Gain of function NOTCH3 variants cause familial partial lipodystrophy due to activation of senescence pathways.

Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant, p.Ala1603Tyr in NOTCH3 meeting the filtering criteria.

Complex dyslipidemia induced by Lorlatinib therapy: A case study.

Context: Lorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is currently used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). Previous reports have noticed an association between lorlatinib and hyperlipidemia, however the specific mechanisms for this side effect remain unknown. Some investigators have reported nephrotic syndrome to be the underlying cause of lorlatinib-induced hyperlipidemia.

Dried blood spot-based free sterol signatures in sitosterolemia diagnostics.

Background: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles.

Materials And Methods: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS).

A Novel Subtype of Acquired Generalized Lipodystrophy Associated With Subcutaneous Panniculitis-Like T-cell Lymphoma.

Acquired generalized lipodystrophy (AGL) is an extremely rare disease that is characterized by loss of body fat affecting nearly all parts of the body. It is often associated with autoimmune diseases or panniculitis, whereas in other patients the underlying etiology is unclear. We report a 52-year-old male individual who was diagnosed with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) that spontaneously went into remission.

Regulated regeneration of adipose tissue in lipodystrophic -null mice partially ameliorates hepatic steatosis.

Both humans and mice with congenital generalized lipodystrophy due to AGPAT2 deficiency develop diabetes mellitus, insulin resistance, and hepatic steatosis, which have been attributed to the near total loss of adipose tissue (AT). Here, we show that regulated AT regeneration in doxycycline (dox)-fed Tg;m mice partially ameliorates hepatic steatosis at 12 weeks of age and causes reduced expression of genes involved in hepatic lipogenesis despite partial (∼30-50%) AT regeneration compared to that in wild-type mice. Compared to chow-fed Tg;m mice, those fed dox diet had markedly reduced serum insulin levels, suggesting an improvement in insulin resistance.

Adipose-specific overexpression of human AGPAT2 in mice causes increased adiposity and mild hepatic dysfunction.

AGPAT2, a critical enzyme involved in the biosynthesis of phospholipids and triacylglycerol (TAG), is highly expressed in adipose tissue (AT). Whether overexpression of AGPAT2 in AT will result in increased TAG synthesis (obesity) and its metabolic complications remains unknown. We overexpressed human specifically in AT using the adiponectin promoter and report increased mass of subcutaneous, gonadal, and brown AT in wild-type mice.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44).

Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family.

Background: Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family.

Regulated adipose tissue-specific expression of human in lipodystrophic -null mice results in regeneration of adipose tissue.

Genetic loss of in humans and mice results in congenital generalized lipodystrophy with near-total loss of adipose tissue and predisposition to develop insulin resistance, diabetes mellitus, hepatic steatosis, and hypertriglyceridemia. The mechanism by which deficiency results in loss of adipose tissue remains unknown. We studied this by re-expressing human (hAGPAT2) in -null mice, regulated by doxycycline.

Restrictive dermopathy due to ZMPSTE24 deficiency.

Restrictive dermopathy (RD) (OMIM 275210) is a rare, lethal genodermatosis belonging to the group of laminopathies. It is caused by biallelic variants in , which is involved in lamin A post-translational processing or, less frequently, by monoallelic variants in , leading to accumulation of truncated prelamin A protein (Navarro et al., 2004; Navarro et al.

The master impersonator: Pulmonary tuberculosis mimicking diffuse cystic lung disease - A mini case series of a rare presentation.

Pulmonary tuberculosis has diverse clinical presentations. Cysts in the lung can arise due to large number of causes out of which tuberculosis is very rare. We report two immunocompetent cases of pulmonary tuberculosis who presented with multiple cysts in the lung parenchyma.

Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study.

Background: Volanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations.

Objective: The present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes.

Methods: BROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods.

Phenotypic Differences Among Familial Partial Lipodystrophy Due to or Variants.

Context: Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous variants and FPLD3 due to 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.

Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

Context: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1.

Lipodystrophy for the Diabetologist-What to Look For.

Purpose Of Review: Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy.

Recent Findings: The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder.

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1).

Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-income Countries.

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.

Decreased caveolae in AGPAT2 lacking adipocytes is independent of changes in cholesterol or sphingolipid levels: A whole cell and plasma membrane lipidomic analysis of adipogenesis.

Background: Adipocytes from lipodystrophic Agpat2 mice have impaired adipogenesis and fewer caveolae. Herein, we examined whether these defects are associated with changes in lipid composition or abnormal levels of caveolae-associated proteins. Lipidome changes were quantified in differentiated Agpat2 adipocytes to identify lipids with potential adipogenic roles.

Severe Liver Injury Associated With High-Dose Atorvastatin Therapy.

Statins are recommended for first-line management of elevated cholesterol in the primary and secondary prevention of atherosclerotic cardiovascular disease. Statins may occasionally be associated with mild transaminase elevations but can also result in life-threatening liver injury. Atorvastatin is the most common cause of clinically significant liver injury in this drug class.

Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an p.R349W Variant.

Background: Pathogenic variants in lamin A/C () cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous c.1045C>T; p.

Absence of AGPAT2 impairs brown adipogenesis, increases IFN stimulated gene expression and alters mitochondrial morphology.

Background: Biallelic loss of function variants in AGPAT2, encoding 1-acylglycerol-3-phosphate O-acyltransferase 2, cause congenital generalized lipodystrophy type 1, a disease characterized by near total loss of white adipose tissue and metabolic complications. Agpat2 deficient (Agpat2) mice completely lacks both white and interscapular brown adipose tissue (iBAT). The objective of the present study was to characterize the effects of AGPAT2 deficiency in brown adipocyte differentiation.