Tangier Disease
-What are the components of HDL (ABCA1, LCAT, apo A-I, apo A-II, apo C-II and apo E) and what are the functions of
these components? ABCA1 is responsible for the translocation across cellular membranes of various substances
including lipids. ABCA1 mediates the first step of efflux of cholesterol from the cell to form HDL reverse cholesterol
transport. The formation of discoidal nascent HDL is from the two step lipidation of APO A-1 by ABCA1. ABCA1 also
stimulates APO A-1 uptake into endosomes. LCAT is localized on the surface of HDL and converts the free cholesterol on
the surface to cholesterol ester which occupies the core of HDL. This process is what changes HDL’s shape to spherical.
APO C-II and APO E are taken from HDL and are given to chylomicrons and VLDLs. APO C-II is used to activate LPL
that hydrolyzes TAG.
-What are the differential diagnoses of tangier’s disease? What are the distinctive features of Tangier’s disease that
will differentiate it from the differential diagnoses? 1. Very low plasma HDL and apoA-1 are also consistent with
familial dyslipidemias like apoA-1 and LCAT deficiencies and obstructive liver diseases. But increased levels of proapo
A-1 compared to the mature apoA-1 levels is a distinctive feature of TD and cane be used to eliminate familial
dyslipidemias. Also, the hypercholesterinemia of obstructive liver disease distinguishes it from TD (TD has low
cholesterol levels). 2. The presence of foam cells may indicate a lipid storage disorder like Niemann-Pick disease, but
those are not usually correlated with low HDL and tonsillar abnormalities. 3. Low plasma cholesterol are also
observed in abetalipoproteinemia, but TD patients also have elevated TAGs and much lower HDL levels.
- What is the genetic pathology in Tangier’s disease? TD is inherited clinically as autosomal recessive but biochemically
as autosomal codominant.
-What are the expected serum levels of HDL, LDL, Triglycerides and proapo A-1 in Tangier’s disease? Why are apo A-I
levels low in Tangier’s disease? apo A-I levels are low in TD because there are low HDL levels. Expected serum levels of
HDL, LDL, TAGs, and proapo A-1 are very low for HDL (1mg/dl), normal for LDL, high for TAGS (~180mg/dl), and
increased levels of proapo A-1 compared to mature apo A-1.
-What are the roles of CETP and SR-B1? They are two pathways for lipid unloading of HDL. Cholesterol ester transfer
protein (CETP) mediates cholesterol transfer from HDL to VLDL and LDL in exchange for TAG. LDL is taken to the liver
via LDLR. HDL binds to SR-B1 and cholesterol esters are selectively taken into the liver cells without internalization of
HDL proteins.
-What happens to intracellular levels of retinyl esters, Vitamin E and Carotene? Why will triglycerides be elevated in
Tangier’s disease? In Tangier Diseases in which ABCA1 is defective formation of nascent HDL particles is compromised
which can cause lipophilic (loves lipids) compounds like V.E. retinyl esters and carotene levels to accumulate inside the
cell. In addition, TAGs are elevated because LPL isn’t activated due to absence of its activator APO C-II which is
normally transferred from HDL to VLDL.
-What are the roles of LXR/RXR in ABCA1 gene activity and maintaining intracellular cholesterol levels? Overloading
macrophages with cholesterol increase ABCA1 transcription which is mediated by LXR/RXR which act like
heterodimers in the presence of oxysterols or retinoic acid. The accumulation of cholesterol must be converted to an
oxysterol to elicit ABCA1 induction.
-What is the association between Tangier’s disease and coronary artery disease? In heterozygotes are associated with
familial HDL deficiency which is associated with an increased risk for CAD. This does not occur in homozygotes
because of their low LDL (<40%) levels.
- Describe the symptoms of Tangier’s disease and explain the rationale for those signs and symptoms. Symptoms
include yellow-orange tonsils or pharyngeal plaques because of the accumulation of retinyl esters, vitamin E and
carotene because of defective ABCA1. Hepatosplenomegaly, anemia, and stomatocytosis are common.
Lymphadenopathy, unexplained diarrhea, and corneal opacities are also slightly common. 30% of TD patients have
peripheral neuropathy: syringomyelialike syndrome (more severe) and multiple mononeuropathy.
- Propose possible treatment protocols for Tangier’s disease. Genetic counseling, surgical removals, supplements,
exercise, weight reduction, dietary cholesterol and saturated fat reduction and smoking cessation, which also prevents
CAD.
Abetalipoproteinemia
-Why did the patient have symptoms of GI distress and why did his symptoms worsen when he moved to the US? He had
symptoms of GI distress because of the malabsorption of lipids in the tract. His symptoms worsened because of the
high-fat Western diet.
-Why did he have the following; bruises, difficulty seeing at night, positive Romberg’s sign and peripheral neuropathy?
Vitamin A deficiencies present progressive night blindness which probably causes his bruises at night because he had a
lower visual acuity. Neuropathy and a positive Romberg sign (proprioception) has to do with prolonged vitamin E
deficiency. -Describe the
rationale for the abnormal hematological findings. Why were acanthocytes present in the blood smear? Acanthocytes
are RBCs with thorny projections due to lack of cholesterol content and abnormal cholesterol: phospholipid ratio.
-Explain the rationale for the abnormal lipid profile. Why do you think this patient does not have Friedreich ataxia?
Friedreich ataxia does not occur in malabsorption disorders.
- Explain the macroscopic and microscopic findings on examination of the intestines. The intestinal lumen has a gelee
blanche or white frothy appearance from massive accumulation of lipids within the mucosa which persists even in the
setting of low-fat diet (macroscopic). Inflammation is usually absent and villi have normal appearance; individuals
cells show cytoplasmic lipid droplets that stain positive for neutral lipids (microscopic)
-What three abnormalities of lipoprotein metabolism share similar characteristics? What are the particular
distinguishing features of each of these conditions?
Disease Gene/mode of
inheritance
Defective assembly
type
Symptoms Plasma lipoproteins
ABL mttp/recessive Biosynthesis of apoB
lipoproteins
Fat malabsorption, fat-soluble
vitamin deficiencies,
spinocerebellar disease, retinitis
pigmentosa, acanthocytosis, gelee
blanche intestine, fatty liver
Absence of all apoB
lipoproteins:
chylomicrons, VLDL
and LDL.
CMRD/Anderson’s disease Sar1b/recessive Budding of vesicles
containing nascent
lipoproteins from ER
of intestinal cells
Same as above minus fatty liver,
failure to thrive in infancy, and
acanthocytosis
Absence of
chylomicrons
CMRD-MSS Sar1b/recessive Same as above Same as above but also congenital
cataracts, mental deficiency, and
cerebellar atrophy
Same as above
hypobetalipoproteinemia ApoB/recessive Synthesis of apoB
peptide
Only in homozygotes or complex
heterozygotes with symptoms
similar to ABL
Low to absent apoB
lipoproteins
-How could you have differentiated this patient’s condition from Celiac disease? Celiac disease is a common
malabsorptive disorder which also presents abdominal distress comfort and diarrhea with frequent remission and
exasperations. Symptoms of celiac disease can be circumvented if the patient is placed on a gluten-free diet, whereas
those associated with ABL do not circumvent this.
-How could you differentiate this condition from HIV enteropathy or chronic diarrhea secondary to malnutrition?
- What are other causes of both acute and chronic diarrhea and what are their mechanisms? Chronic diarrhea results
in nutrient wasting and failure to thrive. Causes for acute diarrhea are infections, food poisoning, medications,
ingestion of large amounts of nonabsorbable sugar, and intestinal ischemia. Causes for chronic diarrhea are irritable
bowel disease, inflammatory bowel disease (Crohns’ Disease), chronic infection, radiation enteritis, medications, local
cancer, previous surgery, endocrine causes, and malabsorption syndromes.
-Describe the process of apoB lipoprotein assembly and the role of MTP (mttp gene). Differentiate between apoB 48
and apoB 100. apoB 48 is in chylomicrons and apoB 100 is in VLDL, IDL, and LDL. In ABL lipoprotein assembly shared
by intestinal and hepatic cells is defective. In order for apo’s to be assemble they need MTP which transfers lipids
between vesicles in vitro and transfer them to apoB.
- How would you treat this patient? Early diagnosis and treatment. Lipid-poor diets and a restriction of TAGs with long
chain FA. Supplementation of vitamin E (mostly because it needs apo proteins at every stage of its transport), vitamin
A and vitamin K
