Abhimanyu Garg

Parkland Memorial Hospital, Dallas, Texas, United States

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Publications (175)1471.27 Total impact

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    ABSTRACT: Background: For patients with autosomal dominant hypercholesterolemia (ADH), it remains unclear whether differences exist in the risk of premature coronary heart disease (CHD) between patients with confirmed mutations in low-density lipoprotein receptor (LDLR) vs those without detectable mutations. Objective: This study sought to assess the risk of premature CHD in ADH patients with mutations in LDLR (referred to as familial hypercholesterolemia [FH]) vs those without detectable mutations (unexplained ADH), stratified by sex. Methods: Comparative study of premature CHD in a multiethnic cohort of 111 men and 165 women meeting adult Simon-Broome criteria for ADH. Results: Women with FH (n = 51) had an increased risk of premature CHD compared with unexplained ADH women (n = 111; hazard ratio [HR], 2.74; 95% confidence interval, 1.40-5.34; P = .003) even after adjustment for lipid levels and traditional CHD risk factors (HR, 2.53 [1.10-5.83]; P = .005). Men with FH (n = 42), in contrast, had a similar risk of premature CHD when compared with unexplained ADH men (n = 66; unadjusted: HR, 1.48 [0.84-2.63]; P = .18; adjusted: HR, 1.04 [0.46-2.37]; P = .72). To address whether mutation status provides additional information beyond LDL-cholesterol level, we analyzed premature CHD risk for FH vs unexplained ADH at various percentiles of LDL-cholesterol: the risk ratios were significant for women at 25th percentile (HR, 4.90 [1.69-14.19]) and 50th percentile (HR, 3.44 [1.42-8.32]) but not at 75th percentile (HR, 1.99 [0.95-4.17]), and were not significant for men at any percentile. Conclusions: Our findings suggest that genetic confirmation of ADH may be important to identify patient's risk of CHD, especially for female LDLR mutation carriers.
    No preview · Article · Sep 2015 · Journal of Clinical Lipidology
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    ABSTRACT: A rare presentation of hypothalamic tumors in infants and young children is profound emaciation and generalized loss of subcutaneous (sc) adipose tissue, also known as 'diencephalic syndrome'. Similar loss of sc fat can be observed in children with acquired (AGL) or congenital generalized lipodystrophy (CGL). Precise diagnosis may be challenging early in the course of the disease, especially in the absence of metabolic abnormalities. We report three males, who presented with poor weight gain and generalized loss of sc fat at birth to 3 years of age consistent with generalized lipodystrophy, with subsequent development of pilocytic astrocytoma. Two of them had hypothalamic tumors and one had a multicentric tumor with a large right parietal mass. Our patients are unique as the onset of lipodystrophy occurred 2.5-7.3 years before the diagnosis of brain tumor and all of them gained body fat or weight after surgical removal and/or chemotherapy. One patient had hepato-splenomegaly and impaired glucose tolerance and another one had severe hyperglycemia and hypertriglyceridemia during the course of the disease. Two patients presented with central precocious puberty and advanced bone age at chronological age of 6.3 years. It is likely that pilocytic astrocytoma may induce generalized lipodystrophy by paraneoplastic anti-adipocyte antibody formation or by excessive hormones or cytokine secretion resulting in excess lipolysis from adipocytes. We conclude that young children presenting with idiopathic AGL or atypical CGL with or without metabolic abnormalities, should prompt investigation for brain tumors.
    No preview · Article · Aug 2015 · The Journal of Clinical Endocrinology and Metabolism
  • Nivedita Patni · Abhimanyu Garg
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    ABSTRACT: Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL.
    No preview · Article · Aug 2015 · Nature Reviews Endocrinology
  • Samata Basani · Abhimanyu Garg
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    ABSTRACT: Bexarotene is a retinoid X receptor agonist, which is currently used for the treatment of cutaneous T-cell lymphoma (CTCL). It is known to induce central hypothyroidism as well as dyslipidemia including elevation of triglycerides (TG) and low-density lipoprotein cholesterol along with slight lowering of high-density lipoprotein cholesterol (HDL-C). Marked lowering of HDL-C has never been previously reported in bexarotene-treated patients and whether it is related to hypothyroidism remains unclear.
    No preview · Article · Aug 2015 · Journal of Clinical Lipidology
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    ABSTRACT: Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Apr 2015 · American Journal of Medical Genetics Part A
  • Iram Hussain · Zahid Ahmad · Abhimanyu Garg
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    ABSTRACT: Pseudohyponatremia has been reported in association with severe hypertriglyceridemia and hyperparaproteinemia, but its association with severe hypercholesterolemia is not well-known. We report a 43-year-old woman with refractory primary biliary cirrhosis who presented with asymptomatic hyponatremia (121 mmol/L; normal range: 135-145 mmol/L). She was ultimately found to have a total serum cholesterol level of 2415 mg/dL (normal range: 120-199 mg/dL) - secondary to accumulation of lipoprotein-X-causing pseudohyponatremia. The diagnosis was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270-300 mOsm/kg H2O) and serum sodium by direct potentiometry (141 mmol/L). Furthermore, following 16 sessions of plasmapheresis over a 4-month period, there was marked lowering of serum cholesterol to 200 mg/dL and normalization of serum sodium (139 mmol/L) as measured by indirect potentiometry. This case shows that extreme hypercholesterolemia from elevation of lipoprotein-X particles in cholestasis can be a rare cause of pseudohyponatremia. It highlights the need to measure serum sodium with direct potentiometry in the setting of extreme hypercholesterolemia and consider this possibility before initiating treatment of hyponatremia. Published by Elsevier Inc.
    No preview · Article · Nov 2014 · Journal of Clinical Lipidology
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    ABSTRACT: Context: Sitosterolemia is an autosomal recessive disorder characterized by increased intestinal absorption of plant sterols. It is caused by mutations in genes encoding ATP-binding cassette, subfamily G5 (ABCG5) or G8 (ABCG8), and clinical features include elevated plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, patients with sitosterolemia also hyperabsorb cholesterol, and serum cholesterol levels tend to be elevated. Objective: We report an infant with sitosterolemia who presented with severe hypercholesterolemia and intertriginous xanthomas. Case report: A 15-month-old Korean girl presented with yellow dermal plaques over flexural areas including the wrist, neck, and gluteal folds, which were consistent with intertriginous xanthomas. The lesions were first noticed at 3 months of age when she was being exclusively breastfed. Her total cholesterol and low-density lipoprotein-cholesterol levels were 675 and 540 mg/dL, respectively. A low-fat/low-cholesterol diet and cholestyramine therapy were introduced. Unexpectedly, her serum cholesterol level decreased dramatically and normalized in 2 months. Cholestyramine was tapered off. The xanthomas also regressed and disappeared by 3 years of age. Gas chromatography-mass spectrometric analysis was performed with serum drawn at 3 years of age when her low-density lipoprotein-cholesterol was 118 mg/dL, which revealed striking elevation of her sitosterol level at 19.36 mg/dL. Direct sequencing for ABCG5 revealed compound heterozygous null mutations c.904+1G>A (p.Met302Asnfs*82) and c.1336C>T(p.Arg446*). Conclusions: Our case suggests that sitosterolemia can present with severe hypercholesterolemia and intertriginous xanthomas. Sitosterolemia should be suspected when a patient with hypercholesterolemia shows unexpectedly good response to dietary modification or bile acid sequestrant therapy.
    No preview · Article · May 2014 · The Journal of Clinical Endocrinology and Metabolism
  • Zahid Ahmad · Beverley Adams-Huet · Xilong Li · Abhimanyu Garg

    No preview · Article · May 2014 · Journal of Clinical Lipidology
  • Abhimanyu Garg · Chao Xing

    No preview · Article · May 2014 · American Journal of Medical Genetics Part A
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    ABSTRACT: Type I hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme hypertriglyceridemia that fails to respond to lipid-lowering agents, predisposing to frequent attacks of acute pancreatitis. Mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), lipase maturation factor 1 (LMF1), glycosyl-phosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and apolipoprotein AV (APOA5) cause T1HLP, but we lack data on phenotypic variations among the different genetic subtypes. To study genotype-phenotype relationships among subtypes of T1HLP patients. Genetic screening for mutations in LPL, APOC2, GPIHBP1, LMF1, and APOA5. Tertiary referral center. Ten patients (7 female, 3 male) with chylomicronemia, serum triglyceride levels about 2000 mg/dL, and no secondary causes of hypertriglyceridemia. Genotyping and phenotypic features. Four patients harbored homozygous or compound heterozygous mutations in LPL, 3 had homozygous mutations in GPIHBP1, and 1 had a heterozygous APOA5 mutation. We failed to fully identify the genetic etiology in 2 cases: 1 had a heterozygous LPL mutation only and another did not have any mutations. We identified 2 interesting phenotypic features: the patient with heterozygous APOA5 mutation normalized triglyceride levels with weight loss and fish oil therapy, and all 7 female patients were anemic. Our data suggest the possibility of novel loci for T1HLP. We observed that heterozygous APOA5 mutation can cause T1HLP but such patients may unexpectedly respond to therapy, and females with T1HLP suffer from anemia. Further studies of larger cohorts may elucidate more phenotype-genotypes relationships among T1HLP subtypes.
    No preview · Article · May 2014 · Journal of Clinical Lipidology
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    ABSTRACT: In this study we examined the role of phosphatidic acid (PA) in hepatic glucose production (HGP) and development of hepatic insulin resistance in mice that lack AGPAT2. Liver LPA and PA levels were increased ~2-fold and ~5-fold respectively in male Agpat2-/- mice compared to WT mice. In the absence of AGPAT2, the liver can synthesize PAs by activating diacylglycerol kinase or phospholipase D, both of which were elevated in the livers of Agpat2-/- mice. We found that PAs C16:0/18:1 and C18:1/20:4 enhanced HGP in primary WT hepatocytes, an effect that was further enhanced in primary hepatocytes from Agpat2-/- mice. LPAs C16:0 and C18:1 failed to increase HGP in primary hepatocytes. The activation of HGP was accompanied by an upregulation of the key gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This activation was suppressed by insulin in the WT primary hepatocytes but not in the Agpat2-/- primary hepatocytes. Thus, the lack of normal insulin signaling in Agpat2-/- livers allows unrestricted PA-induced gluconeogenesis significantly contributing to the development of hyperglycemia in these mice.
    Preview · Article · Jan 2014 · Journal of Biological Chemistry
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    ABSTRACT: Leptin is essential for energy homeostasis and regulation of food intake. Patients with congenital generalized lipodystrophy (CGL) due to mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and the CGL murine model Agpat2-/- mice, both, have severe insulin resistance, diabetes mellitus, hepatic steatosis and low plasma leptin levels. In this study, we show that continuous leptin treatment of Agpat2-/- mice for 28 days reduced plasma insulin and glucose levels and normalized hepatic steatosis and hypertriglyceridemia in Agpat2-/- mice. Leptin also partially, but significantly reversed the low plasma thyroxine and high corticosterone levels found in Agpat2-/- mice. Levels of carbohydrate response element binding protein (ChREBP) were reduced, whereas lipogenic gene expression were increased in the livers of Agpat2-/- mice, suggesting that deregulated ChREBP contributed to the development of fatty livers in these mice and that this transcription factor is a target of leptins beneficial metabolic action. Leptin administration did not change hepatic fatty acid oxidation enzymes mRNA levels in Agpat2-/- mice. The selective deletion of leptin receptors only in hepatocytes did not prevent the positive metabolic actions of leptin in Agpat2-/- mice, supporting the previous studies suggesting that the majority of metabolic actions of leptin are dependent on its action in non-hepatocyte cells and/or the central nervous system.
    Full-text · Article · Nov 2013 · The Journal of Lipid Research
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    ABSTRACT: There is some evidence that bariatric surgery patients who undergo the purely restrictive procedures, such as the gastric banding (GB) or the vertical banded gastroplasty surgery, do not meet the dietary reference intakes for several nutrients. Whether dietary counseling improves micronutrient and macronutrient intakes was examined in GB surgery patients. Twenty-three GB surgery patients received dietary and behavioral counseling for 12 weeks to limit energy intake and improve nutrient intakes. Food intake was assessed by 3-day food record at baseline and 6 and 12 weeks. Postintervention data were available in 21 patients. At baseline, more than 50% of the subjects reported inadequate dietary intakes of 13 nutrients but overconsumption of sodium and percent energy from saturated and trans-fatty acids. Mixed-effects model for repeated measures revealed a significant reduction in energy (P = 0.0007), absolute protein (P = 0.04), cholesterol (P = 0.045), and potassium (P = 0.01) intake and an increase in vitamin K (P = 0.03) intake and percent energy from protein (P = 0.005) during the 12 weeks. The McNemar test showed a reduction in the proportion of the subjects with an inadequate intake of vitamin K (P = 0.008) but an increase in the proportion of the subjects with an inadequate intake of thiamin (P = 0.03) at 12 weeks. The proportion of the subjects who did not meet the nutrient requirements for the remaining 27 nutrients was generally high and remained unchanged. Dietary intervention improved the intake of some nutrients in the GB surgery patients. However, most nutrient intake requirements remained unmet by many subjects. These results indicate that nutritional counseling beyond 12 weeks is warranted in GB surgery patients to improve their dietary nutrient intakes.
    No preview · Article · Oct 2013 · Journal of Investigative Medicine
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    ABSTRACT: Generalized lipodystrophy is a rare disorder characterized by marked loss of adipose tissue with reduced triglyceride storage capacity, leading to a severe form of metabolic syndrome including hypertriglyceridemia, insulin resistance, type 2 diabetes mellitus, and hepatic steatosis. Recent echocardiographic studies suggest that concentric left ventricular (LV) hypertrophy is another characteristic feature of this syndrome, but the mechanism remains unknown. It has recently been hypothesized that the LV hypertrophy could be an extreme clinical example of "lipotoxic cardiomyopathy": excessive myocyte accumulation of triglyceride leading to adverse hypertrophic signaling. To test this hypothesis, the first cardiac magnetic resonance study of patients with generalized lipodystrophy was performed, using magnetic resonance imaging and localized proton spectroscopy to detect excessive triglyceride content in the hypertrophied myocytes. Six patients with generalized lipodystrophy and 6 healthy controls matched for age, gender, and body mass index were studied. As hypothesized, myocardial triglyceride content was threefold higher in patients than controls: 0.6 ± 0.2% versus 0.2 ± 0.1% (p = 0.004). The presence of pericardial fat was also found, representing a previously undescribed adipose depot in generalized lipodystrophy. Patients with generalized lipodystrophy, compared with controls, also had a striking degree of concentric LV hypertrophy, independent of blood pressure: LV mass index 101.0 ± 18.3 versus 69.0 ± 17.7 g/m(2), respectively (p = 0.02), and LV concentricity 1.3 ± 0.3 versus 0.99 ± 0.1 g/ml, respectively (p = 0.04). In conclusion, these findings advance the lipotoxicity hypothesis as a putative underlying mechanism for the dramatic concentric LV hypertrophy found in generalized lipodystrophy.
    Full-text · Article · Jun 2013 · The American journal of cardiology
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    ABSTRACT: Introduction: Familial partial lipodystrophy, Dunnigan variety (FPLD), an autosomal dominant disorder caused by LMNA mutations, is characterized by fat loss from the extremities. However, it is unclear whether these patients appear muscular because of a lack of subcutaneous fat or have an actual increase in muscle mass. Therefore, we compared muscle mass and volume of selected muscles in women with FPLD and control subjects using dual-emission x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Methods: Whole-body axial MRI and DXA scans were obtained on 39 women, aged 18 to 65 years, with FPLD and 17 healthy women matched for body mass index and age (group 1). Volumes of muscles in both the thighs, calves, and psoas were calculated from MRI scans and muscle mass in extremities were calculated from DXA. In addition, abdominal MRI and DXA scans were analyzed from 129 healthy, frequency-matched women (group 2). Comparisons between women with FPLD and control subjects were made using ANOVA, adjusting for height, body mass index, and age. Results: Patients with FPLD, compared with control subjects had significantly greater volumes of the thigh muscles, (6358 ± 1491 vs 5198 ± 716 mL, P = .002), calf muscles (3133 ± 713 vs 2397 ± 335 mL; P < .001), and psoas muscles (210 ± 51 vs 175 ± 34 [group 1] and 165 ± 38 mL [group 2], P < .001). Patients with FPLD also had significantly increased arm and leg muscle masses when measured by DXA (P < .001). Insulin sensitivity, assessed by insulin tolerance tests, was negatively correlated to the calf muscle volume. Conclusions: Female patients with FPLD have increased skeletal muscle volume and mass compared with those of normal women.
    No preview · Article · Jun 2013 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: OBJECTIVE: Hepatic steatosis is a common complication in patients with lipodystrophies and can lead to cirrhosis. There is no proven effective therapy for hepatic steatosis, but cholic acid (CA), a farnesoid X receptor agonist, has previously been shown to reduce hepatic triglyceride (TG) content in mice and serum triglycerides in humans. Our objective was to assess clinical efficacy and tolerability of CA therapy in patients with lipodystrophy and hepatic steatosis. DESIGN: A randomized, double-blind, placebo-controlled, crossover study. METHODS: Eighteen patients with genetic or autoimmune lipodystrophies, and elevated hepatic TG content participated in the study. The intervention was CA (15 mg/kg/day) compared with placebo for a period of 6 months each. Hepatic TG content, the primary outcome variable, was measured with 1H magnetic resonance spectroscopy at baseline and at 3 and 6 months during each study period. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and TG were secondary end-points of the study. RESULTS: Compared to placebo, CA did not reduce hepatic TG content [median (interquartile range) 14.8% (9.4-19.0%) vs. 15.9% (10.5-26.5%), respectively; p = 0.42] or serum TG [340 mg/dL (233 - 433 mg/dL) vs. 390 mg/dL (233 - 595 mg/dL) respectively; p=0.45]. CA therapy also did not change AST, ALT or GGT levels. Two patients developed diarrhea and excessive flatus while taking CA and these symptoms resolved after reducing the dose of CA. CONCLUSION: CA was well tolerated but did not reduce hepatic TG content in patients with lipodystrophy.
    Full-text · Article · Feb 2013 · European Journal of Endocrinology
  • Zahid Ahmad · Beverley Adams-Huet · Chiyaun Chen · Abhimanyu Garg
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    ABSTRACT: Unlabelled: BACKGROUND- Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low-density lipoprotein (LDL)-cholesterol, is caused by variants in at least 3 different genes: LDL receptor (LDLR), apolipoprotein B-100, and proprotein convertase subtilisin-like kexin type 9. There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multiethnic patient cohort from lipid clinics in a large, urban US city. METHODS AND RESULTS- A total of 38 men and 53 women, aged 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of LDLR, and in selected exons of apolipoprotein B-100 and proprotein convertase subtilisin-like kexin type 9. Deletions and duplications of LDLR exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in LDLR were identified in 30 patients and in apolipoprotein B-100 in 1 patient. The remaining 60 patients (65%) had unexplained ADH. A higher proportion of blacks (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had unexplained ADH. Compared with patients with LDLR variants, those with unexplained ADH had lower levels of LDL-cholesterol (292 ± 47 mg/dL versus 239 ± 42 mg/dL, respectively; P<0.0001) and higher levels of high-density lipoprotein cholesterol (45 ± 12 mg/dL versus 54 ± 13 mg/dL, respectively; P=0.003). Conclusions: Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks.
    No preview · Article · Oct 2012 · Circulation Cardiovascular Genetics
  • Z Ahmad · SR Phadke · E Arch · J Glass · AK Agarwal · A Garg
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    ABSTRACT: Ahmad Z, Phadke SR, Arch E, Glass J, Agarwal AK, Garg A. Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity.Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the ‘o’ position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease‐causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly‐shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.
    No preview · Article · Jan 2012 · Clinical Genetics
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    ABSTRACT: Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear. The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin<7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles). DESIGN, SETTING, and We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD. Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months. The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content. Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4). Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.
    No preview · Article · Dec 2011 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Loss-of-function mutations in 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) 2 in humans and mice result in loss of both the white and brown adipose tissues from birth. AGPAT2 generates precursors for the synthesis of glycerophospholipids and triacylglycerols. Loss of adipose tissue, or lipodystrophy, results in hyperinsulinemia, diabetes mellitus, and severe hepatic steatosis. Here, we analyzed biochemical properties of human AGPAT2 and its close homolog, AGPAT1, and we studied their role in liver by transducing their expression via recombinant adenoviruses in Agpat2−/− mice. The in vitro substrate specificities of AGPAT1 and AGPAT2 are quite similar for lysophosphatidic acid and acyl-CoA. Protein homology modeling of both the AGPATs with glycerol-3-phosphate acyltransferase 1 (GPAT1) revealed that they have similar tertiary protein structure, which is consistent with their similar substrate specificities. When co-expressed, both isoforms co-localize to the endoplasmic reticulum. Despite such similarities, restoring AGPAT activity in liver by overexpression of either AGPAT1 or AGPAT2 in Agpat2−/− mice failed to ameliorate the hepatic steatosis. From these studies, we suggest that the role of AGPAT1 or AGPAT2 in liver lipogenesis is minimal and that accumulation of liver fat is primarily a consequence of insulin resistance and loss of adipose tissue in Agpat2−/− mice.
    Full-text · Article · Oct 2011 · Journal of Biological Chemistry

Publication Stats

14k Citations
1,471.27 Total Impact Points


  • 2015
    • Parkland Memorial Hospital
      Dallas, Texas, United States
  • 1988-2015
    • University of Texas Southwestern Medical Center
      • • Division of Nutrition and Metabolic Diseases
      • • Department of Internal Medicine
      • • Division of General Internal Medicine
      • • Center for Human Nutrition
      • • Department of Clinical Nutrition
      Dallas, Texas, United States
  • 1988-2011
    • University of Texas at Dallas
      • Biochemistry
      Richardson, Texas, United States