Spectrum of germline and somatic mitochondrial DNA variants in Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is caused by loss of function variants in either and is characterized by broad phenotypic heterogeneity Currently, there is limited knowledge regarding the role of the mitochondrial genome (mtDNA) in TSC pathogenesis. In this study, we aimed to determine the prevalence and spectrum of germline and somatic mtDNA variants in TSC and identify potential disease modifiers. Analysis of mtDNA amplicon massively parallel sequencing (aMPS) data, off-target mtDNA from whole-exome sequencing (WES), and/or qPCR, revealed mtDNA alterations in 270 diverse tissues (139 TSC-associated tumors and 131 normal tissue samples) from 199 patients and six healthy individuals.

Dysregulated lipid metabolism in lymphangioleiomyomatosis pathogenesis as a paradigm of chronic lung diseases.

A chronic inflammatory condition characterizes various lung diseases. Interestingly, a great contribution to inflammation is made by altered lipids metabolism, that can be caused by the deregulation of the mammalian target of rapamycin complex-1 (mTORC1) activity. There is evidence that one of mTOR downstream effectors, the sterol regulatory element-binding protein (SREBP), regulates the transcription of enzymes involved in the fatty acid synthesis.

Cystic lung disease.

The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually contain air. The differential diagnosis of these lesions can be challenging, requiring both clinical and radiological perspectives. Entities such as pulmonary emphysema and cystic bronchiectasis can simulate cystic disease.

Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis.

Background: A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis.

Research Question: Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis?

Study Design And Methods: We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250 mg/d and escalated every 8 weeks to maximum dose of 1,000 mg/d over 24 weeks.

Diffuse cystic lung diseases: Imaging spectrum and diagnostic approach using high-resolution computed tomography.

The lung cyst is an air-containing lucent area surrounded by thin imperceptible walls. Other lucent lung lesions like centrilobular emphysema, cavity, cystic bronchiectasis, honeycomb cyst, and pneumatoceles are close mimics of a lung cyst on high-resolution computed tomography (HRCT). Various diseases with multiple lung cysts throughout both the lungs are classified as diffuse cystic lung diseases (DCLDs).

Predicting Individualized Lung Disease Progression in Treatment-Naive Patients With Lymphangioleiomyomatosis.

Background: Lung function decline varies significantly in patients with lymphangioleiomyomatosis (LAM), impeding individualized clinical decision-making.

Research Question: Can we aid individualized decision-making in LAM by developing a dynamic prediction model that can estimate the probability of clinically relevant FEV decline in patients with LAM before treatment initiation?

Study Design And Methods: Patients observed in the US National Heart, Lung, and Blood Institute (NHLBI) Lymphangioleiomyomatosis Registry were included. Using routinely available variables such as age at diagnosis, menopausal status, and baseline lung function (FEV and diffusing capacity of the lungs for carbon monoxide [Dlco]), we used novel stochastic modeling and evaluated predictive probabilities for clinically relevant drops in FEV.

Lymphangioleiomyomatosis (LAM) Cell Atlas.

Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition, microenvironment and cellular interactions within the LAM lesion remain unclear. To facilitate data sharing and collaborative LAM research, we performed an integrative analysis of single-cell data compiled from lung, uterus and kidney of patients with LAM from three research centres and developed an LAM Cell Atlas (LCA) Web-Portal.

Clinical features and outcomes of male patients with lymphangioleiomyomatosis: A review.

Background: Lymphangioleiomyomatosis (LAM) is a rare disease involving multiple systems, which is divided into sporadic LAM (S-LAM) and tuberous sclerosis complex-LAM, mostly affecting women who are in childbearing age stage. Data on male patients are limited and scattered. Therefore, it is necessary to conduct a systematic review to investigate the clinical features, diagnosis, treatment, and outcomes of LAM in male.

Lymphangioleiomyomatosis: a metastatic lung disease.

Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease.

A Case of Uterine Lymphangioleiomyomatosis Complicated by Tuberous Sclerosis Complex.

Lymphangioleiomyomatosis (LAM) is one of the presentations of perivascular epithelioid cell neoplasm that is frequently complicated by tuberous sclerosis complex (TSC). Here, we report an uncommon case of uterine LAM treated with everolimus, which is a mechanistic target of rapamycin (mTOR) inhibitor. A 42-year-old female patient (gravida 0) with a history of TSC presented with abdominal pain.

Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation.

Clinical profile of tuberous sclerosis complex patients with and without epilepsy: a need for awareness for early diagnosis.

Background: Tuberous sclerosis complex (TSC) is a multisystemic disorder. Its clinical features manifest differently in several organs, prompting the need for better knowledge.

Objective: The goal of the present study is to evaluate the neurological findings of TSC, such as cerebral lesions and epilepsy, and to raise awareness of non-neurological findings that could contribute to an earlier diagnosis and treatment.

Airspace Enlargement with Fibrosis in a Young Heavy Smoker Mimicking Diffuse Cystic Lung Disease.

The widespread use of computed tomography (CT) has led to the increased recognition of cystic lung lesions. Multiple pulmonary cysts can be observed in heterogeneous disorders called diffuse cystic lung diseases (DCLDs), which include pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, lymphocytic interstitial pneumonia, and Birt-Hogg-Dubé syndrome. Recently, airspace enlargement with fibrosis (AEF) has been recognized as an entity on the spectrum of smoking-related lung diseases.

Surgical Conundrum: A Case of Giant Renal Angiomyolipoma Abutting Inferior Vena Cava With Haemorrhage.

Renal angiomyolipoma (AML) is not only uncommon but often an accidental diagnosis, as it is frequently asymptomatic and affects females disproportionately. Although they may exhibit symptoms of tuberous sclerosis complex and lymphangioleiomyomatosis, the vast majority are sporadic. Due to its vascular nature, AML is prone to bleeding, and AML that bleeds typically belongs to the tuberous sclerosis complex.

Primary retroperitoneal PEComa: an incidental finding.

Perivascular epithelioid cell neoplasm (PEComa) is a rare type of tumour, and primary retroperitoneal PEComa is rarer still. Although pulmonary lymphangioleiomyomatosis (LAM), angiomyolipomas and clear cell 'sugar' tumours of the lung are well described, relatively little is known about other members of the PEComa family. We describe a case of an asymptomatic retroperitoneal PEComa, lymphangioleiomyoma type, which appeared in a previously healthy middle-aged woman as an incidental finding, in a CT scan performed in the context of spontaneous pneumothorax.

Diffusion weighted hyperpolarized Xe MRI of the lung with 2D and 3D (FLORET) spiral.

Purpose: To enable efficient hyperpolarized Xe diffusion imaging using 2D and 3D (Fermat Looped, ORthogonally Encoded Trajectories, FLORET) spiral sequences and demonstrate that Xe ADCs obtained using these sequences are comparable to those obtained using a conventional, 2D gradient-recalled echo (GRE) sequence.

Theory And Methods: Diffusion-weighted Xe MRI (b-values = 0, 7.5, 15 s/cm ) was performed in four healthy volunteers and one subject with lymphangioleiomyomatosis using slice-selective 2D-GRE (scan time = 15 s), slice-selective 2D-Spiral (4 s), and 3D-FLORET (16 s) sequences.

Kidney Podocyte Zebra Bodies after Lung Transplantation for Lymphangioleiomyomatosis.

A 55-year-old woman showed progressive renal dysfunction after unilateral deceased-donor lung transplantation for lymphangioleiomyomatosis. A kidney biopsy showed a striped pattern of interstitial fibrosis, suggesting calcineurin inhibitor toxicity, and zebra body accumulation predominantly in the podocytes, characteristics of Fabry disease. Nevertheless, she had no extra-renal symptoms of the disease, and gene testing identified no known pathogenic variant or exon deletion.

Lung transplantation for lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease, associated with respiratory symptoms of dyspnea and spontaneous pneumothorax, along with various extra-thoracic manifestations. Often a progressive disease, albeit slowly, patients can develop chronic and severe respiratory failure and require supplemental oxygen. Lung transplantation (LTX) can offer improved duration and quality of life for patients with end-stage lung disease due to LAM.

A novel gene mutation causing Birt-Hogg-Dubé syndrome in a Korean family.

Spontaneous pneumothorax is a common manifestation of Birt-Hogg-Dubé (BHD) syndrome, an inherited disorder caused by mutation of the () gene. A 44-year-old female with a history of breast cancer was diagnosed with recurrent pneumothorax. Chest CT showed multiple cysts with left lung pneumothorax, and she received surgery for the diagnosis.

Generation of Pmel-dependent conditional and inducible Cre-driver mouse line for melanocytic-targeted gene manipulation.

Conditional and inducible gene targeting using Cre/loxP-mediated recombination is a powerful reverse genetics approach used to study spatiotemporal gene functions in specified cell types. To enable temporal gene manipulation in the melanocyte lineage, we established a novel inducible Cre-driver mouse line by targeting an all-in-one tetracycline/doxycycline (Dox)-inducible Cre expression cassette into the Pmel locus (Pmel ), a gene locus preferentially expressed in pigment cells. By crossing these Cre-driver mice with a strong Cre-reporter mouse line, Gt(ROSA)26Sor , we show the effectiveness of the Pmel mouse line in facilitating Dox-inducible Cre/loxP recombination in a wide variety of pigment cell lineages including hair follicle melanocytes and their stem cells.

High-Resolution Computed Tomography of Cystic Lung Disease.

The cystic lung diseases (CLD) are characterized by the presence of multiple, thin-walled, air-filled spaces in the pulmonary parenchyma. Cyst formation may occur with congenital, autoimmune, inflammatory, infectious, or neoplastic processes. Recognition of cyst mimics such as emphysema and bronchiectasis is important to prevent diagnostic confusion and unnecessary evaluation.

Angiotensin II receptor type 1 blockade regulates Klotho expression to induce TSC2-deficient cell death.

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear.