Lipodystrophy disorders are characterized by selective loss of fat tissue with metabolic complications including insulin resistance, hypertriglyceridemia, and nonalcoholic liver disease. These complications can be life-threatening, affect quality of life, and result in increased health care costs. Genetic discoveries have been particularly helpful in understanding the pathophysiology of these diseases, and have shown that mutations affect pathways involved in adipocyte differentiation and survival, lipid droplet formation, and lipid synthesis. In addition, genetic testing can identify patients whose phenotypes are not clearly apparent, but who may still be affected by severe metabolic complications.
Context: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. Objective: We aimed to study natural history and disease burden of various subtypes of CGL. Design: We attempted to ascertain nearly all patients with CGL in Turkey. Setting: This was a nationwide study. Patients or Other Participants: Participants included 33 patients (22 families) with CGL and 30 healthy controls. Main Outcome Measure(s): We wanted to ascerta...
#1Nivedita Patni(UTSW: University of Texas Southwestern Medical Center)H-Index: 10
#2Abhimanyu Garg(UTSW: University of Texas Southwestern Medical Center)H-Index: 18
Patients with congenital generalized lipodystrophy (CGL) have a near total absence of body fat owing to mutations in genes involved in lipid storage. This Review describes the genetic pathophysiology of the four main forms of CGL and makes recommendations for their appropriate diagnosis and management. Specific therapies for CGL are currently limited, but the authors highlight novel drugs currently in development to treat this condition.
#1Abhimanyu Garg(UTSW: University of Texas Southwestern Medical Center)H-Index: 18
#2Martin Kircher(UW: University of Washington)H-Index: 41
Last. Anil K. Agarwal(UTSW: University of Texas Southwestern Medical Center)H-Index: 56
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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_480...
#2Szabolcs Szelinger(TGen: Translational Genomics Research Institute)H-Index: 19
Last. Matthew J. Huentelman(TGen: Translational Genomics Research Institute)H-Index: 32
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A 3-year-old female patient presenting with an unknown syndrome of a neonatal progeroid appearance, lipodystrophy, pulmonary hypertension, cutis marmorata, feeding disorder and failure to thrive was investigated by whole-genome sequencing. This revealed a de novo, heterozygous, frame-shift mutation in the Caveolin1 gene (CAV1) (p.Phe160X). Mutations in CAV1, encoding the main component of the caveolae in plasma membranes, cause Berardinelli-Seip congenital lipodystrophy type 3 (BSCL). Although B...
#2Elaine Cochran(NIH: National Institutes of Health)H-Index: 31
Last. Rebecca J. Brown(NIH: National Institutes of Health)H-Index: 29
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Context: Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD). Objective: The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response. Design: This was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January...
Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium ...
#1Rebecca J. Brown(NIH: National Institutes of Health)H-Index: 29
#2Phillip Gorden(NIH: National Institutes of Health)H-Index: 94
Leptin in the form of recombinant human methionyl leptin (metreleptin) has now been approved by the FDA for treatment of generalized forms of lipodystrophy. Leptin deficiency plays a major role in the extreme metabolic derangement of lipodystrophy and, therefore, provides a specific drug target. This is one of the best examples of the translation of a fundamental scientific discovery to a drug directly applicable to patients. Leptin therapy in lipodystrophy leads to a major reduction in serum tr...
#1Sali M.K. Farhan(UWO: University of Western Ontario)H-Index: 12
#2John F. Robinson(UWO: University of Western Ontario)H-Index: 20
Last. Robert A. Hegele(UWO: University of Western Ontario)H-Index: 112
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Abstract Background Familial lipodystrophies are rare inherited disorders associated with redistribution of body fat and development of dyslipidemia, insulin resistance, and diabetes. We previously reported 2 siblings with unusual late-onset familial partial lipodystrophy in whom heretofore known causative genes had been excluded. We hypothesized they had a mutation in a novel lipodystrophy gene. Methods Our approach centred on whole exome sequencing of the patients' DNA, together with genetic l...
Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward...
Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutat...
Last. Khadijeh Mirzaei(Tehran University of Medical Sciences)H-Index: 17
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BACKGROUND Metabolic syndrome (MetS) is associated with an increased risk of morbidity and mortality in almost all chronic diseases. The most frequent methods for the calculation of a continuous MetS (cMetS) score have used the standardized residuals in linear regression (z-score). Recently, emerging data suggest that one of the main genetic targets is the CAV1, which plays a crucial role in regulating body fat distribution. This study is designed to investigate the relationship between CAV1 rs3...
PURPOSE OF REVIEW Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the und...
Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with...
Resume Les lipodystrophies partielles d’origine genetique sont des maladies rares caracterisees par un deficit selectif de tissu adipeux (TA). Leur diagnostic est complexe et leur prevalence est sous-estimee du fait de leur proximite clinique avec le syndrome metabolique. Le diagnostic repose sur la mise en evidence d’une lipoatrophie partielle et sur l’existence de complications metaboliques en lien avec l’absence de TA. Plusieurs genes sont impliques dans ces maladies, bien que dans plus de 50...
#2Alessio D’Alessio(Agostino Gemelli University Polyclinic)H-Index: 3
Caveolae are flask-shaped invaginations of the plasma membrane found in numerous cell types and are particularly abundant in endothelial cells and adipocytes. The lipid composition of caveolae largely matches that of lipid rafts microdomains that are particularly enriched in cholesterol, sphingomyelin, glycosphingolipids, and saturated fatty acids. Unlike lipid rafts, whose existence remains quite elusive in living cells, caveolae can be clearly distinguished by electron microscope. Despite thei...
#2Baris Akinci(UM: University of Michigan)H-Index: 23
Last. Elif A. Oral(UM: University of Michigan)H-Index: 31
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Introduction: Lipodystrophy is a heterogeneous group of rare diseases characterized by various degrees of fat loss which leads to serious morbidity due to metabolic abnormalities associated with in...
Congenital generalized lipodystrophy (CGL) is an autosomal recessive rare disease, with a worldwide prevalence of around 1 in every 12 million people. There are several case reports of patients with CGL in Piura, a region in northern Peru; however its regional prevalence is unknown. The objective was to determine the prevalence of CGL in the region of Piura, Peru during the years 2000-2017. A descriptive, observational study was carried out. A search of clinical histories of patients with the di...
