Download Case report Homozygous Tangier disease with undetectable serum

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Clinical Genetics
Case report
Homozygous Tangier disease with undetectable serum high
density lipoprotein cholesterol levels and no clinical features
Abstract
Introduction
Tangier disease is a very rare inherited disorder characterised by much
reduced high-density lipoprotein
levels, large yellow-orange tonsils
and enlarged liver, spleen and lymph
nodes. It is caused by mutations in
the ATP-binding cassette transporter
A1 gene. This paper reports a case
of homozygous Tangier disease with
undetectable serum high density
lipoprotein cholesterol levels and no
clinical features.
Case report
We report a study of a 40-year-old
female who presented with undetectable high-density lipoprotein
cholesterol but no clinical signs of
Tangier disease. Her family history is
significant for her father having premature cardiovascular disease and a
moderately low high-density lipoprotein cholesterol and other relatives
having low or undetectable highdensity lipoprotein cholesterol levels.
She was found to have a homozygous
mutation in the ATP-binding cassette
transporter A1 gene.
Conclusion
As Tangier disease may not have
clinical features, it may be underdiagnosed, and as more patients are
reported in the literature, the variation
in phenotype will become apparent.
Introduction
Tangier disease is one of the most
severe forms of familial high-density
lipoprotein (HDL) deficiency. Since
its discovery on Tangier Island in
*Corresponding Author: C van Heyningen
Email: [email protected]
Clinical Laboratories, Aintree University
Hospital, Lower Lane, Liverpool L9 7AL, UK
Chesapeake Bay (Virginia, USA) in
19611, Tangier disease has been diagnosed in about 100 patients worldwide2. It is characterised by severe
deficiency or absence of apoA-I, the
major HDL apolipoprotein, and in
some cases by the accumulation of
cholesteryl esters in tissues throughout the body including tonsils, peripheral nerves, intestinal mucosa, spleen,
liver, bone marrow, lymph nodes, thymus, skin and cornea.
The biochemical signs of this
condition include serum HDL cholesterol concentration less than
0.12 mmol/L, apoA-I levels below
0.05 g/L, low total serum cholesterol
below 3.9 mmol/L and normal or
high serum triglycerides. The major
clinical signs of Tangier disease are
hyper-plastic orange-yellow tonsils,
hepatosplenomegaly,
neuropathy,
corneal opacities, thrombocytopenia,
anaemia and stomatocytosis. These
clinical signs combine differently in
each patient2 and we report a patient
without physical signs identified by
finding undetectable serum levels of
HDL cholesterol.
Case report
A 40-year-old female was referred
to the lipid clinic because of persistent undetectable serum HDL cholesterol (HDL-C) levels of <0.1 mmol/L.
The other serum lipids had varied with total cholesterols of 2.9 to
2.3 mmol/L and triglycerides of 2.5
to 1.7 mmol/L. Serum apolipoprotein A1 was found to be undetectable at < 0.05 g/L (reference range:
1.25–2.15) and apolipoprotein B
was within the normal adult reference range of 0.55 to 1.25 g/L at
0.95 g/L. Fasting plasma glucose was
4.7 mmol/L and renal, liver, thyroid
function tests and a blood cell count
were normal. On microscopy a blood
film showed anisopoikilocytosis with
acanthocytes and elliptocytes.
A very low serum HDL-C was first
recorded during her first pregnancy
at age 23 years. At age 35 years, she
underwent a bilateral oophorectomy
and hysterectomy for endometriosis. She takes oestradiol 1 mg/day as
hormone replacement therapy and
tolterodine 4 mg/day, an antimuscarinic for urinary incontinence, and
no over-the-counter medication or
supplements. She stopped smoking
10 years ago, keeps to a healthy diet,
takes exercise and only occasionally
drinks alcohol.
Physical examination showed no
discolouration of tonsils or pharynx,
no enlargement of liver, spleen or
lymph nodes, no peripheral neuropathy and no corneal opacities. She had
a blood pressure of 113/67 mmHg
and body mass index of 30 kg/square
metre. Computed tomography studies showed mild calcification of the
right coronary artery but no stenosis
was found on angiography.
She was found to have family members with reduced HDL-C levels. Her
brother aged 37 years has schizophrenia and a serum HDL-C <0.1 mmol/L.
Her father, her 17-year-old daughter
and 11-year-old son have low levels
of HDL-C of 0.8 mmol/L, 1.0 mmol/L
and 0.8 mmol/L, respectively. Her
father presented at age 40 years with
a stroke and ischaemic heart disease.
Genetic analysis was undertaken
in the medical genetics department,
Oslo University Hospital, Norway.
DNA sequencing of the translated
exons with flanking intron sequences
of the apolipoprotein A-I (apoA-I)
and lecithin-cholesterol acyltransferase (LCAT) genes did not identify
Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)
F
: Gell J, van Heyningen C. Homozygous Tangier disease with undetectable serum high density
lipoprotein cholesterol levels and no clinical features. OA Case Reports 2013 Oct 21;2(13):126.
CompeƟng interests: none declared. Conflict of interests: none declared.
All authors contributed to the concept on, design, and preparaƟon of the manuscript, as well as read and approved the final manuscript.
All authors abide by the AssociaƟon for Medical Ethics (AME) ethical rules of disclosure.
J Gell, C van Heyningen*
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Case report
Discussion
Tangier disease is caused by mutations in the ABCA1 gene which
encodes the membrane transporter
ABCA13. The ABCA1 gene resides
on chromosome 9q22-q31, contains
50 exons, and codes for a 2261-amino
acid long membrane protein4. In this
case, the mutation was found to be a
true homozygote for mutation in exon
14 in the ABCA1 gene. This is a duplication that causes a frame shift, leading to a premature stop codon being
generated 43 codons downstream of
the mutation, which in turn generates a non-functional protein. This
transporter normally plays a key role
in the first step of reverse cholesterol
transport, through which the efflux
of free cholesterol from non-hepatic
peripheral tissues is transferred to
HDL by the ATP-binding cassette
transporter. Lipid-poor apoA-I acts
as an acceptor, and the phospholipid
component of HDL acts as a sink for
the mobilised cholesterol and thereby
plays a central role in both regulating
cellular cholesterol homeostasis and
forming HDL.
A non-functional ABCA1 impairs
free cholesterol efflux from cells. This
may lead to intracellular accumulation of esterified cholesterol, prevention of lipid-poor apoA-I particles
converting into pre-β HDL and rapid
catabolism of the poorly lipidated
apoA-I primarily by the kidney5. This
rapid catabolism explains why this
patient has very low levels of apoA-I
despite a normal apoA-I gene.
There has been an on-going
debate as to whether HDL deficiency in Tangier disease is caused
by increased catabolism or by the
decreased synthesis of apolipoproteins. A number of studies using radiolabeled HDL, apoA-I and apoA-II in
Tangier disease affected patients have
been performed and reveal a markedly increased catabolism of apoA-I,
apoA-II and HDL. These studies support the metabolic basis of Tangier
disease being a rapid catabolism of
apoA-I and HDL6. In our patient, a
frame-shift mutation leads to the
formation of non-functional ABCA1
proteins which in turn prevents the
uptake of free cholesterol and leads
to the loss of HDL particles.
Epidemiological studies demonstrate an inverse association between
low levels of HDL cholesterol and
increased risk of ischaemic heart disease, but population studies suggest
that genetically low HDL cholesterol
per se does not predict an increased
risk of ischaemic heart disease7.
Reduced HDL is associated with cardiovascular disease by its function in
regulating cholesterol efflux, modulation of the inflammatory response,
antioxidant activity and vasomotor
regulation. Some believe that the
main protective effect of HDL in preventing cardiovascular disease is by
inhibiting the oxidative modifications of low density lipoprotein8, an
initial step in the atherosclerotic process. The literature on homozygous
Tangier disease indicates a strong
association with cardiovascular disease and premature onset of coronary artery disease9.
To date, there is no specific treatment for Tangier disease. The hypothesis that elevation of HDL reduces
the atherosclerotic burden and/or
decreases ischaemic cardiovascular
events in humans has unfortunately
been impeded by a lack of drugs that
selectively increase HDL. Most of the
drugs designed to increase HDL levels, have not been shown to be effective in patients with Tangier disease2.
Our patient has no clinical evidence
of cardiovascular disease but imaging
studies of her coronary arteries show
mild calcification without stenosis. As
her father has low HDL cholesterol
and presented with premature cardiovascular disease, it is likely that
she too has a high risk for cardiovascular events. Even though her total
cholesterol is low, she may benefit in
the long term from low density lipoprotein cholesterol lowering therapy
as well as weight reduction and a very
low fat diet.
Conclusion
This case study illustrates how a
patient with Tangier disease without
clinical features may be identified
by serum lipid profile screening and
finding an undetectable HDL-C level.
The diagnosis must be confirmed by
genetic analysis of genes associated
with low HDL-C. The degree of risk
for cardiovascular disease may be
estimated by studying the family history of lipid abnormalities and cardiovascular events.
Consent
Written informed consent was
obtained from the patient for publication of this case report and accompanying images. A copy of the written
consent is available for review by the
Editor-in-Chief of this journal.
Acknowledgements
We thank the Department of Medical
Genetics, Oslo University Hospital,
Norway for genetic analysis.
References
1. Fredrickson DS, Altrocchi PH, Avioli LV,
et al. Tangier disease. Combined clinical staff conference at the National
Institute of Health. Ann Intern Med. 1961
Dec;55:1016.
2. Puntoni M, Sbrana F, Bigazzi F and
Sampietro T. Tangier disease: epidemiology, pathophysiology, and management. Am J Cardiovasc Drugs. 2012
Oct;12(5):303–11.
3. Brunham LR, Singaraja RR, Hayden MR.
Variation on a gene: rare and common
Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)
F
: Gell J, van Heyningen C. Homozygous Tangier disease with undetectable serum high density
lipoprotein cholesterol levels and no clinical features. OA Case Reports 2013 Oct 21;2(13):126.
CompeƟng interests: none declared. Conflict of interests: none declared.
All authors contributed to the concept on, design, and preparaƟon of the manuscript, as well as read and approved the final manuscript.
All authors abide by the AssociaƟon for Medical Ethics (AME) ethical rules of disclosure.
any mutation. DNA sequencing of the
translated exons of the ATP-binding
cassette transporter A1 (ABCA1) gene
revealed that the patient is a true
homozygote for mutation c.1758dupG
in exon 14 in the ABCA1 gene. This
mutation is a duplication that causes
a frame shift, which leads to a premature stop codon being generated
43 codons downstream of the mutation (p.Arg587AlafsX43). This results
in a non-functional protein and indicates a diagnosis of Tangier disease.
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Case report
6.
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EJ,
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by high density lipoprotein. J Clin Invest.
1991 Dec;88:2039–46.
9. Serfaty-Lacrosniere C, Civeira F,
Lanzberg A, Isaia P, Berg J, Janus ED et al.
Homozygous Tangier disease and cardiovascular disease. Atherosclerosis. 1994
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Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)
F
: Gell J, van Heyningen C. Homozygous Tangier disease with undetectable serum high density
lipoprotein cholesterol levels and no clinical features. OA Case Reports 2013 Oct 21;2(13):126.
CompeƟng interests: none declared. Conflict of interests: none declared.
All authors contributed to the concept on, design, and preparaƟon of the manuscript, as well as read and approved the final manuscript.
All authors abide by the AssociaƟon for Medical Ethics (AME) ethical rules of disclosure.
variants in ABCA1 and their impact on
HDL cholesterol levels and atherosclerosis. Annu Rev Nutr. 2006;26:105–29.
4. Von Eckardstein A. Differential diagnosis of familial high density lipoprotein
deficiency syndromes. Atherosclerosis.
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