1-Acylglycerol-3-phosphate O-acyltransferase (1-AGPAT) is an enzyme family composed of 11 isoforms. Notably, 1-AGPAT 2, the most studied isoform since its discovery, is a critical enzyme in the triglyceride synthesis pathway, converting lysophosphatidic acid to phosphatidic acid. In addition, AGPAT2 gene expression is shown to be essential for adipocyte development and maturation. Defects in AGPAT2 are responsible for significant pathophysiological alterations related to adipose tissue (AT). Pathogenic variants in this gene are the molecular etiology of Congenital Generalized Lipodystrophy type 1 (CGL1), in which fatty tissue is absent from birth. Metabolically, these individuals have several metabolic complications, including hypoleptinemia, hypoadiponectinemia, hyperglycemia, and hypertriglyceridemia. Furthermore, numerous AGPAT2 pathogenic variants that enormously affect the amino acid sequence, the tertiary structure of 1-AGPAT 2, and their transmembrane and functional domains were found in CGL1 patients. However, studies investigating the genotype-phenotype relationship in this disease are scarce. Here, we used bioinformatics tools to verify the effect of the main pathogenic variants reported in the AGPAT2 gene: c.366-588del, c.589-2A>G, c.646A>T, c.570C>A, c.369-372delGCTC, c.202C>T, c.514G>A, and c.144C>A in the 1-AGPAT 2 membrane topology. We also correlated the phenotype of CGL1 subjects harboring these variants to understand the genotype-phenotype relationship. We provided an integrative view of clinical, genetic, and metabolic features from CGL1 individuals, helping to understand the role of 1-AGPAT 2 in the pathogenesis of this rare disease. Data reviewed here highlight the importance of new molecular studies to improve our knowledge concerning clinical and genetic heterogeneity in CGL1.

We describe our 8-year clinical experience with metreleptin in a Brazilian adult female patient with congenital generalized lipodystrophy type 2 (due to a mutation in the BSCL2 gene) and severe insulin resistance. The patient was initially treated with antidiabetic medications due to the unavailability of metreleptin. Metreleptin was initiated at age 20 years. Reductions from baseline for glycated hemoglobin (HbA1c) and triglycerides on metreleptin were sustained over a 5-year treatment period. The greatest reductions in HbA1c (from 10.8% [95 mmol/mol] to 6.0% [42 mmol/mol], -4.8%) and triglycerides (from 398 mg/dL [4.5 mmol/mL] to 104 mg/dL [1.2 mmol/L], -74%) occurred after 39 months, accompanied by a -95% decrease in total daily insulin usage (from 1600 to 88 IU/day). No significant adverse events occurred throughout metreleptin therapy. Metreleptin therapy was interrupted for 36 months due to limited access to the medication, during which time metabolic parameters deteriorated, returning to near-baseline levels. Thereafter, metreleptin was restarted. At the most recent clinic evaluation (3 months after resuming metreleptin), HbA1c, triglycerides, and liver enzyme levels reduced relative to the last measurements taken during treatment interruption. These findings provide support for the long-term and continuous use of metreleptin in patients with generalized lipodystrophy.

Rippling muscle disease (RMD) is a rare disorder of muscle hyperexcitability. It is characterized by rippling wave-like muscle contractions induced by mechanical stretch or voluntary contraction followed by sudden stretch, painful muscle stiffness, percussion-induced rapid muscle contraction (PIRC), and percussion-induced muscle mounding (PIMM). RMD can be hereditary (hRMD) or immune-mediated (iRMD). hRMD is caused by pathogenic variants in caveolin-3 (CAV3) or caveolae-associated protein 1/ polymerase I and transcript release factor (CAVIN1/PTRF). CAV3 pathogenic variants are autosomal dominant or less frequently recessive while CAVIN1/PTRF pathogenic variants are autosomal recessive. CAV3-RMD manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic creatine kinase elevation to severe muscle weakness. Overlapping phenotypes are common. Muscle caveolin-3 immunoreactivity is often absent or diffusely reduced in CAV3-RMD. CAVIN1/PTRF-RMD is characterized by congenital generalized lipodystrophy (CGL, type 4) and often accompanied by several extra-skeletal muscle manifestations. Muscle cavin-1/PTRF immunoreactivity is absent or reduced while caveolin-3 immunoreactivity is reduced, often in a patchy way, in CAVIN1/PTRF-RMD. iRMD is often accompanied by other autoimmune disorders, including myasthenia gravis. Anti-cavin-4 antibodies are the serological marker while the mosaic expression of caveolin-3 and cavin-4 is the pathological feature of iRMD. Most patients with iRMD respond to immunotherapy. Rippling, PIRC, and PIMM are usually electrically silent. Different pathogenic mechanisms have been postulated to explain the disease mechanisms. In this article, we review the spectrum of hRMD and iRMD, including clinical phenotypes, electrophysiological characteristics, myopathological findings, and pathogenesis.

In this study, we analysed the mutation spectrum in subjects with suspected lipodystrophy using a targeted Next-generation sequencing (NGS) approach. Subjects with suspected lipodystrophy were for screened six genes (AGPAT2, BSCL2, LMNA, PPARG, ZMPSTE24, INSR) and the variants identified were confirmed through Sanger sequencing. The clinical and biochemical parameters were compared among the mutation positive and negative subjects. We identified eight individuals with pathogenic or likely pathogenic mutations, including both homozygous and heterozygous variants. Homozygous variants included  AGPAT2(NM_006412.4):c.493-2A>G, AGPAT2(NM_006412.4):c.254_258dup, and BSCL2(NM_001122955.4):c.570del, while heterozygous variants encompassed LMNA(NM_170707.4):c.1444C>T, LMNA(NM_170707.4):c.1456A>G, LMNA(NM_170707.4):c.1445G>A, and PPARG(NM_015869.5):c.949T>C mutations. In this cohort, three subjects were diagnosed with congenital generalized lipodystrophy, while the remaining five had familial partial lipodystrophy. Majority (7/8) of the patients with lipodystrophy had hepatic involvement. Notably, more than half of the subjects (5/8) achieved optimal glycemic control through insulin sensitizers (PPARγ agonist and Metformin). Interestingly, even with a limited gene panel test, mutation-positive individuals exhibited a higher prevalence of typical clinical features and biochemical characteristics associated with lipodystrophy compared to their mutation-negative counterparts. In subjects with lipodystrophy, targeted NGS based screening may establish a genetic diagnosis and aid in family screening and genetic counselling. Knowing the clinical and biochemical features typical to lipodystrophy may help in diagnosis especially in resource limited setting.

We herein first report the use of conventional echocardiography combined with two-dimensional speckle-tracking to diagnose and monitor the changing process of cardiac involvement in an infant with congenital lipodystrophy. An 8-month-old girl was admitted to our hospital after first presenting at the age of 3 months with abnormal facial features that had been noticed within 4 weeks of birth. Echocardiography performed at the age of 3 months showed only slightly accelerated blood flow in the right ventricular outflow tract. At the age of 5 months, echocardiography showed myocardial hypertrophy; this finding combined with the physical characteristics and other examination results led to the consideration of congenital lipodystrophy. Genetic testing at the age of 9 months confirmed type 2 congenital lipodystrophy caused by BSCL2 gene mutation, and dietary modification was initiated. Conventional echocardiography performed at the ages of 5, 8, and 14 months showed no significant changes and a normal ejection fraction. However, two-dimensional speckle-tracking performed between the ages of 5 and 8 months showed cardiac systolic abnormalities that tended to improve after treatment. This case highlights the value of echocardiography in detecting structural and early functional cardiac changes in infants with congenital lipodystrophy.