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KURDISTAN REGIONAL GOVERNMENT

MINISTRY OF HIGHER EDUCATION AND
SCIENTIFIC RESEARCH
KOMAR UNIVERSITY OF SCIENCE AND TECHNOLOGY

FA2023 – Biochemistry & Lab

Tangier Disease Report

Fall Semester 2023

Introduction:-

Tangier disease is an autosomal recessive disorder and property of high-density lipoprotien

deficiency, sterol deposition in tissue macrophages , and prevalent atherosclerosis.mutation in
ABCA1 (ATP binding cassette transporter ) cause tangier disease and other familial HDL
deficiencies.A cellular pathway that secretes phospholipids and cholesterol to apolipoproteins
deficient in lipids is controlled by ABCA1.It indicates that the rapid break down of new
synthesised apolipoproteins and the excessive build-up of cholesterol in macrophages are caused
by their incapacity to absorb cellular lipids via the ABCA1 pathway.Therefore, ABCA1 is an
essential component therapeutic target for removing excess cholesterol from macrophages and
avoiding atherosclerosis because it regulates the flux of tissue cholesterol and phospholipids into
their reverse cholesterol transport system
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Figure 1:-Tangier Disease: Familial High-Density Lipoprotein Deficiency.

ABCA1 Gene:-

The metabolism of cholesterol requires the ABCA1 gene. Patients with Tangier syndrome and
familial HDL deficiency have abnormalities in the cholesterol/phospholipid efflux protein,
ABCA1. These patients have defective reverse cholesterol transport, which involves the
mobilisation of cholesterol from peripheral sites and its subsequent return to the liver, as a result
of their incapacity to produce HDL. Given that ABCA1 is expressed in both the enterocyte
basement membrane and the sinusoidal membrane of hepatocytes, it seems likely that it plays a
role in the efflux of phospholipids and cholesterol from the plasma membrane to the urothelial
cell base. ABCA1 was expressed in the lateral plasma membrane of polarised bladder epithelial
cells that were cultured.
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Figure 2:Tangier disease and ABCA1

Clinical manifestations:-
1.Unusual Lipoproteins in Plasma The content of apoA-I in plasma is 10 mg/dL or less, while
plasma HDL-C is generally low, at 5 mg/dL or fewer (mean of known cases 3±3 mg/dL) 21.
Moreover, plasma LDL-C is lowered to around 37% of the typical normal range. It has been
observed that aberrant small, dense LDL particles are caused by the formation of residual
lipoprotein particles, which are rich in triglycerides and act as intermediary products between
VLDL and LDL 21. Plasma HDL-C and apoA-I levels are frequently decreased in individuals
with heterozygous mutations of the ABCA1 gene to roughly 50% of those in normal persons,
however the degree of HDL-C loss varies.

2.Physical Discoveries Reduced cholesterol export as a result of impaired HDL biogenesis

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causes lipid buildup in cells. The tonsils are typically orange in color when this disorder is
present. Patients' tonsils have lobulated, swollen surfaces that are either bright orange or
yellow-grey in color. It is common to note a history of tonsillectomy or recurrent tonsillitis.
Furthermore, there may be presen of splenomegaly, thrombocytopenia, and/or reticulocyte
hyperplasia. About one-third of cases also show hepatomegaly, but liver dysfunction is not
typically evident. 22). Other organs like the thymus, intestinal mucosa, lymph nodes, and skin
also accumulate cholesterol. It builds up in the cornea and results in corneal opacity.

3.The peripheral neuropathy There have been reports of a variety of peripheral neuropathies,
from mild to severe. Movement, sensory, or mixed disorders can manifest temporarily or
permanently. Rarely do tendon reflexes and deep perception decline.
Peripheral neuropathy manifests as syringomyelia-like peripheral neuropathy, neuropathy with
symmetry in the lower limbs, or recurrent asymmetric disorders of peripheral nerves, including
cranial nerves.
4.Heart-related Conditions According to reports, there was an increased risk of atherogenicity in
Tangier disease in 12 out of 35 patients (34.3%) in Japan and 34 out of 109 patients (31.2%) in
other countries. Diffuse calcified coronary artery lesions were found in a prior case study
employing intravascular ultrasound (IVUS), which may have been impacted by HDL deficiency
and glucose intolerance.

Diagnosis:-

There are currently no published formal clinical diagnostic criteria for Tangier disease.
Proposal Results
When a person exhibits any of the following clinical symptoms along with supporting laboratory
results, they may have Tangier disease.
clinical conclusions
1.enlarged tonsils in children and young adults that are yellow or orange in color.
2.peripheral neuropathy
splenomegaly or hepatomegaly
Opacities in the cornea.
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3.Heart disease
A lymphadenopathy
blood conditions, particularly thrombocytopenia
corroborating lab results.
Principal discoveries:
Extremely low concentration of HDL-cholesterol in plasma; usually <5 mg/dL (0.125 mmol/L),
rarely 5–10 mg/dL.
2Very low or nonexistent concentration of apo A-I, typically less than 30 mg/dL (roughly 5
mg/dL)
Alpha band on lipoprotein electrophoresis is small or
nonexistent.
Additional results from the lab:
1.Low concentration of total cholesterol in plasma, usually less than 150 mg/dL (4 mmol/L)
Hypertriglyceridemia, mild to moderate, up to 400 mg/dL (4.5 mmol/L).
2.Reduced levels of LDL cholesterol
Wide pre-beta or small beta band of lipoprotein electrophoresis .
Establishing of diagnosis:
A proband with absent or very low HDI-cholesterol and apo A-I levels and biallelic pathogenic
variants in ABCAl found through molecular genetic testing is diagnosed with Tangier disease
(see Table 1).Note: The presence of cholesterol esters accumulating in tissue biopsies in a person
exhibiting typical clinical features of Tangier disease may be taken into consideration if clinical
molecular genetic testing is not feasible.Molecular genetic testing methods can involve
single-gene testing or the use of a multigene panel when phenotypic and laboratory results point
to the diagnosis of Tangier disease:• Testing on a single gene. Little intragenic deletions and
insertions as well as missense, nonsense, and splice site variants are found by ABCAl sequence
analysis; exon or whole-gene deletions and duplications are usually not found. Sequence analysis
should be done first. If just one or no pathogenic variant is found, perform gene-targeted
deletion/duplication analysis to detect intragenic deletions or duplication.• The most likely way
to determine the genetic cause of the condition is to use a multigene panel that includes ABCAl
and other genes of interest (see Differential Diagnosis). This will limit the identification of
variants with unclear significance and pathogenic variants in genes that do not explain the
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underlying phenotype. (1) Note: (1) The genes in the panel and the diagnostic sensitivity of the
tests performed for each gene differ depending on the laboratory and may change in the future.
(2) Genes unrelated to the ailment covered in this GeneReview may be present in some
multigene panels. (3) Custom laboratory-designed panels and/or phenotype-focused exome
analyses with the clinician's chosen genes may be available as panel options in certain labs. (4) A
panel may employ deletion/duplication, sequence analysi, and/or other non-sequencing-based
tests.

Table 1

Gene 1 Method proportion of pathogenic variants

detectable by method
ABCA1 Sequence analysis >%90
Gene

ABCA1 Gene targeted <%10

gene deletion/duplication
analysis

Treatment:-
While a precise treatment for Tangier disease is still unknown, efforts are being made to raise
HDL cholesterol through modifying one's lifestyle to include regular aerobic exercise,
maintaining a healthy weight, quitting smoking, and substituting saturated fatty acids with
monounsaturated ones. These treatments may alleviate the symptoms, particularly in cases of
peripheral neuropathies. Drug therapy aimed at lowering low HDL cholesterol and optimizing
LDL levels lacks conclusive proof, however lipid-reduction medications including fibrates,
niacin, and statins can be used singly or in combination.The course of treatment is determined by
the symptoms, for example, tonsillectomy in cases when tonsil growth results in mass symptoms
or obstruction of the airway. In cases of corneal opacities, temporary bracing (such as ankle-foot
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orthoses), and exercise for those with peripheral neuropathy, corneal transplantation might be
necessary. If the patient has splenomegaly, precautions such avoiding high-impact sports or
activities should be carefully suggested in order to prevent splenic rupture.(4). Up regulating
hepatocytes' absorption of cholesterol or down regulating HDL metabolism is proposed as a
future therapeutic strategy. Targeted gene therapy, which results in ABC1 overexpression and
increased cholesterol uptake within the cells, can accomplish this.

Figure 3:Tangier disease causes , symptoms , diagnosis and treatment

Clinical Indications:-
Abnormal Plasma Lipoproteins
Plasma HDL-C is mostly low, at 5 mg/dL or less and the apoA-I concentration is 10 mg/dL or
less . Plasma LDL-C is also reduced, to around 37% of the average normal level. The
appearance of remnant lipoprotein particles rich in triglycerides has been reported and this was
found to result in abnormal small, dense LDL particles. In subjects with heterozygous mutations
of the ABCA1 gene, plasma HDL-C and apoA-I levels are often reduced to about 50% of that in
normal subjects.Physical Findings
Impairment of HDL biogenesis results in reduced cholesterol export, which leads to lipid
accumulation in cells. A typical finding of this disorder is orange-colored tonsils. The tonsils of
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patients are lobulated and swollen and present a bright orange or yellow-grey surface. A history
of recurrent tonsillitis or tonsillectomy is often noted. In addition, splenomegaly and associated
thrombocytopenia and/or reticulocyte hyperplasia may be present. Hepatomegaly is also
observed in about one-third of cases. There is also cholesterol accumulation in other organs, such
as lymph nodes, thymus, intestinal mucosa, and skin. Its accumulation in the cornea causes
corneal opacity.

Figure 4:picture shows an Orange-colored tonsils observed in male patient with Tangier disease in his 50s

History and Physical:-

Patients who inherited a heterozygous gene for the disease will have relatively low HDL with no
deposition of cholesterol esters within body organs. In contrast, individuals who inherited both
the recessive genes will have a cholesterol deposition manifestation and an extremely low HDL.
Oral cavity: Cholesterol deposition in tonsils is one the noticeable features. Cholesterol deposits
appear yellow/orange in color, significantly enlarged in children and young adults—usually the
first observed presentation.
Cardiovascular system: Affected people will have premature atherosclerosis; therefore, they are
more prone to coronary artery diseases, and strokes usually occur in an early stage of their age.
Sometimes heart valves could also be affected.
Reticuloendothelial System: cholesterol deposition in these organs leads to hepatosplenomegaly.
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The involvement of spleen can also lead to thrombocytopenia. It also could be deposited within
the lymph nodes.
Pancreas: Diabetes has been reported due to deposition inside the Alpha cells of the pancreas.
Tangier disease appears earlier in life in the 1st decade as a tonsillar enlargement and clouding of
the cornea. Neuropathy and cardiovascular disease are the most devastating developments caused
by Tangier's disease.

Deterrence and Patient Education:-

HDL or good cholesterol plays an important role in preventing cardiovascular events through its
main function of transmitting cholesterol from the peripheral tissues to be excreted by the liver. It
has many other functions:
It plays as an antioxidant and anti-inflammatory agent through the inhibition of LDL oxidation
and endothelial adhesion molecules expression.
It has antithrombotic properties.
It can also improve endothelial function through the promotion of cells repair and promote
angiogenesis.
It helps diabetic patients to have better diabetic control.
To maintain a healthy lifestyle and to keep lipids profile within the regular limit there are many
advises to be given include: regular aerobic exercise, maintaining a healthy weight, smoking
cessation, and replacement of monounsaturated for saturated fatty acids raise HDL cholesterol.
There are also certain types of food which are recommended for patients that are at risk for a
CVS events that are rich in omega-3 fatty acids and could increase the HDL level and lower the
LDL level includes; Olive oil, whole grains, beans and legumes, High fiber fruits, fatty fish, Flax
and chia seeds, nuts and avocado.
Some medications, such as beta-blockers, benzodiazepines, and androgens, are associated with a
decrease in HDL cholesterol.
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Reference :-
1-https://link.springer.com/chapter/10.1007/8904_2014_348
2-Assmann G, von Eckardstein A, Brewer HB Jr. Familial analphalipoproteinemia:
Tangier disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The
Metabolic and Molecular Bases of Inherited Disease. 8 ed. Vol 2. New York, NY:
McGraw-Hill; 2001:2937-80.
3-Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, Drobnik W,
Barlage S, Büchler C, Porsch-Ozcürümez M, Kaminski WE, Hahmann HW, Oette K,
Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette
transporter 1 is mutated in Tangier disease. Nat Genet. 199