A rare case of nephrotic syndrome and Tangier disease.

Rarely, disorders of lipid metabolism cause nephrotic syndrome with progressive kidney disease. Tangier disease is a rare condition belonging to this family of lipid disorders; however, it is not associated with kidney disease. We report a patient presenting with nephrotic syndrome, leading to the unmasking of Tangier disease. A 34-year-old man presented with ankle oedema, nephrotic-range proteinuria and hypoalbuminaemia. Kidney biopsy demonstrated membranous nephropathy with features of immunoperoxidase staining, suggesting a secondary aetiology. Acute serology was negative. Imaging showed lymphadenopathy with splenomegaly suggestive of lymphoproliferative disorder. Bone marrow biopsy revealed foamy macrophages with widespread lipid deposition. Genomic sequencing revealed a pathological homozygous variant for ATP-binding cassette subfamily A member 1 (ABCA1) c.1510-1G > A, consistent with Tangier disease. Review of the ultrastructural kidney biopsy features demonstrated, in addition to membranous subepithelial and intramembranous usual-type electron-dense deposits, intramembranous osmiophilic lipid deposits similar to those in LCAT deficiency. The patient's renal function gradually declined (serum creatinine 133 µmol/L); therefore, he was started on rituximab. Metabolic disorders causing nephrotic syndrome are rare and even more so their association with membranous nephropathy. These should be considered in cases with unexplained persistent nephrotic syndrome with progressive kidney disease and lipid deposits on renal biopsy.

Current Diagnosis and Management of Tangier Disease.

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease.

Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.

Tangier disease in family with the phenotype of familial hypercholesterolemia.

Within the project MedPed (Make Early Diagnosis to Prevent Deaths) we have examined patient with familial hypercholesterolemia in our lipid ambulance. During the following investigation of the patients family we found out that her sister has on the contrary very low levels of  total and LDL-cholesterol. Concentration of  HDL-cholesterol was extreamly low (almost immeasurable). Differential diagnosis uttered a suspicion of rare form of familial hypoalfalipoproteinemia so-called Tangier disease. This suspicion was then confirmed by molecular genetic examination. Tangier disease is a rare lipoprotein metabolism disorder characterized biochemically by  almost complete absence of plasmatic HDL- cholesterol, extremely low level of apolipoprotein A-I and accumulation of cholesterol esters in macrophages. The first case was recorded on the Tangier island in 1961. In our research we describe the first case of a patient with homozygous form of Tangier disease in the history of the Czech Republic.

LCAT, ApoD, and ApoA1 Expression and Review of Cholesterol Deposition in the Cornea.

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies plasma cholesterol and increases the capacity of HDL to carry and potentially remove cholesterol from tissues. Cholesterol accumulates within the extracellular connective tissue matrix of the cornea stroma in individuals with genetic deficiency of LCAT. LCAT can be activated by apolipoproteins (Apo) including ApoD and ApoA1. ApoA1 also mediates cellular synthesis of HDL. This study examined the expression of LCAT by epithelial cells, keratocytes, and endothelial cells, the cell types that comprise from anterior to posterior the three layers of the cornea. LCAT and ApoD were immunolocalized to all three cell types within the cornea, while ApoA1 was immunolocalized to keratocytes and endothelium but not epithelium. In situ hybridization was used to detect LCAT, ApoD, and ApoA1 mRNA to learn what cell types within the cornea synthesize these proteins. No corneal cells showed mRNA for ApoA1. Keratocytes and endothelium both showed ApoD mRNA, but epithelium did not. Epithelium and endothelium both showed LCAT mRNA, but despite the presence of LCAT protein in keratocytes, keratocytes did not show LCAT mRNA. RNA sequencing analysis of serum-cultured dedifferentiated keratocytes (commonly referred to as corneal stromal fibroblasts) revealed the presence of both LCAT and ApoD (but not ApoA1) mRNA, which was accompanied by their respective proteins detected by immunolabeling of the cultured keratocytes and Western blot analysis of keratocyte lysates. The results indicate that keratocytes in vivo show both ApoA1 and LCAT proteins, but do not synthesize these proteins. Rather, keratocytes in vivo must take up ApoA1 and LCAT from the corneal interstitial tissue fluid.

Tangier disease may cause early onset of atherosclerotic cerebral infarction: A case report.

RATIONALE: The present study explored the relationship between the adenosine triphosphate (ATP)-binding cassette A1 (ABCA1) gene, atherosclerosis, and cerebral infarction. The diagnosis and treatment ideas of stroke caused by Tangier disease via the summary of the diagnosis and treatment process of one case with juvenile stroke were explored. The relevant literature on the clinical manifestations, laboratory examinations, and treatment of Tangier disease was reviewed. PATIENT CONCERNS: The brain magnetic resonance imaging (MRI) of a juvenile man with acute onset of sudden right limb weakness and speechlessness revealed infarct lesions. The laboratory tests found low serum high-density lipoprotein (HDL), while further genetic testing identified ABCD1 gene mutation. The mother also carried the mutant gene. DIAGNOSES: Tangier disease was diagnosed. INTERVENTIONS: Statin treatment was administered for platelet aggregation. OUTCOMES: After 3 years of follow-up, the patient was declared to be in a stable condition. LESSONS: ABCA1 gene mutation caused early onset of atherosclerosis, leading to the occurrence of cerebral infarction. The cerebral infarction associated with reduced high-density lipoprotein (HDL), was under intensive focus with respect to ABCA1 gene. Child and Juvenile stroke patients with low HDL should not be excluded from the possibility of Tangier disease.

Accelerated Atherogenicity in Tangier Disease.

We report a case of Tangier disease with Leriche syndrome and bleeding tendency. In this male patient, nasal hemorrhage had been observed frequently throughout childhood. At 46 years old, he experienced effort angina, and coronary angiography demonstrated 75% stenosis in the right coronary artery. Orange-colored tonsils, mild hepatosplenomegaly and very low levels of serum high-density lipoprotein cholesterol (HDL-C) were observed, and the patient was diagnosed with Tangier disease. At 52 years old, effort angina recurred. Coronary angiography revealed 75% stenosis of the left main trunk, left anterior descending, and right coronary arteries. Stenosis of the brachiocephalic and right common iliac arteries was also recorded. Stents were implanted, and coronary artery bypass surgery was performed. At 53 years old, 15 months after surgery, the patient reported intermittent claudication, coldness of feet, and impotence. Aortic angiography showed progression of the stenosis at the bifurcation of the common iliac artery. The patient was diagnosed with Leriche syndrome, and aorta-left external iliac artery graft bypass surgery was performed. After surgery, oozing from subcutaneous tissue and leaking from the anastomotic region were observed. Additional analysis revealed two single-nucleotide polymorphisms (V825I and N935T) in the ATP-binding cassette transporter A1 (ABCA1) gene, and accumulation of small dense low-density lipoprotein together with low levels of HDL-C. In Tangier disease, HDL-C is markedly decreased because of ABCA1 deficiency. However, this is the first reported case to exhibit extensive atherosclerosis and bleeding tendency. This patient had atypical extensive and multiple atherosclerotic lesions, accompanied by Leriche syndrome and uncontrollable bleeding.

Can Tangier disease cause male infertility? A case report and an overview on genetic causes of male infertility and hormonal axis involved.

Tangier disease is an autosomal recessive disorder caused by mutations in the ABCA1 gene and characterized by the accumulation of cholesteryl ester in various tissues and a near absence of high-density lipoprotein. The subject in this investigation was a 36-year-old Italian man with Tangier disease. He and his wife had come to the In Vitro Fertilization Unit, Pesaro Hospital (Azienda Ospedaliera Ospedali Riuniti Marche Nord) seeking help regarding fertility issues. The man was diagnosed with severe oligoasthenoteratozoospermia. Testosterone is the sex hormone necessary for spermatogenesis and cholesterol is its precursor; hence, we hypothesized that the characteristic cholesterol deficiency in Tangier disease patients could compromise their fertility. The aim of the study was to therefore to determine if there is an association between Tangier disease and male infertility. After excluding viral, infectious, genetic and anatomical causes of the subject's oligoasthenoteratozoospermia, we performed a hormonal analysis to verify our hypothesis. The patient was found to be negative for frequent bacteria and viruses. The subject showed a normal male karyotype and tested negative for Yq microdeletions and Cystic Fibrosis Transmembrane Conductance Regulator gene mutations. A complete urological examination was performed, and primary hypogonadism was also excluded. Conversely, hormonal analyses showed that the subject had a high level of follicle stimulating hormone and luteinizing hormone, low total testosterone and a significant decline in inhibin B. We believe that the abnormally low cholesterol levels typically found in subjects with Tangier disease may result in a reduced testosterone production which in turn could affect the hormonal axis responsible for spermatogenesis leading to a defective maturation of spermatozoa.

Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.

Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described.

[Valve Replacement for Severe Aortic Stenosis in a Patient with Tangier Disease].

We report a case of severe aortic valve stenosis in a patient with Tangier disease. A 64-year-old female was diagnosed with Tangier disease on the basis of gene mutation. The serum levels of total cholesterol and high-density lipoprotein were 124 mg/dl and 4.3 mg/dl, respectively. She had a symptom of dyspnea and echocardiography revealed severe aortic valve stenosis with the maximum gradient of 60.5 mmHg. Chest computed tomography showed severe calcification of the ascending aorta and the aortic root. Aortic valve replacement using a bioprosthetic valve was performed. Several reports have been made on coronary artery revascularization in Tangier disease patients, but one on surgical treatment for aortic valve stenosis is extremely rare.

ATP-binding cassette transporter 1 (ABCA1) deficiency decreases platelet reactivity and reduces thromboxane A2 production independently of hematopoietic ABCA1.

UNLABELLED: ESSENTIALS: The role of ATP-binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1-deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1. BACKGROUND: The ATP-binding cassette transporter ABCA1 is required for the conversion of apolipoprotein A-1 to high-density lipoprotein (HDL), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA1 in platelet functions remains poorly characterized. OBJECTIVE: To determine the role of ABCA1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition. METHODS AND RESULTS: We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA1-deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium-induced phosphatidylserine exposure. Interestingly, ABCA1-deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 (TXA2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA2, was primarily dependent on external environment and not on the hematopoietic ABCA1. Decreased aggregation and production of TXA2 and eicosanoids were also observed in platelets from Tangier patients. CONCLUSIONS: Absence of ABCA1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA2 production through a hematopoietic ABCA1-independent mechanism.

Clinical, Electrodiagnostic, and Genetic Features of Tangier Disease in an Adolescent Girl with Presentation of Peripheral Neuropathy.

Tangier disease (TD) is a rare, autosomal recessive inherited disorder caused by a mutation in the adenosine triphosphate-binding cassette transporter 1 (ABCA1) gene, which results in a decrease in plasma high-density lipoprotein (HDL) levels. Peripheral neuropathy can be seen in approximately 50% of patients with TD, which usually occurs after the age of 15 years, and is characterized by relapsing-remitting mono- or polyneuropathy or syringomyelia-like neuropathy. Herein, we report a 16-year-old female patient who was initially diagnosed with peripheral neuropathy at the age of 13 years. Whole exome sequencing was performed, and a nonsense mutation (p.Arg1817X) in ABCA1 was identified. The patient was investigated for systemic findings of TD after the genetic diagnosis was made, and low (< 5 mg/dL) levels of HDL cholesterol were detected by lipid electrophoresis. Other family members were reexamined after the diagnosis of the proband, and asymptomatic sister of the proband was diagnosed with TD. We would like to emphasize that TD should be considered in the differential diagnosis of pediatric patients presenting with peripheral neuropathy; furthermore detection of HDL levels by lipid electrophoresis is a simple but indicative diagnostic test.

Functional analysis and transcriptomic profiling of iPSC-derived macrophages and their application in modeling Mendelian disease.

RATIONALE: An efficient and reproducible source of genotype-specific human macrophages is essential for study of human macrophage biology and related diseases. OBJECTIVE: To perform integrated functional and transcriptome analyses of human induced pluripotent stem cell-derived macrophages (IPSDMs) and their isogenic human peripheral blood mononuclear cell-derived macrophage (HMDM) counterparts and assess the application of IPSDM in modeling macrophage polarization and Mendelian disease. METHODS AND RESULTS: We developed an efficient protocol for differentiation of IPSDM, which expressed macrophage-specific markers and took up modified lipoproteins in a similar manner to HMDM. Like HMDM, IPSDM revealed reduction in phagocytosis, increase in cholesterol efflux capacity and characteristic secretion of inflammatory cytokines in response to M1 (lipopolysaccharide+interferon-γ) activation. RNA-Seq revealed that nonpolarized (M0) as well as M1 or M2 (interleukin-4) polarized IPSDM shared transcriptomic profiles with their isogenic HMDM counterparts while also revealing novel markers of macrophage polarization. Relative to IPSDM and HMDM of control individuals, patterns of defective cholesterol efflux to apolipoprotein A-I and high-density lipoprotein-3 were qualitatively and quantitatively similar in IPSDM and HMDM of patients with Tangier disease, an autosomal recessive disorder because of mutations in ATP-binding cassette transporter AI. Tangier disease-IPSDM also revealed novel defects of enhanced proinflammatory response to lipopolysaccharide stimulus. CONCLUSIONS: Our protocol-derived IPSDM are comparable with HMDM at phenotypic, functional, and transcriptomic levels. Tangier disease-IPSDM recapitulated hallmark features observed in HMDM and revealed novel inflammatory phenotypes. IPSDMs provide a powerful tool for study of macrophage-specific function in human genetic disorders as well as molecular studies of human macrophage activation and polarization.

HDL particle size is a critical determinant of ABCA1-mediated macrophage cellular cholesterol export.

RATIONALE: High-density lipoprotein (HDL) is a heterogeneous population of particles. Differences in the capacities of HDL subfractions to remove cellular cholesterol may explain variable correlations between HDL-cholesterol and cardiovascular risk and inform future targets for HDL-related therapies. The ATP binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux to lipid-free apolipoprotein A-I, but the majority of apolipoprotein A-I in the circulation is transported in a lipidated state and ABCA1-dependent efflux to individual HDL subfractions has not been systematically studied. OBJECTIVE: Our aims were to determine which HDL particle subfractions are most efficient in mediating cellular cholesterol efflux from foam cell macrophages and to identify the cellular cholesterol transporters involved in this process. METHODS AND RESULTS: We used reconstituted HDL particles of defined size and composition, isolated subfractions of human plasma HDL, cell lines stably expressing ABCA1 or ABCG1, and both mouse and human macrophages in which ABCA1 or ABCG1 expression was deleted. We show that ABCA1 is the major mediator of macrophage cholesterol efflux to HDL, demonstrating most marked efficiency with small, dense HDL subfractions (HDL3b and HDL3c). ABCG1 has a lesser role in cholesterol efflux and a negligible role in efflux to HDL3b and HDL3c subfractions. CONCLUSIONS: Small, dense HDL subfractions are the most efficient mediators of cholesterol efflux, and ABCA1 mediates cholesterol efflux to small dense HDL and to lipid-free apolipoprotein A-I. HDL-directed therapies should target increasing the concentrations or the cholesterol efflux capacity of small, dense HDL species in vivo.

Tangier disease in a Turkish family.

In this report we describe the upper gastrointestinal tractus involvement in a rare genetic disease of lipid metabolism. A 12-year-old boy presented with sore throat and fever. On physical examination, orange-yellow tonsils and adenoid tissue were noted. Mild hepatosplenomegaly was present. Lipid profile was compatible with Tangier disease (TD). Endoscopy of the upper gastrointestinal tract showed white-yellowish fatty deposits on the gastric mucosa. Microscopically, biopsy specimens contained numerous histiocytes with a foamy cytoplasm packed in the lamina propria of the gastric mucosa and at the crypt basement of the duodenum. His sister, 8 years old, was also diagnosed with TD based on abnormal lipid profile and orange-yellow tonsils. TD is a rare familial disorder of lipid metabolism, characterized by deposition of cholesteryl esters, probably involving the entirety of the gastrointestinal tract from the mouth to the anus.

A novel mutation in the ABCA1 gene causing an atypical phenotype of Tangier disease.

Tangier disease is a rare autosomal-recessive disorder caused by mutation in the ATP binding cassette transporter 1 (ABCA1) gene. Typically, Tangier disease manifests with symptoms and signs resulting from the deposition of cholesteryl esters in nonadipose tissues; chiefly, in peripheral nerves leading to neuropathy and in reticulo-endothelial organs, such as liver, spleen, lymph nodes, and tonsils, causing their enlargement and discoloration. An association with early cardiovascular disease can be variable. We describe a patient with a unique phenotype of Tangier disease from a novel splice site mutation in the ABCA1 gene that is associated with a central nervous system presentation resembling multiple sclerosis, and the presence of premature atherosclerosis.

Histiocytic disorders of the gastrointestinal tract.

The morphologic diagnosis of histiocytic lesions of the gastrointestinal tract can be challenging, and several disorders have to be considered in their differential diagnosis. We present one of the most widespread examples of xanthomatosis of the gastrointestinal tract published so far and give a short review on histiocytic disorders of the gastrointestinal tract in general. The primary histiocytic disorders of uncertain origin, Rosai-Dorfman disease, Langerhans cell histiocytosis, and Erdheim-Chester disease, are addressed. Reactive and infectious conditions such as xanthomatosis, xanthogranulomatous inflammation, juvenile xanthogranuloma, Whipple's disease and malacoplakia are discussed as well. We also briefly go into primary histiocytic disorders of neoplastic origin, systemic diseases with secondary gastrointestinal tract involvement like the lysosomal storage disorders, and pigmented lesions. Using a panel of histochemical stains and immunohistochemical markers, together with conventional microscopy, clinical information, and imaging studies, the diagnosis of histiocytic disorders of the gastrointestinal tract can be established in most instances.