213 Tangier Disease Selcan ÖZTÜRK, Hüseyin PER Erciyes University Faculty of Medicine, Division of Pediatric Neurology, Department of Pediatrics, Kayseri, Turkey INTRODUCTION Tangier Disease (TD) (OMIM # 205400) is a rare human genetic disorder that is seen in plasma lipoprotein metabolism, characterized by high-density lipoprotein (HDL) deficiency and cholesterol ester deposition. Mutation in the ATP-Binding-Cassette Transporter A1 (ABCA1) gene is the cause of disease and, it presents with cholesterol ester accumulation mainly in peripheral nerves, tonsils, bone marrow, cornea, and other reticuloendothelial system components.1 Relapsing-remitting multifocal pattern of motor and sensory loss, multifocal mono- or polyneuropathy, hyperplastic orange-yellow tonsils, lymphadenopathy, hepatosplenomegaly, thrombocytopenia, anemia, corneal clouding and cardiovascular disease are the main clinical symptoms.2 Tangier Disease was first reported in 1961 by Fredrickson et al.3 During the tonsillectomy operation of a 5-year-old boy, living in the Tangier Island in Chesapeake Bay (Virginia, USA), orange and multilobular tonsils were observed and foam cells gathering on the surface of tonsils extending to the lymph follicles were noted in histopathological examination.2,3 Although Hand-Schuler-Christian Disease (HSCD) and Nieman Pick Disease(NPD) were considered in differential diagnosis in the first place when hepatomegaly was diagnosed, the absence of granulomas and reticulo-histiocytic hyperplasia which is typical for HSCD, and the appearence of cholestherol esters on foam cells rather than sphingolipid deposits, which is typical for NPD; enforced a change in diagnosis and a new form of metabolic disease was considered.3 The new disease was called Tangier Disease (TD) after the patient mentioned above, and her sister was found to have significant HDL deficiency and abnormal-looking tonsils, as well.3 EPIDEMIOLOGY Tangier Disease (TD) is an extremely rare disease estimated to have about 100 cases diagnosed worldwide.2 The onset of disease ranges between the ages 2 to 67.4 Tangier Disease (TD) is an autosomal recessive disease and is seen as 25% being affected, of 50% being a carrier, and 25% has no clinical findings.4,5 Most parents are hetero- Focusing on Pediatric Immunology & Neurology 214 zygous carriers. Carriers are asymptomatic but tend to have hypoalphalipoproteinemia.5 For these reasons, it is appropriate to evaluate asymptomatic elderly and young relatives at risk. PATHOPHYSIOLOGY OF TANGIER DISEASE The main components are cholesterol, triglyceride, and HDL in human body composition. 6 As cholesterol is the precursor of steroid hormones produced in the adrenal and gonadal glands and bile acid, HDL has anti-inflammatory, anti-apoptotic, and anti-oxidant, anti-atherogenic, and anti-thrombotic properties.6,7 It is crucial for vasomotor regulation.8 HDL holds redundant cholesterol from peripheral tissues and canalizes it to the liver for bile excretion.9 First, there is new HDL biogenesis from cellular lipids and extracellular lipid-free or lipid-poor apoprotein A1 in a process Mediated by ABCA1 and this cellular cholesterol and phospholipid flow process is the main source of plasmic HDL. HDL metabolism begins with ApoA-1 synthesis in the liver and intestine, but HDL formation requires interaction with ABCA1 and ApoA-1.10 HDL contains most of the ApoA-1. It contains of 45-55% apolipoprotein, 26-32% phospholipid, 15-20% esterified cholesterol, 5% triglycerides and 3-5% free cholesterol.11 ABCA1 is a member of a large ABC (ATP-binding-cassette) gene family with several subfamilies that play various roles in lipid and ion transportation. Mutations in specific ABC proteins are the cause of various diseases such as Cystic Fibrosis, Adrenoleukodystrophy, Zellweger’s disease, and macular degeneration.12 The ABCA gene is located on the 9q22-q31 chromosome which contains 50 exons.2,4 To the date, more than 200 mutations have been revealed in ABCA1 gene, which may also be causatives for TD ( homozygous-compound heterozygous) and familial HDL deficiency.13 ABCA1 is a 2261-amino acid integral membrane protein consisting of 12 transmembrane domains and two ATP-binding cassettes (ABC).10 ABCA1 regulates the secretion of cholesterol and phospholipids into lipid-poor apolipoproteins (lipid-poor ApoA-I).14 When there is a mutation in the gene, the cholesterol flow activity of fibroblasts to ApoA-I in HDL remains insufficient,free cholesterol flow ceases, cellular lipid cannot be obtained into apolipoproteins.14 When there is an imbalance between cholesterol and phospholipid, foam-cells formation occurs in the macrophage and the reticuloendothelial system.14 As the flow becomes insufficient, foam cells often die, and cholesterol-rich necrotic plaques accumulate in the arterial intima. This process is the most critical step for atherosclerotic lesion development.15Abnormal lipoprotein metabolism is an important factor for atherosclerosis. There is an inverse correlation between HDL levels and atherosclerosis.15 Individuals with Tangier Disease have HDL levels of less than 5% of the normal.1 Significant Apolipoprotein A-1 deficiency, low-density lipoprotein (LDL) deficiency and mild hypertriglyceridemia can be seen.16 The pathophysiology of demyelination in TD neuropathy is not clear. How- Tangier Disease 215 ever, there is paranodal malfunction against the accumulation of cholesterol ester in the regional Schwann cells.17 CLINICAL FEATURES Tangier Disease is identified by the absence of HDL and Apolipoprotein A1 and cholesterol esters’ accumulation in several parts of the body, including tonsils, peripheral nerves, and intestinal mucosa spleen, liver, bone, bone marrow, lymph nodes, thymus, skin, and cornea.2 DIAGNOSIS TD should be suspected in individuals with clinical features and supportive laboratory findings.5 Clinical findings • Large, lobulated, hyperplastic, orange-yellow tonsils in children and young adults • Peripheral neuropathy • Organomegaly (Hepatosplenomegaly) • Atherosclerotic cardiovascular disease • Corneal opacities • Lymphadenopathy ( cervical, axillary, thoracic) • Abnormal hematological findings (especially thrombocytopenia) Supportive laboratory findings • Major findings: o Plasma HDL-cholesterol is usually <5 mg/dL, o Apo A-I is very low or absent, usually <30 mg/dL (typically <5 mg/dL) o Small or absent alpha band on lipoprotein electrophoresis • Other laboratory findings: o Total plasma cholesterol is low ( typically <150 mg/dL o Triglyceridemia is normal or high ( up to 400 mg/dL ) o Low-density lipoprotein is low o Small beta or wide pre-beta-lipid band on lipoprotein electrophoresis o Thrombocytopenia, stomatocytes at the peripheral blood smear o Reduced osmotic resistance of erythrocytes Whilst the clinical phenotype of TD is autosomal recessive, the biochemical phenotype is autosomal co-dominant.2 The phenotypic features observed in TD vary according to the degree of involvement of organs and systems.18 Almost all children have large orange tonsils; however, it is not detected in adults due to tonsillectomy or may be overlooked. Focusing on Pediatric Immunology & Neurology 216 Heterozygous individuals may have no symptoms. Tonsillar anomaly and neuropathy are not expected in these. HDL and Apo-A1 levels are between normal levels and TD levels.2 Therefore, TD diagnosis is sometimes overlooked in the first and second screening.2 While almost half of the adult patients receive several treatment forms for neuropathy, the remainder of the population may be followed by hepatomegaly, splenomegaly, premature myocardial infarction, or stroke due to lipid storage in reticuloendothelial system cells (macrophages, kupffer cells, histiocytes).2,16 The pathophysiology of demyelination in TD neuropathy is not clear.19 However, Schwann cells in the region have a paranodal malfunction and ‘tomaculo formation’ against cholesterol ester deposition. 17 Schwann cells have abnormal lipid storage in unmyelinated fibers.4 HISTIOCYTIC FINDINGS Large orange tonsils can cause breathing and swallowing difficulties from time to time and may result in ear and sinus infections and obstructive sleep apnea ( Figure 1: Orange-yellow tonsils in a homozygous patient with Tangier disease, published with permission, from Erciyes University) Ear-Nose-Throat (ENT) consultation should be carried out for each application. Tonsillectomy should be performed if necessary.5 Hepatomegaly and splenomegaly are commonly seen in adults. Abdominal ultrasonography may be performed for surveillance. In the endoscopic examination of the intestine and rectal mucosa, orange-brown focal deposits and, foam cells accumulation may be observed, but the patients may not have any significant symptoms.2,18 Cervical, axillary and thoracic lymphadenopathies may be found.5 Fig.1. Orange-yellow tonsils in a homozygous patient with Tangier disease, published with permission, from Erciyes University Tangier Disease 217 NEUROLOGICAL FINDINGS Peripheral neuropathic symptoms like numbness, tingling, loss of distal sensation,and, distal weakness due to muscle atrophy can be seen in approximately 50% of the patients. It is generally relapsing-remitting and may be progressive in some cases. TD neuropathy displays two distinctive findings.19 There may be multifocal mono/polyneuropathy involving cranial, trunk or extremity nerves; Syringomyelia-like neuropathy may be expected presenting by pain and temperature sensation affecting the upper extremity, slow progressive fasiobrachial weakness, and muscle loss. Rarely, there may be subclinical or distal symmetrical polyneuropathy.16 If necessary, nerve conduction studies and EMG may be performed.5 Physical medicine and rehabilitation and neurologic surveillance should be recommended for TD patients. Clinically proven treatments are not yet available. Appropriate exercise and ankle-foot orthosis may be recommended.5 Studies have shown that HDL reduction can increase the risk of cerebral infarction 1.8 times and increase the total stroke risk 1.5 times.20,21 OPHTHALMOLOGICAL FINDINGS Spot opacities appearing later in life can be seen. Ophthalmologic evaluation is recommended every year. Corneal transplantation may be necessary.5 CARDIAC FINDINGS Early atherosclerotic cardiovascular disease (CVD) can be seen, which is usually not obvious before the age of 40,22 and becomes apparent in the 50s and 60s.23 Although low HDL is an important precursor for early CVD, simultaneous reduction in LDL may provide some protection from CVD. Therefore, cardiovascular disease risk is not significantly increased in TD. Echocardiography and, if necessary, CT coronary angiography should be performed for follow-up. Some patients may present with heart valve involvement. Reduction of cardiovascular risks, statin therapy, and a low-fat diet are recommended in this population.2,5 HEMATOLOGICAL FINDINGS Mild thrombocytopenia, reticulocytosis, stomatocytosis, hemolytic anemia may be seen. Complete blood counts should be performed at each check-up. Standard treatments are recommended.24 Focusing on Pediatric Immunology & Neurology 218 DERMATOLOGICAL FINDINGS Although no apparent skin findings have been reported, skin ulcers, prurigo nodularis, and painless scald or burn scars have been reported in some individuals.25 Xanthomas have not been encountered.26 GENETIC FEATURES Thanks to advances in genetic studies of neuropathies, genetic classifications have recently replaced classifications based on electrophysiology and histopathology, previously using even a nerve biopsy method for diagnosis.2,19 In one study, the p.Arg1817x mutation was reported in the ABCA1 gene in a patient with similar clinical findings, except for thrombocytopenia.27 Currently, More than 100 ABCA1 mutations have been identified in patients affected by TD and intermediate HDL deficiency phenotypes.2 The TD diagnosis is made by absent or extremely low HDL-cholesterol and apo A-I levels in a proband and biallelic pathogenic variants in ABCA1 gene in molecular genetic tests.5 The molecular genetic approach may include single-gene testing or use of a multigene panel for diagnosis of TD5,28 • Single-gene testing. Sequence analysis of ABCA1 • A multigene panel that includes ABCA1 and other genes If clinical molecular genetic testing cannot be performed, the presence of acholesterol esters accumulation in tissue biopsies can be considered in individuals with typical clinical features of TD. Table 1. Molecular Genetic Tests Used in Tangier Disease5,28 Gene Method Proportion of Pathogenic Variants Detectable by Method ABCA1 Sequence analysis >90% Gene-targeted deletion/duplication analysis <10% DIFFERENTIAL DIAGNOSIS Severe HDL deficiency:29 - hypertriglyceridemia, paraproteinemia - secondary causes (e.g., androgenic anabolic steroids, paradoxic response to PPAR (peroxisome proliferator-activated receptor) agonists, malaria, HIV infection, malignancy, liver disease Tangier Disease 219 Hereditary disorders with severe HDL deficiency30 - ApoA-1deficiency - LCAT deficiency ( OMIM#245900) - Fish eye disease ( OMIM#136120) TREATMENT AND PROGNOSIS Treatment The only definitive intervention recommended for TD is a very low-fat diet, potentially reducing the potential for the fatty liver’s development.19 Commonly used old medications such as fibric acid derivatives and niacin (nicotinic acid) have been shown to be ineffective in patients with TD.31,32 Following Up Annual neurology and ophthalmology evaluation Evaluation of cardiovascular risk in adults Toxic drugs such as Vincristine should be refrained in prone to obesity and the development of peripheral neuropathy, and contact sports in those with hepatosplenomegaly. PROGNOSIS Though the prognosis is usually good, it relies on peripheral neuropathy and/or atherosclerosis progression. Individuals have moderate CVD risk, which can be managed with traditional preventive treatments.33 Prenatal testing is possible for pregnant women at risk if pathogenic variants are known in the family.5 RESULTS Plasma HDL levels and genetic analysis are critical in the differential diagnosis of peripheral neuropathy and chronic demyelinating neuropathy. TD should be kept in mind in cases of unexplained splenomegaly, thrombocytopenia, and hypocholesterolemia. Whole Exome Sequencing (WES) is one of the leading genetic tests to clarify the diagnosis in pediatric disorders.19 REFERENCES 1. Serfaty-Lacrosniere C, Civeira F, Landzberg A, Isaia P, Berg J, et al Homozygous Tangier Disease and Cardiovaskular Disease. Atherosclerosis. 1994 May;107(1):85-98. 2. Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology, and management. 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