Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants.

Context: Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. Objective: To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. Methods: A retrospective, cross-sectional comparison of patients from 2 tertiary referral centers-UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. A total of 196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years) were included. The main outcome measures were skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia. Results: Compared with subjects with FPLD2, subjects with FPLD3 had significantly increased prevalence of hypertriglyceridemia (66% vs 84%) and diabetes (44% vs 72%); and had higher median fasting serum triglycerides (208 vs 255 mg/dL), and mean hemoglobin A1c (6.4% vs 7.5%). Compared with subjects with FPLD2, subjects with FPLD3 also had significantly higher mean upper limb fat (21% vs 27%) and lower limb fat (16% vs 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs 11.3 mm), calf (4 vs 6 mm), triceps (5.5 vs 7.5 mm), and biceps (4.3 vs 6.8 mm). Conclusion: Compared with subjects with FPLD2, subjects with FPLD3 have milder lipodystrophy but develop more severe metabolic complications, suggesting that the remaining adipose tissue in subjects with FPLD3 may be dysfunctional or those with mild metabolic disease are underrecognized.

Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome.

CONTEXT: Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated. OBJECTIVE: To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP. METHODS: Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1. RESULTS: Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family. CONCLUSIONS: We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.

Free fatty acid processing diverges in human pathologic insulin resistance conditions.

BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma ß-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). ß-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.

Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety.

CONTEXT: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. OBJECTIVE: To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. METHODS: We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. RESULTS: The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. CONCLUSIONS: The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.

Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations.

CONTEXT: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN: Single-arm, open-label study of liothyronine. SETTING: National Institutes of Health. PARTICIPANTS: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

Clinical and laboratory characteristics and follow up of 62 cases of ketotic hypoglycemia: a retrospective study.

INTRODUCTION: Idiopathic ketotic hypoglycemia (KH) is the most common cause of hypoglycemia in non-diabetic children ages 0.5-6 years old and typically occurs after a period of poor food intake. There are no large studies looking at the value of common laboratory testing in children presenting with KH or how often other diagnoses are made. OBJECTIVES: To examine the clinical presentations and the value of laboratory testing done in a cohort of children clinically diagnosed with KH. METHODS: Billing records were searched from 2008 to 2017 for patients seen by the endocrine service for "hypoglycemia, not otherwise specified". Charts were reviewed to determine age, sex, presenting symptoms and testing ordered at the time of the consult. Through chart reviews after the event and parent phone calls, diagnoses other than idiopathic KH were searched. RESULTS: Of 150 charts reviewed, 62 had sufficient information to make a clinical diagnosis of KH (32 males 30 females, mean age 2.9 years). Most had a history of gastrointestinal illness or prolonged fasting but 29% had no apparent precipitating event. Laboratory testing was quite variable and while low serum CO2 was seen in over half, no routine hormone testing, metabolic testing or supervised fasting resulted in a relevant diagnosis. We identified 4 out of 62 (6.5%) with relevant diagnoses which explained KH, including one child with failure to thrive found to have growth hormone (GH) deficiency and 3 by genetic testing, including one case of GSD type 9α, but all had atypical presentations. CONCLUSIONS: In the typical setting of a healthy 0.5-6 year-old child with an uncomplicated episode of KH following poor food intake and a normal exam including growth, hormonal and metabolic testing can safely be deferred. However, frequent recurrences and atypical features should prompt further investigation. TRIAL REGISTRATION: Not needed for a retrospective chart review study.

Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants.

CONTEXT: Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group. OBJECTIVE: To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. DESIGN: Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides. INTERVENTION: Metreleptin (0.08 to 0.16 mg/kg) for 12 months. OUTCOME: Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. RESULTS: Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%. CONCLUSION: Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.