrophy and metabolic complications such as hyperlipidemias and diabetes mellitus. These have been attributed to the use of protease inhibitors, but other factors may be involved, particularly the use of nucleoside reverse transcriptase inhibitors, especially stavudine. The pathogenesis of any of the manifestations of the syndrome remains to be explained. The metabolic complications may respond to standard treatments, but most therapies directed at fat changes have been unsuccessful. This review will summarize the state of knowledge in the field.

Anti-HIV Agents↗
PubMedDate not supplied

Benfluorex as a therapeutic option for insulin resistance in HIV lipodystrophy syndrome.

BACKGROUND: HIV lipodystrophy syndrome, characterized by a significant excess of visceral adiposity and a reduced subcutaneous fat mass in association with insulin resistance and dyslipidemia, still affects the majority of antiretroviral-treated HIV-infected patients. The therapeutic management of this syndrome has not yet been well established. Benfluorex is known to decrease insulin resistance with no side effects on lactate levels in HIV-negative patients. METHOD: We conducted an open-label study of benfluorex (150 mg, 2-3 times a day) that was prescribed for 60 HIV-infected patients who were diagnosed with glucose metabolism abnormalities by oral glucose tolerance test (OGTT); 47 of these patients had visceral fat accumulation measured by computed tomography (VAT). Median follow-up was 12 months (interquartile range [IQR] = 6-12 months). The great majority of patients (90%) were treated with at least triple therapy (in 70% the therapy included at least one PI), with a nonsignificant change over the study period. RESULTS: Added to antiretroviral therapy, benfluorex improved OGTT in 47/60 cases, including total normalization in 34/60 without lactate concentration modification. A trend toward a decrease in VAT distribution was observed (p =.06). No significant difference was observed in subcutaneous fat distribution, although an increase in subcutaneous thigh adipose tissue was observed in 17/47 (36.2%) cases and 6 patients (12.7%) presented both subcutaneous fat increase and VAT decrease.

Adipose Tissue↗
PubMedDate not supplied

Cardiovagal autonomic dysfunction in relation to HIV-associated lipodystrophy.

PURPOSE: Human immunodeficiency virus (HIV)-associated lipodystrophy (LD) may be mediated by changes in the autonomic nervous system. We examined the autonomic function among HIV-infected patients with LD compared to HIV-infected patients without LD (non-LD) and HIV-negative controls (controls). METHOD: This cross-sectional study examined cardiovagal autonomic function among the three groups. LD was defined in HIV-infected patients as increased visceral adipose accumulation and peripheral lipoatrophy. Cardiovagal autonomic testing was assessed by measuring heart rate variability during rest, paced breathing, and upright tilt and was analyzed in time and frequency domains. RESULTS: Cardiovagal testing was performed on 58 participants: 26 controls, 20 non-LD, and 12 LD. After adjustment for visceral fat, time domain analysis showed decreased heart rate variability in patients with LD compared to the other groups (p < .05). The frequency domain analysis showed decreased high-frequency power and increased low- to high-frequency power ratio in the LD group compared to both groups during rest and to non-LD during tilt (p < .05). CONCLUSION: Patients with LD have altered cardiovagal modulation. Patients with LD had lower heart rate variability and higher sympathetic modulation compared to non-LD and controls. These alterations may be prognostic of increased cardiovascular disease morbidity and mortality.

Adult↗
PubMedDate not supplied

Lipodystrophy in 685 HIV-1-treated patients: influence of antiretroviral treatment and immunovirological response.

PURPOSE: To describe the clinical features in HIV-1-infected patients treated with protease inhibitors (PIs) or not, and to determine factors related to occurrence of lipodystrophy (LD). METHOD: We performed a cross-sectional analysis of 685 treated HIV-1-infected patients that were routinely followed in 6 Paris hospital centers between January and May 1999. Demographic data, familial and personal vascular risk factors, history of antiretroviral treatment, HIV plasma viral load, CD4 cell count, and metabolic data were collected. Clinical examination was based on an assessment of changes in abdominal, dorso-cervical, and breast girth and wasting of the limbs, face, and skin as quoted by the clinician. RESULTS: The mean age at inclusion in the study was 38 years; 29.5% were women. At study assessment, 77.5% of patients were PI-treated and 22.5% had never received a PI. LD was observed in 403 (58.8%) patients, of whom 340 were currently receiving a PI and 63 had never received a PI. More than half of the lipodystrophic patients had a mixed form (53.9%), while 25.3% were classified as exclusive lipoatrophic and 20.8% as exclusive hypertrophic. In multivariate analysis, older age, duration of antiretroviral treatment (ART), antiretroviral combinations including stavudine, antiretroviral combinations including a PI, AIDS status, and a low HIV RNA were independently associated with occurrence of LD. CONCLUSION: LD is frequently observed in PI-treated patients, but it is also observed in patients receiving an ART regimen without PIs. Our study suggests different underlying mechanisms, because immunovirological response to treatment as well as certain therapies were linked to the occurrence of LD. This hypothesis would be best clarified in a large prospective cohort of naive patients.

Adult↗
PubMedDate not supplied

Comparison of metabolic abnormalities and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART: the Trizal study.

PURPOSE: To analyze the evolution of clinical lipodystrophy (LD) and metabolic abnormalities in patients continuing to receive HAART versus patients switched to Trizivir (zidovudine, lamivudine, abacavir) after 48 weeks. METHOD: Patients treated with HAART >6 months with plasma HIV-1 RNA viral load (VL) <400 copies/mL and <50 copies/mL at screening were randomly assigned to continue HAART (103 patients) or to receive Trizivir (106 patients). Clinical LD was evaluated using a standardized patient questionnaire only at baseline, weeks 4 and 8, and then every 8 weeks until Week 48. Laboratory evaluation was performed every 4 weeks. RESULTS: The proportion of patients exhibiting >or=1 LD symptom at baseline was 40% in the Trizivir arm and 50% in HAART arm (difference not significant). After 48 weeks, the prevalence was 28% and 42% respectively (p =.03), and the median number of LD symptoms per patient was 2 in the Trizivir arm and 4 in the continued HAART arm (p =.016). Median decreases in cholesterol levels over the 48-week study period were greater in the Trizivir arm than in the continued HAART arm (-0.80 vs. -0.44 mmol/L; p lt.001). Median triglyceride levels decreased in the Trizivir arm but increased in the continued HAART arm (-0.17 and +0.01 mmol/L; p =.006). Suppression of VL was maintained in most patients with no differences between the two arms. CONCLUSION: A switch from "standard" HAART to Trizivir was associated with an improvement in clinical LD and blood lipid abnormalities after 48 weeks.

Adult↗
PubMedDate not supplied

Update on HIV lipodystrophy.

When prescribed appropriately and taken adherently, antiretroviral therapy can consistently and durably suppress HIV replication, potentially translating into years of near normal health for HIV-infected persons. However, presently available antiretrovirals are associated with a cluster of physical and metabolic symptoms termed HIV lipodystrophy. This article reviews the state of knowledge about the pathogenesis and treatment of the various manifestations of these adverse effects.

Anti-HIV Agents↗
PubMed2006

Long-term effects of recombinant human insulin-like growth factor I treatment on glucose and lipid metabolism and the growth of a patient with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is a disease characterized by generalized lack of body fat, insulin resistance, hypertriglyceridemia, and fatty liver. We studied the long-term effects of recombinant human insulin-like growth factor I (rhIGF-I) treatment on glucose and lipid metabolism and the growth in a patient with CGL. During rhIGF-I treatment, the serum triglyceride level was maintained almost within the normal range, and the plasma glycosylated hemoglobin A1c (HbA1c) levels were maintained under 8.0% (5.8%-7.9%). Thus, rhIGF-I treatment was effective in lowering glucose and triglyceride levels over the long-term in a CGL patient. However, it was difficult to suppress the patient's voracious appetite. Although serum total IGF-I levels were extremely high (1000-1700 ng/ml), growth was not accelerated after the start of rhIGF-I treatment, likely because of normal IGF binding protein 3 (IGFBP-3) levels. During rhIGF-I treatment, the patient developed a recurrence of mild hypertrophic cardiomyopathy and a mild elevation of intraocular pressure.

Adolescent↗
PubMed1976

Post-traumatic anterior pituitary insufficiency developed in a patient with partial lipodystrophy.

A case of partial lipodystrophy developing anterior pituitary insufficiency, chronic glomerulonephritis and pulmonary fibrosis was reported. The patient died of respiratory failure secondary to pituitary crisis during the hospital course. From the clinical course in recent several years and the postmortem examination the head injury following car accident in the past history was considered to be the most plausible cause of hypopituitarism. The etiology of pulmonary fibrosis remained unresolved.

Adrenal Glands↗
PubMed2002

Triglyceride-induced diabetes mellitus in congenital generalized lipodystrophy.

High levels of triglycerides and free fatty acids have been implicated in the pathogenesis of type 2 diabetes mellitus (DM). Congenital generalized lipodystrophy (CGL) is an autosomal recessive syndrome characterized by intense whole body reduction of subcutaneous fat. Its clinical manifestations appear during the first years of life. However, DM is usually a late event. We report a patient with CGL, diagnosed at 4 months of age, who has severe hypertriglyceridemia (serum triglyceride 12.34 mmol/l and cholesterol 3.90 mmol/l), muscular hypertrophy, hepatomegaly and DM (fasting glycemia 25.9 mmol/l). Hepatic biopsy revealed steatosis and fibrosis. A modified normolipidic (composed of medium chain triglycerides) normocaloric normoproteic milky diet and insulin therapy were instituted. After 1 month treatment a reduction of serum glucose and triglyceride levels (4.13 mmol/I and 7.7 mmol/l, respectively) was noted, with later normalization, which led to the discontinuation of insulin therapy. The patient has been maintaining good control with diet alone, presenting normal serum lipid levels (triglycerides 1.07 mmol/l, total cholesterol 2.71 mmol/l) and the following glycemic profile at OGTT: 0' 4.4 mmol/l; 30' 7.0 mmol/l; 60' 3.8 mmol/l; 90' 5.3 mmol/l, and 120' 5.2 mmol/l. The disappearance of hepatic steatosis was evidenced by a biopsy obtained 1 year after the beginning of treatment. In conolusion, this report suggests that the DM occurring in CGL can be precipitated by high triglyceride levels.

Abnormalities, Multiple↗