Tangier_Disease

Mendelian MONDO:0008783 Pathograph 38 Hypoalphalipoproteinemia Hypolipoproteinemia Neurometabolic Disorder

Tangier disease is an autosomal recessive ABCA1 deficiency disorder of HDL biogenesis and cellular cholesterol efflux. Biallelic ABCA1 pathogenic variants impair apolipoprotein-mediated cholesterol and phospholipid export, producing extremely low or absent HDL cholesterol and apoA-I, reduced cholesterol removal from peripheral cells, and cholesteryl ester accumulation in tissues. The clinical phenotype includes orange tonsils, hepatosplenomegaly, lymphadenopathy, peripheral neuropathy, ocular and skin/nail findings, and variable premature atherosclerotic cardiovascular disease.

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1
Inheritance
4
Pathophys.
23
Phenotypes
1
Hypotheses
38
Pathograph
1
Genes
6
Treatments
13
References
1
Deep Research
1
Hyp. Reports
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:31150 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for Tangier disease.
PMID:33994407 SUPPORT Human Clinical
"Tangier disease is an autosomal recessive disease"
This clinical management review states the autosomal recessive inheritance pattern.
◈

Mechanistic Hypotheses

1
Canonical ABCA1 HDL Efflux Model
canonical_abca1_hdl_efflux_model CANONICAL
Biallelic ABCA1 pathogenic variants impair apolipoprotein-mediated phospholipid and cholesterol efflux, blocking nascent HDL formation. Cellular cholesterol export falls in macrophages, Schwann cells, and other peripheral cells, leading to cholesteryl ester storage in tissues and a combination of reticuloendothelial, neurologic, biochemical, and vascular manifestations.
Retained as CANONICAL. The 2026 openscientist hypothesis-search report (kb/hypotheses/Tangier_Disease/canonical_abca1_hdl_efflux_model) reviewed 134 papers and found zero refutations of the ABCA1 efflux-failure pathway, but identified eight mechanistic qualifications that expand the model beyond cholesterol storage alone: (1) NLRP3 inflammasome activation confirmed in TD patients, (2) sphingosine-1-phosphate depletion via HDL loss, (3) PMP22-ABCA1 interaction in Schwann cell cholesterol homeostasis, (4) hematopoietic stem cell myeloproliferation feed-forward, (5) platelet dense-body deficiency, (6) pancreatic beta-cell dysfunction, (7) the distinction between HDL-C concentration and cholesterol efflux capacity as cardiovascular risk metrics, and (8) the macrophage-versus-total-body ABCA1 knockout dissection of the cardiovascular paradox.
Deep research
OpenScientist citations 35 citations 2026-05-22T22:41:05.038961
Show evidence (11 references)
PMID:33994407 SUPPORT Human Clinical
"gene, the mandatory gene for generation of HDL particles from cellular"
This review links ABCA1 to HDL particle generation from cellular lipid export.
PMID:33994407 SUPPORT Human Clinical
"Cholesterol therefore accumulates in these cells, causing orange-colored pharyngeal tonsillar swelling, corneal opacity, hepatosplenomegaly, lymphadenopathy and peripheral neuropathy."
This review summarizes the downstream tissue-storage phenotype.
PMID:28602350 SUPPORT Other
"Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency."
Cryo-EM structural biology directly connects ABCA1 to Tangier disease and provides an atomic-resolution framework for interpreting the diverse mutations that cause loss of cholesterol/phospholipid efflux.
+ 8 more references
⚙

Pathophysiology

4
ABCA1 Dysfunction
Disease-causing germline ABCA1 variants impair the ATP-binding cassette transporter required for apolipoprotein-mediated cellular lipid export. Human genetic studies identified ABCA1 mutations in Tangier disease kindreds, and cell-based studies show that ABCA1 promotes phospholipid and cholesterol efflux by loading apoA-I with lipids.
cholesterol efflux link ↓ DECREASED phospholipid efflux link ↓ DECREASED
ATPase-coupled transmembrane transporter activity link apolipoprotein binding link
Downstream
Impaired HDL Biogenesis ABCA1 dysfunction reduces apolipoprotein-mediated cholesterol and phospholipid export needed to assemble HDL.
Show evidence (4 references)
ORPHA:31150 SUPPORT Other
"ABCA1 | ATP binding cassette subfamily A member 1 | hgnc:29 | Disease-causing germline mutation(s) in"
Orphanet records ABCA1 as the disease-causing gene.
PMID:10431236 SUPPORT Human Clinical
"ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic."
Human genetic linkage and mutation detection support ABCA1 as the causal locus.
PMID:10431238 SUPPORT Human Clinical
"encoding a member of the ABC transporter superfamily, are the cause of TD."
Independent human kindred study identifies ABCA1 defects as the cause of Tangier disease.
+ 1 more reference
Impaired HDL Biogenesis
Loss of ABCA1-dependent lipid efflux blocks normal generation of nascent and mature HDL particles. The plasma consequence is severe HDL-C and apoA-I deficiency, with associated hypocholesterolemia and often hypertriglyceridemia.
high-density lipoprotein particle assembly link ↓ DECREASED cholesterol efflux link ↓ DECREASED
Downstream
Decreased HDL cholesterol concentration HDL particle assembly failure produces very low or absent HDL-C.
Low HDL cholesterol HDL particle assembly failure is measured clinically as absent or extremely low plasma HDL-C.
Low apolipoprotein A-I Failure to generate normal HDL particles is accompanied by absent or extremely low apoA-I levels.
Hypocholesterolemia Severe HDL deficiency and altered lipoprotein remodeling lower total cholesterol.
Low total cholesterol Severe HDL-C depletion contributes to low total plasma cholesterol.
Hypertriglyceridemia Tangier disease commonly includes normal to high or elevated plasma triglycerides.
Elevated plasma triglycerides Plasma triglycerides are normal to high or elevated in many Tangier disease patients.
Cholesteryl Ester Tissue Storage Loss of HDL-mediated cellular lipid removal promotes cholesterol ester accumulation in tissues.
Atherosclerotic Vascular Risk Failure of ABCA1-dependent HDL generation impairs the initial reverse cholesterol transport step, increasing atherosclerotic vascular risk despite often low LDL-C.
Show evidence (3 references)
PMID:10525055 SUPPORT In Vitro
"activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured"
Cell-based studies support impaired apolipoprotein-mediated efflux as the proximal mechanism.
PMID:33994407 SUPPORT Human Clinical
"With functional deficiency in ABCA1, spherical HDL particles are not produced resulting in extremely low plasma HDL-C levels"
Clinical review links ABCA1 deficiency to failure of spherical HDL production and very low HDL-C.
PMID:7130397 SUPPORT Human Clinical
"cholesterol, apoA-I, and apoA-II concentrations that were 4, 2, and 11% of"
Human kinetic studies document the biochemical HDL and apolipoprotein deficiency in homozygotes.
Cholesteryl Ester Tissue Storage
Impaired ABCA1-mediated cholesterol export causes cholesteryl esters to accumulate in reticuloendothelial tissues, Schwann cells, skin, smooth muscle, and mucosa. Tissue storage explains the orange tonsils, hepatosplenomegaly, lymphadenopathy, corneal opacity, skin and nail findings, and neuropathy spectrum.
macrophage link Schwann cell link
Downstream
Orange discolored tonsils Cholesteryl ester storage in tonsillar tissue produces orange tonsils.
Hepatosplenomegaly Reticuloendothelial lipid storage enlarges liver and spleen.
Chronic noninfectious lymphadenopathy Reticuloendothelial storage contributes to lymph-node enlargement.
Corneal opacity Lipid storage in ocular tissue can produce corneal opacity.
Dry skin Skin lipid deposition can contribute to dermatologic findings.
Nail dystrophy Skin and appendage involvement can include nail dystrophy.
Ectropion Tissue storage and dermatologic involvement can include eyelid malposition, but the precise intervening mechanism is not specified in the cited sources.
Abdominal pain Reticuloendothelial and hepatosplenic involvement can produce abdominal symptoms, though the exact path is not resolved in the cited sources.
Thrombocytopenia Splenomegaly and reticuloendothelial involvement can be accompanied by thrombocytopenia.
Anemia Reticuloendothelial and splenic involvement can be accompanied by anemia in reported Tangier cohorts.
Peripheral axonal neuropathy Schwann-cell and peripheral-nerve lipid storage contributes to neuropathy.
Progressive peripheral neuropathy Peripheral-nerve involvement may be chronic and progressive.
Facial diplegia Cranial nerve involvement can manifest as facial diplegia.
Impaired temperature sensation Sensory nerve involvement can impair temperature sensation.
Distal muscle weakness Motor neuropathy can produce distal weakness.
Syringomyelia A syringomyelia-like neuropathy phenotype has been described.
Show evidence (3 references)
PMID:162820 SUPPORT Human Clinical
"cholesteryl esters were found in: reticuloendothelial cells (foam cells) in"
Histopathologic study directly demonstrates cholesteryl ester storage in patient tissues.
PMID:162820 SUPPORT Human Clinical
"Schwann cells in peripheral"
The pathology study supports Schwann-cell involvement in peripheral nerves.
PMID:33994407 SUPPORT Human Clinical
"cellular cholesterol export is impaired due to ABCA1 deficiency in peripheral cells, including macrophages and Schwann cells."
This review connects ABCA1 deficiency to impaired cholesterol export in macrophages and Schwann cells.
Atherosclerotic Vascular Risk
Tangier disease impairs the initial stage of reverse cholesterol transport despite often-low LDL-C. Reviews report increased atherosclerotic and coronary disease risk in a subset of patients, especially adults with less marked splenomegaly or higher non-HDL cholesterol.
cholesterol transport link ↓ DECREASED cholesterol metabolic process link
Downstream
Accelerated atherosclerosis Impaired reverse cholesterol transport increases atherosclerotic risk in susceptible patients.
Coronary artery stenosis Atherosclerotic vascular involvement can include coronary artery disease.
Carotid artery stenosis Atherosclerotic vascular involvement can include carotid artery stenosis.
Left ventricular hypertrophy Cardiovascular disease burden can include left ventricular hypertrophy.
Show evidence (3 references)
PMID:10431238 SUPPORT Human Clinical
"Impaired cholesterol efflux from macrophages leads to the"
Human genetic paper connects impaired macrophage efflux to foam-cell accumulation.
PMID:33994407 SUPPORT Human Clinical
"impairment of the initial stage of reverse cholesterol transport should be considered to be a risk for developing atherosclerotic diseases"
This review links the efflux defect to atherosclerotic risk.
PMID:27565770 SUPPORT Human Clinical
"25% had CVD, which increased to 52% in those between the ages of 40 and 65 years"
Review of reported Tangier cases supports age-dependent cardiovascular disease risk.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Tangier_Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Blood 2
Thrombocytopenia OCCASIONAL Thrombocytopenia (HP:0001873)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0001873 | Thrombocytopenia | Occasional (29-5%)"
Orphanet records thrombocytopenia as occasional.
Anemia OCCASIONAL Anemia (HP:0001903)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0001903 | Anemia | Occasional (29-5%)"
Orphanet records anemia as occasional.
Cardiovascular 3
Hepatosplenomegaly FREQUENT Hepatosplenomegaly (HP:0001433)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
Orphanet records hepatosplenomegaly as frequent.
Coronary artery stenosis FREQUENT Coronary artery stenosis (HP:0005145)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0005145 | Coronary artery stenosis | Frequent (79-30%)"
Orphanet records coronary artery stenosis as frequent.
Left ventricular hypertrophy OCCASIONAL Left ventricular hypertrophy (HP:0001712)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0001712 | Left ventricular hypertrophy | Occasional (29-5%)"
Orphanet records left ventricular hypertrophy as occasional.
Eye 1
Corneal opacity OCCASIONAL Corneal opacity (HP:0007957)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0007957 | Corneal opacity | Occasional (29-5%)"
Orphanet records corneal opacity as occasional.
Integument 2
Dry skin FREQUENT Dry skin (HP:0000958)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0000958 | Dry skin | Frequent (79-30%)"
Orphanet records dry skin as frequent.
Nail dystrophy FREQUENT Nail dystrophy (HP:0008404)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0008404 | Nail dystrophy | Frequent (79-30%)"
Orphanet records nail dystrophy as frequent.
Metabolism 2
Decreased HDL cholesterol concentration Decreased HDL cholesterol concentration (HP:0003233)
Show evidence (2 references)
PMID:22913675 SUPPORT Human Clinical
"plasma HDL concentrations less than 5 mg/dL"
The review describes the severe HDL-C depletion characteristic of Tangier disease.
PMID:33994407 SUPPORT Human Clinical
"Plasma HDL-C is mostly low, at 5 mg/dL or less"
The management review provides a concrete HDL-C diagnostic range.
Hypertriglyceridemia VERY_FREQUENT Hypertriglyceridemia (HP:0002155)
Show evidence (2 references)
ORPHA:31150 SUPPORT Other
"HP:0002155 | Hypertriglyceridemia | Very frequent (99-80%)"
Orphanet records hypertriglyceridemia as very frequent.
PMID:22913675 SUPPORT Human Clinical
"normal or high plasma triglycerides"
This review supports the triglyceride abnormality.
Musculoskeletal 1
Distal muscle weakness FREQUENT Distal muscle weakness (HP:0002460)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0002460 | Distal muscle weakness | Frequent (79-30%)"
Orphanet records distal muscle weakness as frequent.
Constitutional 1
Abdominal pain FREQUENT Abdominal pain (HP:0002027)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0002027 | Abdominal pain | Frequent (79-30%)"
Orphanet records abdominal pain as frequent.
Other 11
Hypocholesterolemia VERY_FREQUENT Hypocholesterolemia (HP:0003146)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0003146 | Hypocholesterolemia | Very frequent (99-80%)"
Orphanet records hypocholesterolemia as very frequent.
Orange discolored tonsils FREQUENT Orange discolored tonsils (HP:0030814)
Show evidence (2 references)
ORPHA:31150 SUPPORT Other
"HP:0030814 | Orange discoloured tonsils | Frequent (79-30%)"
Orphanet records orange discolored tonsils as frequent.
PMID:7130397 SUPPORT Human Clinical
"enlarged orange"
Classic human study supports orange enlarged tonsils as a hallmark finding.
Chronic noninfectious lymphadenopathy FREQUENT Chronic noninfectious lymphadenopathy (HP:0002730)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0002730 | Chronic noninfectious lymphadenopathy | Frequent (79-30%)"
Orphanet records chronic noninfectious lymphadenopathy as frequent.
Peripheral axonal neuropathy FREQUENT Peripheral axonal neuropathy (HP:0003477)
Show evidence (2 references)
ORPHA:31150 SUPPORT Other
"HP:0003477 | Peripheral axonal neuropathy | Frequent (79-30%)"
Orphanet records peripheral axonal neuropathy as frequent.
PMID:33994407 SUPPORT Human Clinical
"Various peripheral neuropathies, ranging from mild to severe, have been reported."
Clinical review supports peripheral neuropathy as part of Tangier disease.
Progressive peripheral neuropathy FREQUENT Progressive peripheral neuropathy (HP:0007133)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0007133 | Progressive peripheral neuropathy | Frequent (79-30%)"
Orphanet records progressive peripheral neuropathy as frequent.
Facial diplegia OCCASIONAL Facial diplegia (HP:0001349)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0001349 | Facial diplegia | Occasional (29-5%)"
Orphanet records facial diplegia as occasional.
Impaired temperature sensation OCCASIONAL Impaired temperature sensation (HP:0010829)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0010829 | Impaired temperature sensition | Occasional (29-5%)"
Orphanet records impaired temperature sensation as occasional; the ORPHA row contains a spelling variant.
Syringomyelia OCCASIONAL Syringomyelia (HP:0003396)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0003396 | Syringomyelia | Occasional (29-5%)"
Orphanet records syringomyelia as occasional.
Ectropion FREQUENT Ectropion (HP:0000656)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0000656 | Ectropion | Frequent (79-30%)"
Orphanet records ectropion as frequent.
Accelerated atherosclerosis FREQUENT Accelerated atherosclerosis (HP:0004943)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0004943 | Accelerated atherosclerosis | Frequent (79-30%)"
Orphanet records accelerated atherosclerosis as frequent.
Carotid artery stenosis OCCASIONAL Carotid artery stenosis (HP:0100546)
Show evidence (1 reference)
ORPHA:31150 SUPPORT Other
"HP:0100546 | Carotid artery stenosis | Occasional (29-5%)"
Orphanet records carotid artery stenosis as occasional.
🧬

Genetic Associations

1
Biallelic ABCA1 Pathogenic Variants (Causative)
Autosomal recessive
Show evidence (2 references)
ORPHA:31150 SUPPORT Other
"ABCA1 | ATP binding cassette subfamily A member 1 | hgnc:29 | Disease-causing germline mutation(s) in"
Orphanet records ABCA1 as a disease-causing germline gene.
PMID:31751110 SUPPORT Human Clinical
"pathogenic variants in ABCA1 identified by molecular genetic testing."
GeneReviews identifies ABCA1 molecular testing as diagnostic.
💊

Treatments

6
Statin-Based Cardiovascular Risk Management
Action: Pharmacotherapy NCIT:C15986
Agent: statin ↗
There is no curative Tangier-specific therapy. Management emphasizes prevention of atherosclerosis and optimization of non-HDL cardiovascular risk factors; if LDL-C is not already low, reviews recommend statin therapy or other LDL-lowering approaches.
Mechanism Target:
MODULATES Atherosclerotic Vascular Risk — Statin therapy is used to reduce modifiable LDL-C and non-HDL cardiovascular risk when present.
Show evidence (1 reference)
PMID:33994407 SUPPORT Human Clinical
"Plasma LDL-C levels are generally low in patients with Tangier disease but if this is not the case, they should be reduced through administration of statins or other means."
The management review recommends LDL-lowering therapy with statins when LDL-C is not low.
Show evidence (2 references)
PMID:33994407 SUPPORT Human Clinical
"No specific curative treatment"
This supports framing statins as risk management rather than curative disease therapy.
PMID:27565770 SUPPORT Human Clinical
"Optimizing the LDL-C levels in Tangier patients with normal LDL-C levels using statin therapy is clearly warranted in our view."
HDL-deficiency treatment review recommends statin-based LDL-C optimization in at-risk Tangier patients.
Low-Fat Diet and Lipid Risk Reduction
Action: dietary intervention MAXO:0000088
Low-fat diet is recommended as part of cardiovascular risk-factor mitigation, alongside lipid-profile optimization and surveillance for atherosclerotic disease.
Mechanism Target:
MODULATES Atherosclerotic Vascular Risk — Diet is used to mitigate modifiable cardiovascular risk rather than restore ABCA1 function.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"using statin therapy and a low-fat diet."
GeneReviews lists low-fat diet with statin therapy as risk mitigation.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"cardiovascular risk factors, including improvement of plasma lipid profiles"
GeneReviews supports risk-factor mitigation as prevention of primary manifestations.
Peripheral Neuropathy Rehabilitation
Action: physical therapy MAXO:0000011
Supportive management for peripheral neuropathy includes bracing and exercise when weakness or gait impairment is present.
Mechanism Target:
MODULATES Peripheral axonal neuropathy — Bracing and exercise target functional impairment from neuropathy.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"and exercise for those with peripheral neuropathy"
GeneReviews recommends exercise for neuropathy manifestations.
MODULATES Distal muscle weakness — Orthotic support can mitigate motor weakness from peripheral neuropathy.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"transient bracing (such as ankle-foot orthosis)"
GeneReviews lists bracing for peripheral neuropathy-related weakness.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"and exercise for those with peripheral neuropathy"
GeneReviews supports supportive rehabilitation for neuropathy.
Tonsillectomy for Obstructive Tonsillar Disease
Action: surgical procedure MAXO:0000004
Tonsillectomy is used when enlarged orange tonsils cause airway obstruction or mass symptoms; it is symptomatic management and does not address the ABCA1 lipid-efflux defect.
Mechanism Target:
MODULATES Orange discolored tonsils — Surgery addresses obstructive or mass-effect symptoms from enlarged tonsils.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"Tonsillectomy in those with airway"
GeneReviews recommends tonsillectomy when airway obstruction or mass symptoms are present.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"Tonsillectomy in those with airway"
GeneReviews supports tonsillectomy as treatment of tonsillar manifestations.
Corneal Transplantation for Vision-Limiting Corneal Opacity
Action: corneal transplantation MAXO:0010034
Corneal transplantation is used for corneal opacities that interfere with daily living; it is symptomatic management of ocular lipid-storage complications rather than restoration of ABCA1 function.
Mechanism Target:
MODULATES Corneal opacity — Corneal transplantation addresses vision-limiting corneal opacity.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"corneal transplantation for corneal opacities that interfere with daily living"
GeneReviews recommends corneal transplantation when corneal opacities interfere with daily living.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"corneal transplantation for corneal opacities that interfere with daily living"
GeneReviews supports corneal transplantation as treatment for vision-limiting corneal opacity in Tangier disease.
Genetic Counseling and Family Screening
Action: genetic counseling MAXO:0000079
Genetic counseling, lipid-profile screening, apoA-I testing, and targeted familial variant testing can identify at-risk relatives and support reproductive counseling.
Show evidence (2 references)
PMID:31751110 SUPPORT Human Clinical
"Carrier testing for at-risk relatives and prenatal testing"
GeneReviews supports genetic counseling and familial testing when variants are known.
PMID:39817629 SUPPORT Human Clinical
"Family screening should be recommended"
Pediatric cohort review recommends family screening after diagnosis.
🔬

Biochemical Markers

4
Low HDL cholesterol (DECREASED)
Context: Plasma HDL-C is absent or extremely low and is a core diagnostic readout of failed ABCA1-dependent HDL biogenesis.
Pathograph Readouts
Readout Of Impaired HDL Biogenesis Negative Diagnostic
Lower HDL-C reports impaired ABCA1-dependent HDL particle generation.
Show evidence (1 reference)
PMID:33994407 SUPPORT Human Clinical
"Plasma HDL-C is mostly low, at 5 mg/dL or less"
The management review supports HDL-C as a diagnostic readout of Tangier disease.
Show evidence (1 reference)
PMID:33994407 SUPPORT Human Clinical
"Plasma HDL-C is mostly low, at 5 mg/dL or less"
The review provides the typical severe HDL-C depletion range in Tangier disease.
Low apolipoprotein A-I (DECREASED)
Context: ApoA-I is absent or extremely low because ABCA1-dependent lipidation and HDL particle formation fail.
Pathograph Readouts
Readout Of Impaired HDL Biogenesis Negative Diagnostic
Lower apoA-I reports failed HDL particle generation and rapid loss of apoA-I-containing HDL.
Show evidence (1 reference)
PMID:31751110 SUPPORT Human Clinical
"with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic"
GeneReviews supports apoA-I depletion as a diagnostic readout in Tangier disease.
Show evidence (1 reference)
PMID:33994407 SUPPORT Human Clinical
"apoA-I concentration is 10 mg/dL or less"
The management review reports markedly low apoA-I concentrations in Tangier disease.
Low total cholesterol (DECREASED)
Context: Total plasma cholesterol is low, largely reflecting the profound HDL-C deficit and altered lipoprotein cholesterol distribution.
Pathograph Readouts
Correlates With Impaired HDL Biogenesis Negative Diagnostic
Low total cholesterol accompanies the severe HDL-C deficit in Tangier disease.
Show evidence (1 reference)
PMID:22913675 SUPPORT Human Clinical
"low total plasma cholesterol (below 150 mg/dL)"
The epidemiology review supports low total cholesterol as part of the diagnostic biochemical profile.
Show evidence (1 reference)
PMID:22913675 SUPPORT Human Clinical
"low total plasma cholesterol (below 150 mg/dL)"
The review supports low total plasma cholesterol in Tangier disease.
Elevated plasma triglycerides (INCREASED)
Context: Plasma triglycerides may be normal to high or elevated in the Tangier lipoprotein profile.
Pathograph Readouts
Correlates With Impaired HDL Biogenesis Positive Diagnostic
Higher triglycerides are part of the altered lipoprotein profile accompanying severe HDL biogenesis failure.
Show evidence (1 reference)
PMID:22913675 SUPPORT Human Clinical
"normal or high plasma triglycerides"
The review supports normal-to-high triglycerides in the Tangier biochemical profile.
Show evidence (1 reference)
PMID:22913675 SUPPORT Human Clinical
"normal or high plasma triglycerides"
The review supports triglyceride elevation or high-normal triglycerides in Tangier disease.
{ }

Source YAML

click to show 
name: Tangier_Disease
creation_date: '2026-05-04T06:39:03Z'
updated_date: '2026-05-21T20:36:59Z'
category: Mendelian
description: >
  Tangier disease is an autosomal recessive ABCA1 deficiency disorder of HDL
  biogenesis and cellular cholesterol efflux. Biallelic ABCA1 pathogenic
  variants impair apolipoprotein-mediated cholesterol and phospholipid export,
  producing extremely low or absent HDL cholesterol and apoA-I, reduced
  cholesterol removal from peripheral cells, and cholesteryl ester accumulation
  in tissues. The clinical phenotype includes orange tonsils, hepatosplenomegaly,
  lymphadenopathy, peripheral neuropathy, ocular and skin/nail findings, and
  variable premature atherosclerotic cardiovascular disease.
disease_term:
  preferred_term: Tangier disease
  term:
    id: MONDO:0008783
    label: Tangier disease
synonyms:
- ATP-binding cassette transporter A1 deficiency
- Analphalipoproteinemia
- HDL lipoprotein deficiency disease
- High density lipoprotein deficiency, Tangier type
parents:
- Hypoalphalipoproteinemia
- Hypolipoproteinemia
- Neurometabolic Disorder
notes: >-
  ORPHA:31150 maps Tangier disease exactly to MONDO:0008783 and also lists
  MeSH:D013631, MedDRA:10051875, OMIM:205400, UMLS:C0039292, ICD-10:E78.6,
  and ICD-11:5C81.0.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for Tangier disease.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tangier disease is an autosomal recessive disease"
    explanation: This clinical management review states the autosomal recessive inheritance pattern.
prevalence:
- population: Worldwide
  percentage: <1 per 1,000,000
  notes: >-
    Orphanet records a worldwide point-prevalence estimate below 1 per
    1,000,000; published reviews describe roughly 100 to 150 reported cases.
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:22913675"
    explanation: Orphanet provides the worldwide point-prevalence estimate.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "35 cases have been reported in Japan and 109 cases"
    explanation: This review supports the ultra-rare reported-case count.
progression:
- phase: Onset
  age_range: Neonatal to adult
  notes: >-
    Orphanet lists neonatal, infancy, childhood, adolescent, and adult onset,
    reflecting broad ascertainment from childhood tonsillar findings through
    adult neuropathy or cardiovascular presentations.
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet includes neonatal onset among natural-history categories.
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet includes adult onset among natural-history categories.
  - reference: PMID:22913675
    reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large, yellow-orange tonsils"
    explanation: Children are frequently identified through orange tonsils.
  - reference: PMID:22913675
    reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptoms of neuropathy"
    explanation: Adult presentations often involve neuropathic symptoms.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_abca1_hdl_efflux_model
  hypothesis_label: Canonical ABCA1 HDL Efflux Model
  status: CANONICAL
  description: >
    Biallelic ABCA1 pathogenic variants impair apolipoprotein-mediated
    phospholipid and cholesterol efflux, blocking nascent HDL formation.
    Cellular cholesterol export falls in macrophages, Schwann cells, and other
    peripheral cells, leading to cholesteryl ester storage in tissues and a
    combination of reticuloendothelial, neurologic, biochemical, and vascular
    manifestations.
  notes: >-
    Retained as CANONICAL. The 2026 openscientist hypothesis-search report
    (kb/hypotheses/Tangier_Disease/canonical_abca1_hdl_efflux_model) reviewed
    134 papers and found zero refutations of the ABCA1 efflux-failure
    pathway, but identified eight mechanistic qualifications that expand the
    model beyond cholesterol storage alone: (1) NLRP3 inflammasome activation
    confirmed in TD patients, (2) sphingosine-1-phosphate depletion via HDL
    loss, (3) PMP22-ABCA1 interaction in Schwann cell cholesterol homeostasis,
    (4) hematopoietic stem cell myeloproliferation feed-forward, (5) platelet
    dense-body deficiency, (6) pancreatic beta-cell dysfunction, (7) the
    distinction between HDL-C concentration and cholesterol efflux capacity
    as cardiovascular risk metrics, and (8) the macrophage-versus-total-body
    ABCA1 knockout dissection of the cardiovascular paradox.
  evidence:
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gene, the mandatory gene for generation of HDL particles from cellular"
    explanation: This review links ABCA1 to HDL particle generation from cellular lipid export.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholesterol therefore accumulates in these cells, causing orange-colored pharyngeal tonsillar swelling, corneal opacity, hepatosplenomegaly, lymphadenopathy and peripheral neuropathy."
    explanation: This review summarizes the downstream tissue-storage phenotype.
  - reference: PMID:28602350
    reference_title: "Structure of the Human Lipid Exporter ABCA1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency."
    explanation: >
      Cryo-EM structural biology directly connects ABCA1 to Tangier disease
      and provides an atomic-resolution framework for interpreting the
      diverse mutations that cause loss of cholesterol/phospholipid efflux.
  - reference: PMID:40617357
    reference_title: "Functional characterization of ABCA1 intracellular domain variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we have characterized 74 variants affecting the intracellular domains of ABCA1 by assessing cholesterol efflux activity"
    explanation: >
      Large-scale in vitro variant characterization shows that cholesterol
      efflux activity stratifies ABCA1 variants by pathogenicity, providing
      functional support for efflux failure as the canonical mechanism.
  - reference: PMID:20418488
    reference_title: "A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001)"
    explanation: >
      Population-genetic and functional characterization of the ABCA1 R230C
      variant provides independent dose-response validation of the
      efflux-to-HDL relationship at population scale.
  - reference: PMID:12771001
    reference_title: "Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infusion of apoA-I/PC disks increased plasma HDL to 1.3+/-0.4 mmol/L in ABCA1 heterozygotes, which resulted in"
    explanation: >
      Acute HDL replacement in ABCA1 heterozygotes restored endothelial
      vasomotor responses, providing direct interventional evidence that the
      ABCA1-HDL axis is required for normal vascular function.
  - reference: PMID:29588315
    reference_title: "Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with Tangier disease, who have increased myeloid cholesterol content, showed markers of inflammasome activation"
    explanation: >
      Qualifies the canonical model by showing that the NLRP3 inflammasome
      pathway is activated in TD patients, identifying inflammation as a
      mechanistic layer that operates in parallel with passive cholesterol
      storage.
  - reference: PMID:37601634
    reference_title: "Hepatocyte ABCA1 deficiency is associated with reduced HDL sphingolipids."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "drastic reduction of total SL levels in plasma of a Tangier patient with compound heterozygosity for mutations in ABCA1"
    explanation: >
      Qualifies the canonical model by showing that HDL-carried
      sphingosine-1-phosphate and other sphingolipids are depleted in
      Tangier disease, adding a signaling-lipid dimension to the cholesterol
      efflux defect.
  - reference: PMID:38979632
    reference_title: "Roles for PMP22 in Schwann cell cholesterol homeostasis in health and disease."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "PMP22 and ABCA1 in cholesterol efflux"
    explanation: >
      Review of in vitro Schwann cell studies showing that PMP22 and ABCA1
      cooperate in cholesterol efflux, providing a tissue-specific mechanism
      for the demyelinating peripheral neuropathy that distinguishes TD from
      simple cholesterol storage.
  - reference: PMID:11950702
    reference_title: "Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation"
    explanation: >
      Qualifies the cardiovascular component of the canonical model by
      dissecting macrophage-specific from total-body ABCA1 loss; total ABCA1
      knockout did not accelerate atherosclerosis owing to concurrent LDL
      reduction, whereas macrophage-specific loss did.
  - reference: PMID:29582519
    reference_title: "Peripheral neuropathy in Tangier disease: A literature review and assessment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Syringomyelia-like neuropathy subtype (52.4%) was more frequent than multifocal sensorial and motor neuropathy subtype (26.2%)"
    explanation: >
      Literature review of 54 TD patients establishes four neuropathy
      subtypes downstream of ABCA1 loss, supporting the canonical model's
      claim that ABCA1 dysfunction in peripheral nerve cells produces
      heterogeneous neurologic manifestations.
pathophysiology:
- name: ABCA1 Dysfunction
  description: >
    Disease-causing germline ABCA1 variants impair the ATP-binding cassette
    transporter required for apolipoprotein-mediated cellular lipid export.
    Human genetic studies identified ABCA1 mutations in Tangier disease kindreds,
    and cell-based studies show that ABCA1 promotes phospholipid and cholesterol
    efflux by loading apoA-I with lipids.
  gene:
    preferred_term: ABCA1
    term:
      id: hgnc:29
      label: ABCA1
  molecular_functions:
  - preferred_term: ATPase-coupled transmembrane transporter activity
    term:
      id: GO:0042626
      label: ATPase-coupled transmembrane transporter activity
  - preferred_term: apolipoprotein binding
    term:
      id: GO:0034185
      label: apolipoprotein binding
  biological_processes:
  - preferred_term: cholesterol efflux
    term:
      id: GO:0033344
      label: cholesterol efflux
    modifier: DECREASED
  - preferred_term: phospholipid efflux
    term:
      id: GO:0033700
      label: phospholipid efflux
    modifier: DECREASED
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCA1 | ATP binding cassette subfamily A member 1 | hgnc:29 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records ABCA1 as the disease-causing gene.
  - reference: PMID:10431236
    reference_title: "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic."
    explanation: Human genetic linkage and mutation detection support ABCA1 as the causal locus.
  - reference: PMID:10431238
    reference_title: "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "encoding a member of the ABC transporter superfamily, are the cause of TD."
    explanation: Independent human kindred study identifies ABCA1 defects as the cause of Tangier disease.
  - reference: PMID:11309399
    reference_title: "ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cellular phospholipid and cholesterol efflux by loading free apoA-I with these"
    explanation: In vitro evidence supports ABCA1 as a transporter involved in apoA-I lipid loading.
  downstream:
  - target: Impaired HDL Biogenesis
    description: ABCA1 dysfunction reduces apolipoprotein-mediated cholesterol and phospholipid export needed to assemble HDL.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11309399
      reference_title: "ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "cellular phospholipid and cholesterol efflux by loading free apoA-I with these"
      explanation: This functional study supports ABCA1-mediated apoA-I lipid loading as the proximal step required for HDL biogenesis.
- name: Impaired HDL Biogenesis
  description: >
    Loss of ABCA1-dependent lipid efflux blocks normal generation of nascent and
    mature HDL particles. The plasma consequence is severe HDL-C and apoA-I
    deficiency, with associated hypocholesterolemia and often hypertriglyceridemia.
  biological_processes:
  - preferred_term: high-density lipoprotein particle assembly
    term:
      id: GO:0034380
      label: high-density lipoprotein particle assembly
    modifier: DECREASED
  - preferred_term: cholesterol efflux
    term:
      id: GO:0033344
      label: cholesterol efflux
    modifier: DECREASED
  chemical_entities:
  - preferred_term: high-density lipoprotein
    term:
      id: CHEBI:39025
      label: high-density lipoprotein
    modifier: DECREASED
  - preferred_term: high-density lipoprotein cholesterol
    term:
      id: CHEBI:47775
      label: high-density lipoprotein cholesterol
    modifier: DECREASED
  evidence:
  - reference: PMID:10525055
    reference_title: "The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured"
    explanation: Cell-based studies support impaired apolipoprotein-mediated efflux as the proximal mechanism.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With functional deficiency in ABCA1, spherical HDL particles are not produced resulting in extremely low plasma HDL-C levels"
    explanation: Clinical review links ABCA1 deficiency to failure of spherical HDL production and very low HDL-C.
  - reference: PMID:7130397
    reference_title: "Tangier disease. High density lipoprotein deficiency due to defective metabolism of an abnormal apolipoprotein A-i (ApoA-ITangier)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cholesterol, apoA-I, and apoA-II concentrations that were 4, 2, and 11% of"
    explanation: Human kinetic studies document the biochemical HDL and apolipoprotein deficiency in homozygotes.
  downstream:
  - target: Decreased HDL cholesterol concentration
    description: HDL particle assembly failure produces very low or absent HDL-C.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "With functional deficiency in ABCA1, spherical HDL particles are not produced resulting in extremely low plasma HDL-C levels"
      explanation: The clinical review directly links ABCA1 deficiency and failed HDL production to extremely low HDL-C.
  - target: Low HDL cholesterol
    description: HDL particle assembly failure is measured clinically as absent or extremely low plasma HDL-C.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Plasma HDL-C is mostly low, at 5 mg/dL or less"
      explanation: The management review supports low HDL-C as the diagnostic biochemical readout of impaired HDL biogenesis.
  - target: Low apolipoprotein A-I
    description: Failure to generate normal HDL particles is accompanied by absent or extremely low apoA-I levels.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic"
      explanation: GeneReviews supports apoA-I depletion as part of the diagnostic biochemical signature of Tangier disease.
  - target: Hypocholesterolemia
    description: Severe HDL deficiency and altered lipoprotein remodeling lower total cholesterol.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - severe HDL-C depletion and altered HDL-to-VLDL/LDL cholesterol transfer
    evidence:
    - reference: PMID:22913675
      reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "low total plasma\ncholesterol (below 150 mg/dL)"
      explanation: The epidemiology review supports low total cholesterol as part of the biochemical Tangier phenotype.
  - target: Low total cholesterol
    description: Severe HDL-C depletion contributes to low total plasma cholesterol.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - severe HDL-C depletion and altered HDL-to-VLDL/LDL cholesterol transfer
    evidence:
    - reference: PMID:22913675
      reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "low total plasma\ncholesterol (below 150 mg/dL)"
      explanation: The review supports total cholesterol as a low biochemical readout in Tangier disease.
  - target: Hypertriglyceridemia
    description: Tangier disease commonly includes normal to high or elevated plasma triglycerides.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22913675
      reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "normal or high plasma triglycerides"
      explanation: The review supports normal-to-high plasma triglycerides as part of the Tangier biochemical pattern.
  - target: Elevated plasma triglycerides
    description: Plasma triglycerides are normal to high or elevated in many Tangier disease patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22913675
      reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "normal or high plasma triglycerides"
      explanation: The review supports triglycerides as a biochemical readout of the disordered lipoprotein state.
  - target: Cholesteryl Ester Tissue Storage
    description: Loss of HDL-mediated cellular lipid removal promotes cholesterol ester accumulation in tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Impairment of HDL biogenesis results in reduced cholesterol export, which leads to lipid accumulation in cells."
      explanation: The review directly links impaired HDL biogenesis/reduced cholesterol export to cellular lipid accumulation.
  - target: Atherosclerotic Vascular Risk
    description: >
      Failure of ABCA1-dependent HDL generation impairs the initial reverse
      cholesterol transport step, increasing atherosclerotic vascular risk
      despite often low LDL-C.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        impairment of the initial stage of reverse cholesterol transport should
        be considered to be a risk for developing atherosclerotic diseases
      explanation: >
        The review links the impaired initial reverse-cholesterol-transport step
        downstream of ABCA1/HDL dysfunction to atherosclerotic disease risk.
- name: Cholesteryl Ester Tissue Storage
  description: >
    Impaired ABCA1-mediated cholesterol export causes cholesteryl esters to
    accumulate in reticuloendothelial tissues, Schwann cells, skin, smooth
    muscle, and mucosa. Tissue storage explains the orange tonsils,
    hepatosplenomegaly, lymphadenopathy, corneal opacity, skin and nail
    findings, and neuropathy spectrum.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  chemical_entities:
  - preferred_term: cholesteryl ester
    term:
      id: CHEBI:17002
      label: cholesteryl ester
    modifier: INCREASED
  evidence:
  - reference: PMID:162820
    reference_title: "The pathology of Tangier disease. A light and electron microscopic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cholesteryl esters were found in: reticuloendothelial cells (foam cells) in"
    explanation: Histopathologic study directly demonstrates cholesteryl ester storage in patient tissues.
  - reference: PMID:162820
    reference_title: "The pathology of Tangier disease. A light and electron microscopic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Schwann cells in peripheral"
    explanation: The pathology study supports Schwann-cell involvement in peripheral nerves.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cellular cholesterol export is impaired due to ABCA1 deficiency in peripheral cells, including macrophages and Schwann cells."
    explanation: This review connects ABCA1 deficiency to impaired cholesterol export in macrophages and Schwann cells.
  downstream:
  - target: Orange discolored tonsils
    description: Cholesteryl ester storage in tonsillar tissue produces orange tonsils.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cholesterol therefore accumulates in these cells, causing orange-colored pharyngeal tonsillar swelling, corneal opacity, hepatosplenomegaly, lymphadenopathy and peripheral neuropathy."
      explanation: The review directly links cellular cholesterol accumulation to orange pharyngeal tonsillar swelling.
  - target: Hepatosplenomegaly
    description: Reticuloendothelial lipid storage enlarges liver and spleen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cholesterol therefore accumulates in these cells, causing orange-colored pharyngeal tonsillar swelling, corneal opacity, hepatosplenomegaly, lymphadenopathy and peripheral neuropathy."
      explanation: The review directly links cellular cholesterol accumulation to hepatosplenomegaly.
  - target: Chronic noninfectious lymphadenopathy
    description: Reticuloendothelial storage contributes to lymph-node enlargement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cholesterol therefore accumulates in these cells, causing orange-colored pharyngeal tonsillar swelling, corneal opacity, hepatosplenomegaly, lymphadenopathy and peripheral neuropathy."
      explanation: The review directly links cellular cholesterol accumulation to lymphadenopathy.
  - target: Corneal opacity
    description: Lipid storage in ocular tissue can produce corneal opacity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cholesterol therefore accumulates in these cells, causing orange-colored pharyngeal tonsillar swelling, corneal opacity, hepatosplenomegaly, lymphadenopathy and peripheral neuropathy."
      explanation: The review directly links cellular cholesterol accumulation to corneal opacity.
  - target: Dry skin
    description: Skin lipid deposition can contribute to dermatologic findings.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000958 | Dry skin | Frequent (79-30%)"
      explanation: Orphanet records dry skin as a frequent phenotype in Tangier disease.
  - target: Nail dystrophy
    description: Skin and appendage involvement can include nail dystrophy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008404 | Nail dystrophy | Frequent (79-30%)"
      explanation: Orphanet records nail dystrophy as a frequent phenotype in Tangier disease.
  - target: Ectropion
    description: Tissue storage and dermatologic involvement can include eyelid malposition, but the precise intervening mechanism is not specified in the cited sources.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000656 | Ectropion | Frequent (79-30%)"
      explanation: Orphanet records ectropion as a frequent phenotype in Tangier disease.
  - target: Abdominal pain
    description: Reticuloendothelial and hepatosplenic involvement can produce abdominal symptoms, though the exact path is not resolved in the cited sources.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002027 | Abdominal pain | Frequent (79-30%)"
      explanation: Orphanet records abdominal pain as a frequent phenotype in Tangier disease.
  - target: Thrombocytopenia
    description: Splenomegaly and reticuloendothelial involvement can be accompanied by thrombocytopenia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - splenomegaly-associated platelet sequestration or reticuloendothelial involvement
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "splenomegaly and associated thrombocytopenia"
      explanation: The management review links splenomegaly with associated thrombocytopenia.
  - target: Anemia
    description: Reticuloendothelial and splenic involvement can be accompanied by anemia in reported Tangier cohorts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001903 | Anemia | Occasional (29-5%)"
      explanation: Orphanet records anemia as an occasional phenotype in Tangier disease.
  - target: Peripheral axonal neuropathy
    description: Schwann-cell and peripheral-nerve lipid storage contributes to neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "cellular cholesterol export is impaired due to ABCA1 deficiency in peripheral cells, including macrophages and Schwann cells."
      explanation: The review supports impaired cholesterol export in Schwann cells as a cellular basis for peripheral neuropathy.
  - target: Progressive peripheral neuropathy
    description: Peripheral-nerve involvement may be chronic and progressive.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Schwann-cell cholesterol accumulation and peripheral nerve dysfunction
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Various peripheral neuropathies, ranging from mild to severe, have been reported."
      explanation: The clinical review supports the peripheral neuropathy spectrum downstream of Tangier tissue storage.
  - target: Facial diplegia
    description: Cranial nerve involvement can manifest as facial diplegia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cranial peripheral nerve involvement
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001349 | Facial diplegia | Occasional (29-5%)"
      explanation: Orphanet records facial diplegia as an occasional neurologic phenotype in Tangier disease.
  - target: Impaired temperature sensation
    description: Sensory nerve involvement can impair temperature sensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - sensory peripheral nerve involvement
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010829 | Impaired temperature sensition | Occasional (29-5%)"
      explanation: Orphanet records impaired temperature sensation as an occasional neurologic phenotype in Tangier disease.
  - target: Distal muscle weakness
    description: Motor neuropathy can produce distal weakness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - motor peripheral nerve involvement
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002460 | Distal muscle weakness | Frequent (79-30%)"
      explanation: Orphanet records distal muscle weakness as a frequent neuromuscular phenotype in Tangier disease.
  - target: Syringomyelia
    description: A syringomyelia-like neuropathy phenotype has been described.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - syringomyelia-like peripheral neuropathy pattern
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "syringomyelia-like peripheral neuropathy"
      explanation: The management review describes a syringomyelia-like peripheral neuropathy pattern in Tangier disease.
- name: Atherosclerotic Vascular Risk
  description: >
    Tangier disease impairs the initial stage of reverse cholesterol transport
    despite often-low LDL-C. Reviews report increased atherosclerotic and
    coronary disease risk in a subset of patients, especially adults with less
    marked splenomegaly or higher non-HDL cholesterol.
  biological_processes:
  - preferred_term: cholesterol transport
    term:
      id: GO:0030301
      label: cholesterol transport
    modifier: DECREASED
  - preferred_term: cholesterol metabolic process
    term:
      id: GO:0008203
      label: cholesterol metabolic process
  chemical_entities:
  - preferred_term: cholesterol
    term:
      id: CHEBI:16113
      label: cholesterol
  evidence:
  - reference: PMID:10431238
    reference_title: "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired cholesterol efflux from macrophages leads to the"
    explanation: Human genetic paper connects impaired macrophage efflux to foam-cell accumulation.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impairment of the initial stage of reverse cholesterol transport should be considered to be a risk for developing atherosclerotic diseases"
    explanation: This review links the efflux defect to atherosclerotic risk.
  - reference: PMID:27565770
    reference_title: "Diagnosis and treatment of high density lipoprotein deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "25% had CVD, which increased to 52% in those between the ages of 40 and 65 years"
    explanation: Review of reported Tangier cases supports age-dependent cardiovascular disease risk.
  downstream:
  - target: Accelerated atherosclerosis
    description: Impaired reverse cholesterol transport increases atherosclerotic risk in susceptible patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impairment of the initial stage of reverse cholesterol transport should be considered to be a risk for developing atherosclerotic diseases"
      explanation: The review directly supports impaired reverse cholesterol transport as a risk for atherosclerotic disease.
  - target: Coronary artery stenosis
    description: Atherosclerotic vascular involvement can include coronary artery disease.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0005145 | Coronary artery stenosis | Frequent (79-30%)"
      explanation: Orphanet records coronary artery stenosis as a frequent cardiovascular phenotype in Tangier disease.
  - target: Carotid artery stenosis
    description: Atherosclerotic vascular involvement can include carotid artery stenosis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100546 | Carotid artery stenosis | Occasional (29-5%)"
      explanation: Orphanet records carotid artery stenosis as an occasional cardiovascular phenotype in Tangier disease.
  - target: Left ventricular hypertrophy
    description: Cardiovascular disease burden can include left ventricular hypertrophy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:31150
      reference_title: "Tangier disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001712 | Left ventricular hypertrophy | Occasional (29-5%)"
      explanation: Orphanet records left ventricular hypertrophy as an occasional cardiovascular phenotype in Tangier disease.
phenotypes:
- name: Decreased HDL cholesterol concentration
  category: Biochemical
  description: HDL cholesterol is absent or extremely low.
  phenotype_term:
    preferred_term: Decreased HDL cholesterol concentration
    term:
      id: HP:0003233
      label: Decreased HDL cholesterol concentration
  evidence:
  - reference: PMID:22913675
    reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plasma HDL concentrations less than 5 mg/dL"
    explanation: The review describes the severe HDL-C depletion characteristic of Tangier disease.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma HDL-C is mostly low, at 5 mg/dL or less"
    explanation: The management review provides a concrete HDL-C diagnostic range.
- name: Hypertriglyceridemia
  category: Biochemical
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002155 | Hypertriglyceridemia | Very frequent (99-80%)"
    explanation: Orphanet records hypertriglyceridemia as very frequent.
  - reference: PMID:22913675
    reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal or high plasma triglycerides"
    explanation: This review supports the triglyceride abnormality.
- name: Hypocholesterolemia
  category: Biochemical
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypocholesterolemia
    term:
      id: HP:0003146
      label: Hypocholesterolemia
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003146 | Hypocholesterolemia | Very frequent (99-80%)"
    explanation: Orphanet records hypocholesterolemia as very frequent.
- name: Orange discolored tonsils
  category: Head and Neck
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Orange discolored tonsils
    term:
      id: HP:0030814
      label: Orange discolored tonsils
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030814 | Orange discoloured tonsils | Frequent (79-30%)"
    explanation: Orphanet records orange discolored tonsils as frequent.
  - reference: PMID:7130397
    reference_title: "Tangier disease. High density lipoprotein deficiency due to defective metabolism of an abnormal apolipoprotein A-i (ApoA-ITangier)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enlarged orange"
    explanation: Classic human study supports orange enlarged tonsils as a hallmark finding.
- name: Hepatosplenomegaly
  category: Hepatic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
    explanation: Orphanet records hepatosplenomegaly as frequent.
- name: Chronic noninfectious lymphadenopathy
  category: Lymphatic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic noninfectious lymphadenopathy
    term:
      id: HP:0002730
      label: Chronic noninfectious lymphadenopathy
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002730 | Chronic noninfectious lymphadenopathy | Frequent (79-30%)"
    explanation: Orphanet records chronic noninfectious lymphadenopathy as frequent.
- name: Peripheral axonal neuropathy
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003477 | Peripheral axonal neuropathy | Frequent (79-30%)"
    explanation: Orphanet records peripheral axonal neuropathy as frequent.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various peripheral neuropathies, ranging from mild to severe, have been reported."
    explanation: Clinical review supports peripheral neuropathy as part of Tangier disease.
- name: Progressive peripheral neuropathy
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Progressive peripheral neuropathy
    term:
      id: HP:0007133
      label: Progressive peripheral neuropathy
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007133 | Progressive peripheral neuropathy | Frequent (79-30%)"
    explanation: Orphanet records progressive peripheral neuropathy as frequent.
- name: Distal muscle weakness
  category: Neuromuscular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002460 | Distal muscle weakness | Frequent (79-30%)"
    explanation: Orphanet records distal muscle weakness as frequent.
- name: Facial diplegia
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Facial diplegia
    term:
      id: HP:0001349
      label: Facial diplegia
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001349 | Facial diplegia | Occasional (29-5%)"
    explanation: Orphanet records facial diplegia as occasional.
- name: Impaired temperature sensation
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Impaired temperature sensation
    term:
      id: HP:0010829
      label: Impaired temperature sensation
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010829 | Impaired temperature sensition | Occasional (29-5%)"
    explanation: Orphanet records impaired temperature sensation as occasional; the ORPHA row contains a spelling variant.
- name: Syringomyelia
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Syringomyelia
    term:
      id: HP:0003396
      label: Syringomyelia
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003396 | Syringomyelia | Occasional (29-5%)"
    explanation: Orphanet records syringomyelia as occasional.
- name: Corneal opacity
  category: Ophthalmologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007957 | Corneal opacity | Occasional (29-5%)"
    explanation: Orphanet records corneal opacity as occasional.
- name: Dry skin
  category: Dermatologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000958 | Dry skin | Frequent (79-30%)"
    explanation: Orphanet records dry skin as frequent.
- name: Nail dystrophy
  category: Dermatologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008404 | Nail dystrophy | Frequent (79-30%)"
    explanation: Orphanet records nail dystrophy as frequent.
- name: Ectropion
  category: Ophthalmologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ectropion
    term:
      id: HP:0000656
      label: Ectropion
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000656 | Ectropion | Frequent (79-30%)"
    explanation: Orphanet records ectropion as frequent.
- name: Abdominal pain
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002027 | Abdominal pain | Frequent (79-30%)"
    explanation: Orphanet records abdominal pain as frequent.
- name: Thrombocytopenia
  category: Hematologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001873 | Thrombocytopenia | Occasional (29-5%)"
    explanation: Orphanet records thrombocytopenia as occasional.
- name: Anemia
  category: Hematologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Occasional (29-5%)"
    explanation: Orphanet records anemia as occasional.
- name: Accelerated atherosclerosis
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Accelerated atherosclerosis
    term:
      id: HP:0004943
      label: Accelerated atherosclerosis
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004943 | Accelerated atherosclerosis | Frequent (79-30%)"
    explanation: Orphanet records accelerated atherosclerosis as frequent.
- name: Coronary artery stenosis
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Coronary artery stenosis
    term:
      id: HP:0005145
      label: Coronary artery stenosis
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005145 | Coronary artery stenosis | Frequent (79-30%)"
    explanation: Orphanet records coronary artery stenosis as frequent.
- name: Carotid artery stenosis
  category: Cardiovascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Carotid artery stenosis
    term:
      id: HP:0100546
      label: Carotid artery stenosis
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100546 | Carotid artery stenosis | Occasional (29-5%)"
    explanation: Orphanet records carotid artery stenosis as occasional.
- name: Left ventricular hypertrophy
  category: Cardiovascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001712 | Left ventricular hypertrophy | Occasional (29-5%)"
    explanation: Orphanet records left ventricular hypertrophy as occasional.
biochemical:
- name: Low HDL cholesterol
  presence: DECREASED
  context: >
    Plasma HDL-C is absent or extremely low and is a core diagnostic readout of
    failed ABCA1-dependent HDL biogenesis.
  biomarker_term:
    preferred_term: high-density lipoprotein cholesterol
    term:
      id: CHEBI:47775
      label: high-density lipoprotein cholesterol
  readouts:
  - target: Impaired HDL Biogenesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower HDL-C reports impaired ABCA1-dependent HDL particle generation.
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Plasma HDL-C is mostly low, at 5 mg/dL or less"
      explanation: The management review supports HDL-C as a diagnostic readout of Tangier disease.
  evidence:
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma HDL-C is mostly low, at 5 mg/dL or less"
    explanation: The review provides the typical severe HDL-C depletion range in Tangier disease.
- name: Low apolipoprotein A-I
  presence: DECREASED
  context: >
    ApoA-I is absent or extremely low because ABCA1-dependent lipidation and HDL
    particle formation fail.
  biomarker_term:
    preferred_term: apolipoprotein A-I
    term:
      id: CHEBI:39015
      label: apolipoprotein
  readouts:
  - target: Impaired HDL Biogenesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower apoA-I reports failed HDL particle generation and rapid loss of apoA-I-containing HDL.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic"
      explanation: GeneReviews supports apoA-I depletion as a diagnostic readout in Tangier disease.
  evidence:
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "apoA-I concentration is 10 mg/dL or less"
    explanation: The management review reports markedly low apoA-I concentrations in Tangier disease.
- name: Low total cholesterol
  presence: DECREASED
  context: >
    Total plasma cholesterol is low, largely reflecting the profound HDL-C
    deficit and altered lipoprotein cholesterol distribution.
  biomarker_term:
    preferred_term: cholesterol
    term:
      id: CHEBI:16113
      label: cholesterol
  readouts:
  - target: Impaired HDL Biogenesis
    relationship: CORRELATES_WITH
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low total cholesterol accompanies the severe HDL-C deficit in Tangier disease.
    evidence:
    - reference: PMID:22913675
      reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "low total plasma\ncholesterol (below 150 mg/dL)"
      explanation: The epidemiology review supports low total cholesterol as part of the diagnostic biochemical profile.
  evidence:
  - reference: PMID:22913675
    reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low total plasma\ncholesterol (below 150 mg/dL)"
    explanation: The review supports low total plasma cholesterol in Tangier disease.
- name: Elevated plasma triglycerides
  presence: INCREASED
  context: >
    Plasma triglycerides may be normal to high or elevated in the Tangier
    lipoprotein profile.
  biomarker_term:
    preferred_term: triglyceride
    term:
      id: CHEBI:17855
      label: triglyceride
  readouts:
  - target: Impaired HDL Biogenesis
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Higher triglycerides are part of the altered lipoprotein profile accompanying severe HDL biogenesis failure.
    evidence:
    - reference: PMID:22913675
      reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "normal or high plasma triglycerides"
      explanation: The review supports normal-to-high triglycerides in the Tangier biochemical profile.
  evidence:
  - reference: PMID:22913675
    reference_title: "Tangier disease: epidemiology, pathophysiology, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal or high plasma triglycerides"
    explanation: The review supports triglyceride elevation or high-normal triglycerides in Tangier disease.
genetic:
- name: Biallelic ABCA1 Pathogenic Variants
  association: Causative
  gene_term:
    preferred_term: ABCA1
    term:
      id: hgnc:29
      label: ABCA1
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tangier disease is inherited in an autosomal recessive"
      explanation: GeneReviews supports autosomal recessive inheritance.
  variants:
  - name: Biallelic ABCA1 pathogenic variants
    description: >
      Affected individuals typically have homozygous or compound heterozygous
      ABCA1 pathogenic variants. Reported pathogenic alleles include deletions,
      insertion-deletions, and missense variants that reduce ABCA1 lipid-efflux
      function.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "pathogenic variants in ABCA1 identified by molecular genetic testing."
      explanation: GeneReviews defines diagnosis by biallelic pathogenic variants in ABCA1.
    - reference: PMID:10431237
      reference_title: "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "identified seven different mutations"
      explanation: Human kindred study documents multiple ABCA1 pathogenic variants.
    - reference: PMID:10431238
      reference_title: "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a 1-bp deletion in exon 13"
      explanation: Human kindred study reports a truncating ABCA1 deletion allele.
  features: >
    ABCA1 encodes ATP-binding cassette subfamily A member 1, a membrane
    transporter required for cellular phospholipid and cholesterol efflux to
    lipid-poor apolipoproteins. Biallelic pathogenic variants cause Tangier
    disease; heterozygotes can have partially reduced HDL-C without the full
    clinical phenotype.
  evidence:
  - reference: ORPHA:31150
    reference_title: "Tangier disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCA1 | ATP binding cassette subfamily A member 1 | hgnc:29 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records ABCA1 as a disease-causing germline gene.
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathogenic variants in ABCA1 identified by molecular genetic testing."
    explanation: GeneReviews identifies ABCA1 molecular testing as diagnostic.
diagnosis:
- name: HDL-C, ApoA-I, and ABCA1 Genetic Testing
  description: >
    Diagnosis is based on absent or extremely low HDL-C and apoA-I, compatible
    clinical features, exclusion of secondary hypo-HDL-cholesterolemia and
    related inherited disorders, and confirmation by ABCA1 molecular genetic
    testing when possible.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic"
    explanation: GeneReviews states the core biochemical and genetic diagnostic criteria.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma (serum) HDL-cholesterol less than 25 mg/dL"
    explanation: The Japanese diagnostic criteria include very low HDL-C.
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis can be definite if pathogenic mutations in the"
    explanation: The diagnostic criteria require ABCA1 mutation confirmation for definite diagnosis.
  - reference: PMID:39817629
    reference_title: "The clinical presentation and genetic diagnosis of Tangier disease in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "carried out if necessary. Family screening should be recommended"
    explanation: Pediatric cohort review supports genetic testing when clinical and HDL findings suggest Tangier disease.
treatments:
- name: Statin-Based Cardiovascular Risk Management
  description: >
    There is no curative Tangier-specific therapy. Management emphasizes
    prevention of atherosclerosis and optimization of non-HDL cardiovascular
    risk factors; if LDL-C is not already low, reviews recommend statin therapy
    or other LDL-lowering approaches.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: statin
      term:
        id: CHEBI:87631
        label: statin
  target_mechanisms:
  - target: Atherosclerotic Vascular Risk
    treatment_effect: MODULATES
    description: Statin therapy is used to reduce modifiable LDL-C and non-HDL cardiovascular risk when present.
    evidence:
    - reference: PMID:33994407
      reference_title: "Current Diagnosis and Management of Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Plasma LDL-C levels are generally low in patients with Tangier disease but if this is not the case, they should be reduced through administration of statins or other means."
      explanation: The management review recommends LDL-lowering therapy with statins when LDL-C is not low.
  evidence:
  - reference: PMID:33994407
    reference_title: "Current Diagnosis and Management of Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No specific curative treatment"
    explanation: This supports framing statins as risk management rather than curative disease therapy.
  - reference: PMID:27565770
    reference_title: "Diagnosis and treatment of high density lipoprotein deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Optimizing the LDL-C levels in Tangier patients with normal LDL-C levels using statin therapy is clearly warranted in our view."
    explanation: HDL-deficiency treatment review recommends statin-based LDL-C optimization in at-risk Tangier patients.
- name: Low-Fat Diet and Lipid Risk Reduction
  description: >
    Low-fat diet is recommended as part of cardiovascular risk-factor mitigation,
    alongside lipid-profile optimization and surveillance for atherosclerotic
    disease.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Atherosclerotic Vascular Risk
    treatment_effect: MODULATES
    description: Diet is used to mitigate modifiable cardiovascular risk rather than restore ABCA1 function.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "using statin therapy and a low-fat diet."
      explanation: GeneReviews lists low-fat diet with statin therapy as risk mitigation.
  evidence:
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiovascular risk factors, including improvement of plasma lipid profiles"
    explanation: GeneReviews supports risk-factor mitigation as prevention of primary manifestations.
- name: Peripheral Neuropathy Rehabilitation
  description: >
    Supportive management for peripheral neuropathy includes bracing and exercise
    when weakness or gait impairment is present.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_mechanisms:
  - target: Peripheral axonal neuropathy
    treatment_effect: MODULATES
    description: Bracing and exercise target functional impairment from neuropathy.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "and exercise for those with peripheral neuropathy"
      explanation: GeneReviews recommends exercise for neuropathy manifestations.
  - target: Distal muscle weakness
    treatment_effect: MODULATES
    description: Orthotic support can mitigate motor weakness from peripheral neuropathy.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "transient bracing (such as ankle-foot orthosis)"
      explanation: GeneReviews lists bracing for peripheral neuropathy-related weakness.
  evidence:
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and exercise for those with peripheral neuropathy"
    explanation: GeneReviews supports supportive rehabilitation for neuropathy.
- name: Tonsillectomy for Obstructive Tonsillar Disease
  description: >
    Tonsillectomy is used when enlarged orange tonsils cause airway obstruction
    or mass symptoms; it is symptomatic management and does not address the
    ABCA1 lipid-efflux defect.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_mechanisms:
  - target: Orange discolored tonsils
    treatment_effect: MODULATES
    description: Surgery addresses obstructive or mass-effect symptoms from enlarged tonsils.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tonsillectomy in those with airway"
      explanation: GeneReviews recommends tonsillectomy when airway obstruction or mass symptoms are present.
  evidence:
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tonsillectomy in those with airway"
    explanation: GeneReviews supports tonsillectomy as treatment of tonsillar manifestations.
- name: Corneal Transplantation for Vision-Limiting Corneal Opacity
  description: >
    Corneal transplantation is used for corneal opacities that interfere with
    daily living; it is symptomatic management of ocular lipid-storage
    complications rather than restoration of ABCA1 function.
  treatment_term:
    preferred_term: corneal transplantation
    term:
      id: MAXO:0010034
      label: corneal transplantation
  target_mechanisms:
  - target: Corneal opacity
    treatment_effect: MODULATES
    description: Corneal transplantation addresses vision-limiting corneal opacity.
    evidence:
    - reference: PMID:31751110
      reference_title: "Tangier Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "corneal transplantation for\ncorneal opacities that interfere with daily living"
      explanation: GeneReviews recommends corneal transplantation when corneal opacities interfere with daily living.
  evidence:
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "corneal transplantation for\ncorneal opacities that interfere with daily living"
    explanation: GeneReviews supports corneal transplantation as treatment for vision-limiting corneal opacity in Tangier disease.
- name: Genetic Counseling and Family Screening
  description: >
    Genetic counseling, lipid-profile screening, apoA-I testing, and targeted
    familial variant testing can identify at-risk relatives and support
    reproductive counseling.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:31751110
    reference_title: "Tangier Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carrier testing for at-risk relatives and prenatal testing"
    explanation: GeneReviews supports genetic counseling and familial testing when variants are known.
  - reference: PMID:39817629
    reference_title: "The clinical presentation and genetic diagnosis of Tangier disease in the pediatric age group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Family screening should be recommended"
    explanation: Pediatric cohort review recommends family screening after diagnosis.
references:
- reference: ORPHA:31150
  title: Tangier disease
- reference: PMID:22913675
  title: "Tangier disease: epidemiology, pathophysiology, and management."
- reference: PMID:31751110
  title: "Tangier Disease."
  tags:
  - GeneReviews
- reference: PMID:33994407
  title: "Current Diagnosis and Management of Tangier Disease."
- reference: PMID:10431236
  title: "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency."
- reference: PMID:10431237
  title: "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease."
- reference: PMID:10431238
  title: "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1."
- reference: PMID:10525055
  title: "The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway."
- reference: PMID:7130397
  title: "Tangier disease. High density lipoprotein deficiency due to defective metabolism of an abnormal apolipoprotein A-i (ApoA-ITangier)."
- reference: PMID:162820
  title: "The pathology of Tangier disease. A light and electron microscopic study."
- reference: PMID:11309399
  title: "ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein."
- reference: PMID:27565770
  title: "Diagnosis and treatment of high density lipoprotein deficiency."
- reference: PMID:39817629
  title: "The clinical presentation and genetic diagnosis of Tangier disease in the pediatric age group."
📚

References & Deep Research

References

13
ORPHA:31150
Tangier disease
No top-level findings curated for this source.
PMID:22913675
Tangier disease: epidemiology, pathophysiology, and management.
No top-level findings curated for this source.
PMID:31751110
Tangier Disease.
No top-level findings curated for this source.
PMID:33994407
Current Diagnosis and Management of Tangier Disease.
No top-level findings curated for this source.
PMID:10431236
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
No top-level findings curated for this source.
PMID:10431237
The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
No top-level findings curated for this source.
PMID:10431238
Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
No top-level findings curated for this source.
PMID:10525055
The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway.
No top-level findings curated for this source.
PMID:7130397
Tangier disease. High density lipoprotein deficiency due to defective metabolism of an abnormal apolipoprotein A-i (ApoA-ITangier).
No top-level findings curated for this source.
PMID:162820
The pathology of Tangier disease. A light and electron microscopic study.
No top-level findings curated for this source.
PMID:11309399
ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein.
No top-level findings curated for this source.
PMID:27565770
Diagnosis and treatment of high density lipoprotein deficiency.
No top-level findings curated for this source.
PMID:39817629
The clinical presentation and genetic diagnosis of Tangier disease in the pediatric age group.
No top-level findings curated for this source.

Deep Research

1
Tangier Disease Deep Research Fallback ▸

Tangier Disease Deep Research Fallback

Provider attempts

  • timeout 120 just research-disorder falcon Tangier_Disease
  • Result: timed out after 120 seconds.
  • Terminal output ended with: Recipe research-disorder was terminated by signal 15.
  • No research/Tangier_Disease-deep-research-falcon.md file was produced.
  • timeout 120 just research-disorder openai Tangier_Disease
  • Result: timed out after 120 seconds.
  • Terminal output ended with: Recipe research-disorder was terminated by signal 15.
  • No research/Tangier_Disease-deep-research-openai.md file was produced.

Evidence scope used

The curation proceeded from generated Orphanet cache ORPHA:31150 plus validator-fetched PubMed caches for the core Tangier disease literature:

  • PMID:22913675 - epidemiology, pathophysiology, and management review.
  • PMID:31751110 - GeneReviews Tangier disease entry.
  • PMID:33994407 - current diagnosis and management review.
  • PMID:10431236, PMID:10431237, PMID:10431238 - independent 1999 ABCA1/Tangier disease discovery papers.
  • PMID:10525055 and PMID:11309399 - ABCA1 lipid-efflux functional studies.
  • PMID:7130397 and PMID:162820 - classic HDL/apolipoprotein kinetics and tissue pathology studies.
  • PMID:27565770 - HDL deficiency diagnosis and treatment review.
  • PMID:39817629 - pediatric clinical presentation and genetic diagnosis cohort.

Curation conclusion

The evidence consistently supports a canonical mechanism in which biallelic ABCA1 pathogenic variants impair apoA-I-mediated cholesterol and phospholipid efflux, blocking HDL particle formation and causing extremely low HDL-C/apoA-I. Reduced cellular cholesterol export leads to cholesteryl ester accumulation in reticuloendothelial tissues and Schwann cells, explaining orange tonsils, hepatosplenomegaly, lymphadenopathy, corneal/skin/nail findings, and peripheral neuropathy. Cardiovascular risk is variable but supported by reviews of reported cases; treatment remains non-curative and focuses on modifiable cardiovascular risk, supportive neuropathy care, tonsillectomy when obstructive, and genetic counseling/family screening.