Atypical Presentation of Tangier Disease-Expanding the Clinical Spectrum.

ABSTRACT: Tangier disease is an autosomal recessive multisystem metabolic disorder with neuromuscular manifestations including peripheral neuropathy such as multifocal mononeuropathy or pseudosyringomyelia patterns. We report a novel phenotype of Tangier disease with predominant anterior horn cell involvement. A 16-year-old adolescent girl born to consanguineous parents had a 1-year history of hip girdle weakness with waddling gait and progressive atrophy of the right leg. She had orange tonsils, prominent lingual tonsils, soft skin, distal joint laxity, diffuse hypotonia with asymmetric wasting of legs, proximodistal moderate weakness in lower limbs, and tendon reflexes were hypoactive. The creatine kinase level was 70 U/L. Serum showed an abnormally low level of high- and low-density lipoprotein. Whole-exome sequencing showed a novel likely pathogenic splice site homozygous mutation c.2542+1G > A in the ABCA1 gene at intron 17. Hence, a high degree of suspicion and search for peripheral clinical markers is needed in patients with unusual anterior horn cell syndromes.

A case of mesenteric panniculitis in a patient with Tangier disease.

Mesenteric panniculitis is a rare disease caused by idiopathic inflammation of adipose tissue, most commonly affecting the mesentery of the small bowel. We present a unique case of mesenteric panniculitis in a patient with Tangier disease; a rare genetic disorder caused by mutations in the ABCA1 gene, leading to deficiency of high-density lipoprotein in the blood and accumulation of cholesterol esters within various tissues. The accumulation of cholesterol esters in body tissues in patients with Tangier disease may contribute to the pathogenesis of mesenteric panniculitis; although there is limited evidence to support this hypothesis due to the rarity of concurrent disease.

A case of premature and recurrent myocardial infarction associated with ABCA.1 gene mutation.

Coronary heart disease (CHD) is the most important cause of cardiovascular death and when premature, it affects the most productive population of the community. Premature CHD usually has a specific etiology, which on diagnosis, might help in the secondary prevention in that individual. We report a case of young adult with recurrent myocardial infarction, who on evaluation had mildly reduced HDL and Protein C levels with elevated serum homocysteine. Clinical exome identified a possibly pathogenic variant of ABCA1 gene, associated with Tangier disease.

Tangier disease: update for 2020.

PURPOSE OF REVIEW: To appraise recent advances in our knowledge of the severe genetic HDL deficiency disorder, Tangier disease. RECENT FINDINGS: While Tangier disease can cause premature atherosclerotic cardiovascular disease (ASCVD), new evidence suggests that heterozygous ABCA1 variant carriers are also at increased risk. Advances have been made in the study of the neurological abnormalities observed in Tangier disease, both in their assessment and the identification of potential new therapies. SUMMARY: Tangier disease is an extremely rare condition and, as such, the published literature around its range of clinical manifestations, including peripheral neuropathy, premature ASCVD and platelet abnormalities is limited. Patient registries may assist in this regard.

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.

A novel splicing mutation in the ABCA1 gene, causing Tangier disease and familial HDL deficiency in a large family.

Tangier disease is a rare disorder of lipoprotein metabolism that presents with extremely low levels of HDL cholesterol and apoprotein A-I. It is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene. Clinical heterogeneity and mutational pattern of Tangier disease are poorly characterized. Moreover, also familial HDL deficiency may be caused by mutations in ABCA1 gene. ATP-binding cassette transporter A1 (ABCA1) gene mutations in a patient with Tangier disease, who presented an uncommon clinical history, and in his family were found and characterized. He was found to be compound heterozygous for two intronic mutations of ABCA1 gene, causing abnormal pre-mRNAs splicing. The novel c.1510-1G > A mutation was located in intron 12 and caused the activation of a cryptic splice site in exon 13, which determined the loss of 22 amino acids of exon 13 with the introduction of a premature stop codon. Five heterozygous carriers of this mutation were also found in proband's family, all presenting reduced HDL cholesterol and ApoAI (0.86 ±â€¯0.16 mmol/L and 92.2 ±â€¯10.9 mg/dL respectively), but not the typical features of Tangier disease, a phenotype compatible with the diagnosis of familial HDL deficiency. The other known mutation c.1195-27G > A was confirmed to cause aberrant retention of 25 nucleotides of intron 10 leading to the insertion of a stop codon after 20 amino acids of exon 11. Heterozygous carriers of this mutation also showed the clinical phenotype of familial HDL deficiency. Our study extends the catalog of pathogenic intronic mutations affecting ABCA1 pre-mRNA splicing. In a large family, a clear demonstration that the same mutations may cause Tangier disease (if in compound heterozygosis) or familial HDL deficiency (if in heterozygosis) is provided.

Identification of the first Tangier disease patient in Lebanon carrying a new pathogenic variant in ABCA1.

BACKGROUND: The Middle East region is characterized by low levels of high-density lipoprotein cholesterol (HDL-C). To date, no genetic study has investigated the cause of low HDL-C in the Lebanese population. OBJECTIVE: Our objective was to study the genetic causes for hypoalphalipoproteinemia in a Lebanese family with extremely low HDL-C levels. METHODS: We sequenced the ABCA1 gene and evaluated cholesterol efflux, inflammatory, and metabolic profiles in the proband and his family. RESULTS: We identified the first Lebanese pathogenic variant in ABCA1 gene causing Tangier disease in a consanguineous family. The proband carried a novel homozygous pathogenic variant p.Gly592Asp in exon 14 of ABCA1, which segregated with the disease in the family. Functional study of the p.Gly592Asp pathogenic variant revealed that lipid-free apolipoprotein A-I-dependent cholesterol efflux was completely abolished in cholesterol-loaded human monocytes-derived macrophages isolated from the proband when compared to controls. Systemic inflammatory and metabolic assessments showed that plasma cytokines (MCP-1, MIP-1α, IL-6, CRP, TNF-α), adhesion molecules (ICAM-1, VCAM-1, E-selectin), inflammatory soluble receptors (sIL-6r, sTNFRI, sTNFRII), and metabolic markers (Insulin, C-peptide) were elevated in the proband when compared to controls. Noninvasive cardiovascular investigation revealed the presence of premature artery lesions in the proband. CONCLUSIONS: It is the first case of Tangier disease reported in Lebanon harboring a novel pathogenic variant in ABCA1. Further genetic research is needed in the Middle East where the consanguinity rate is elevated, to understand the cause of the highly prevalent dyslipidemia. This will help guiding the early diagnosis, management, and prevention of cardiovascular complications.

A novel homozygous ABCA1 variant in an asymptomatic man with profound hypoalphalipoproteinemia.

Low high-density lipoprotein cholesterol (HDL-C) can be caused by several acquired secondary causes as well as primary genetic disorders. However, only a few conditions are associated with profoundly reduced levels below 10 mg/dL. We present an unusual case of a healthy man with severely decreased HDL-C because of a novel homozygous variant causing a Proline > Arginine amino acid change at position 1412 in the ATP-binding cassette transporter A1 gene. Homozygous variations in ATP-binding cassette transporter A1 typically cause Tangier disease, a rare autosomal recessive condition linked with several other abnormalities (eg, enlarged discolored tonsils). Despite having an HDL-C below 10 mg/dL, our patient presented without any other clinical symptoms or physical signs suggestive of Tangier disease. This case of presumptive Tangier disease adds support to the growing body of evidence that this genetic disorder may have greater phenotypic heterogeneity along with a more varied presentation than traditionally considered.

Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis.

BACKGROUND: The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that antagonism of interleukin (IL)-1ß reduces coronary heart disease in patients with a previous myocardial infarction and evidence of systemic inflammation, indicating that pathways required for IL-1ß secretion increase cardiovascular risk. IL-1ß and IL-18 are produced via the NLRP3 inflammasome in myeloid cells in response to cholesterol accumulation, but mechanisms linking NLRP3 inflammasome activation to atherogenesis are unclear. The cholesterol transporters ATP binding cassette A1 and G1 (ABCA1/G1) mediate cholesterol efflux to high-density lipoprotein, and Abca1/g1 deficiency in myeloid cells leads to cholesterol accumulation. METHODS: To interrogate mechanisms connecting inflammasome activation with atherogenesis, we used mice with myeloid Abca1/g1 deficiency and concomitant deficiency of the inflammasome components Nlrp3 or Caspase-1/11. Bone marrow from these mice was transplanted into Ldlr-/- recipients, which were fed a Western-type diet. RESULTS: Myeloid Abca1/g1 deficiency increased plasma IL-18 levels in Ldlr-/- mice and induced IL-1ß and IL-18 secretion in splenocytes, which was reversed by Nlrp3 or Caspase-1/11 deficiency, indicating activation of the NLRP3 inflammasome. Nlrp3 or Caspase-1/11 deficiency decreased atherosclerotic lesion size in myeloid Abca1/g1-deficient Ldlr-/- mice. Myeloid Abca1/g1 deficiency enhanced caspase-1 cleavage not only in splenic monocytes and macrophages, but also in neutrophils, and dramatically enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques, with reversal by Nlrp3 or Caspase-1/11 deficiency, suggesting that inflammasome activation promotes neutrophil recruitment and neutrophil extracellular trap formation in atherosclerotic plaques. These effects appeared to be indirectly mediated by systemic inflammation leading to activation and accumulation of neutrophils in plaques. Myeloid Abca1/g1 deficiency also activated the noncanonical inflammasome, causing increased susceptibility to lipopolysaccharide-induced mortality. Patients with Tangier disease, who carry loss-of-function mutations in ABCA1 and have increased myeloid cholesterol content, showed a marked increase in plasma IL-1ß and IL-18 levels. CONCLUSIONS: Cholesterol accumulation in myeloid cells activates the NLRP3 inflammasome, which enhances neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques. Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation, suggesting human relevance.

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.

Reduced platelet count, but no major platelet function abnormalities, are associated with loss-of-function ATP-binding cassette-1 gene mutations.

Loss-of-function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol (HDL-C) and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1-/- murine models reported defects in platelet count, morphology, and function, but the issue is still controversial. We analyzed three subjects with low to very low HDL-C levels due to the loss-of-function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all the patients. No morphological platelet abnormalities were detected under optical or EM. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin αIIbß3 were observed in one FHD patient. While α-granule secretion (P-selectin), content, and secretion of platelet δ-granules (serotonin, ATP, and ADP) and thromboxane (TX) A2 synthesis were normal in all the patients, the expression of lysosomal CD63, in response to some agonists, was reduced in TD patients. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists or bleeding.

The usefulness of advanced lipid and oxidative stress testing for diagnosis and management of low HDL-cholesterol phenotype: A case report.

OBJECTIVE: Plasma high-density lipoprotein cholesterol (HDL-C) level is a strong inverse predictor of cardiovascular disease (CVD) development. Tangier disease, a consequence of mutations in the ATP binding cassette transporter 1 (ABCA1) gene, is associated with very low HDL-C levels. Still, the relationship between Tangier disease and CVD is not always evident. The study investigates usefulness of lipoprotein subfractions, oxidative stress and paraoxonase 1 (PON1) status assessment for evaluation and management of patient with low HDL-C phenotype. PATIENT AND METHODS: A 12-year-old boy was hospitalised due to hypertension. Laboratory evaluation revealed low HDL-C level, and subsequent molecular diagnostic confirmed Tangier disease. Lipoprotein subfractions were assessed by gradient-gel electrophoresis. Oxidative stress status was estimated by measuring total antioxidative status, total oxidative status, prooxidative-antioxidative balance, malondialdehyde and advanced oxidation protein products levels. Activity of paraoxonase 1 in serum and its distribution within HDL subclasses was also determined (ten healthy boys aged 13.1±3.4years served as the reference group). RESULTS: Analysis of oxidative stress status biomarkers revealed a state of prolonged prooxidants activity. In turn, serum PON1 activity was substantially reduced. The majority of PON1 activity was present on HDL 2 particles. CONCLUSION: Impaired antioxidative potential of HDL may point toward hidden cardiovascular risk in isolated low HDL-phenotype.

Methods for Monitoring ABCA1-Dependent Sterol Release.

Releasing sterols to the extracellular milieu is an important part of sterol homeostasis in cells and in the body. ATP-binding cassette transporter A1 (ABCA1) plays an essential role in cellular phospholipid and sterol release to lipid-free or lipid-poor apolipoprotein A-I (apoA-I), the major apolipoprotein in high-density lipoprotein (HDL), and constitutes the first step in the formation of nascent HDL. Loss-of-function mutations in the ABCA1 gene lead to a rare disease known as Tangier disease that causes severe deficiency in plasma HDL level. Mammalian cells receive exogenous cholesterol mainly from low-density lipoprotein. In addition, they synthesize cholesterol endogenously, as well as multiple precursor sterols that are sterol intermediates en route to be converted to cholesterol. HDL contains phospholipids, cholesterol, and precursor sterols, and ABCA1 has an ability to release phospholipids and various sterol molecules. Recent studies using model cell lines showed that ABCA1 prefers to use sterols newly synthesized endogenously as its preferred substrate, rather than cholesterol derived from LDL or cholesterol being recycled within the cells. Here, we describe several methods at the cell culture level to monitor ABCA1-dependent release of sterol molecules to apoA-I present at the cell exterior. Sterol release can be assessed by using a simple colorimetric enzymatic assay, and/or by monitoring the radioactivities of radiolabeled cholesterol incorporated into the cells, and/or of sterols biosynthesized from radioactive acetate, and/or by using gas chromatography-mass spectrometry analysis of various sterols present in medium and in cells. We also discuss the pros and cons of these methods. Together, these methods allow researchers to detect the release not only of cholesterol but also of other sterols present in minor quantities.

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.

Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation.

Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high-performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL-type particles accumulate over time, would experience an increased propensity for developing atherosclerosis.

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.