MIGLUSTAT FOR TANGIER DISEASE 1

Miglustat for Tangier Disease

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Tangier disease is a rare hereditary disease defined by markedly lower blood levels of
high-density lipoproteins (HDL), commonly referred to as "good cholesterol" because it aids in
the elimination of cholesterol from artery walls, particularly the coronary (heart) arteries. Tangier
Island in the Chesapeake Bay; is the name given to this illness when it was first detected there.
Later, more is known about the condition when described when additional people appear to have
the sickness in various locations across the United States and throughout the globe.
Tangier disease symptoms depend on which organs are symptomatic and the intensity of
those symptoms. Swollen orange or yellow tonsils most commonly distinguish Tangier disease.
This discoloration is due to the accumulation of fatty deposits in the tonsils. Fatty deposits can
also accumulate in other organs, producing throat, liver, spleen, or lymph node swelling. Fat
accumulations in nerves can cause sensory abnormalities and loss, known as peripheral
neuropathy. The digestive tract, specifically the rectum and large intestine, can also become
discolored. Adults with Tangier illness have been shown to have cardiovascular problems. A
clouding of the eye's cornea can develop in rare circumstances, although it is usually minor and
does not impede vision. There have been reports of moderate to severe peripheral neuropathies.
Sensory, motor or combined problems might arise suddenly or gradually. Depth perception and
tendon reflexes may be impaired, but this is uncommon. Peripheral neuropathy manifests as a
recurring asymmetric condition of peripheral nerves, including cranial nerves, as neuropathy
with lower limb symmetry, or as syringomyelia-like peripheral neuropathy (Koseki, Masahiro, et
al., 2021).
Tangier disease is a genetic disorder marked by a lack of or relatively low levels of high-
density lipoprotein, known as “good cholesterol” caused by a defective mutation in the A1
(ABCA1) gene. The A1 (ABCA1) gene is important for cholesterol homeostasis and HDL
metabolism, allowing cells to dump excess cholesterol efficiently. Tangier disease has an
autosomal recessive genetic profile; a genetic characteristic where the offspring receives one
copy of a mutated gene from each parent. However, the parents are only carriers of the gene and
are not affected since they each carry only one of the mutated genes. The offspring develops the
disease by receiving two mutated genes; one gene from each parent (GARD, n.d.).
In Tangier disease, the HDL-C threshold is mostly below 5 mg/dL when there is a
disruption in genetic discrepancies in or more alternative forms; arising from mutation. In
addition, there is 10 mg/dL or less of apoA-I, the main protein element of HDL that combines
with a lipid to form a lipoprotein. Therefore, despite having lower levels of low-density
lipoprotein (LDL)-cholesterol (LDL-C), people are more likely to develop early coronary artery
disease. Because there are currently no specific treatment options available, early patient
diagnosis and management of artery disease are crucial. Aside from low HDL-C, risk factors
such as LDL-C (bad cholesterol), high blood pressure, and smoking are also under monitoring.
Furthermore, since insulin deficit generates from pancreatic beta cells, a hyperglycemia
diagnosis may be a solution (Berberich, Amanda J, and Robert A Hegele, 2022).
A proposed study by Dr. Tarekegn Hiwot called Investigating the role of miglustat in the
management of a patient with Tangier Disease references a 58-year-old woman who was
misdiagnosed and underwent treatment for Niemann-Pick C. NPC is a result of NPC1 or NPC2
MIGLUSTAT FOR TANGIER DISEASE 3

gene deficiencies. In contrast, Tangier disease is a result of an ABCA1 gene deficit. Tangier
illness presently has no treatment, while NPC treatment exists via miglustat, an enzyme inhibitor
(Colaco, Alexandria, et al., 2020).
The woman under observation suffers from complicated clinical symptoms; an enlarged
spleen, dysarthria, difficulty speaking, poor muscle control, tongue enlargement, skin disorder of
itchy nodules, swollen legs, low red and blood cell count, and bone marrow foam cells. The 58-
year-old woman was put under treatment with miglustat (300 mg/day), leading to an
improvement in brain abnormalities, improving skin conditions, and leg swelling. Similar to
Tangier disease, NPC is an uncommon hereditary condition defined by the body's inability to
transport cholesterol and other fatty compounds (lipids) within cells, causing an aberrant buildup
of these chemicals in numerous human tissues, including brain tissue. The buildup of these
chemicals harms the afflicted regions. However, molecular analyses for NPC genes were then
negative. Lipid profiling revealed a significant HDL shortage of 2 mg/dl (n.v. 45-65) and apoAI
deficiency of 5.19 mg/dl (n.v. 110-170), indicating Tangier disease as the likely diagnosis. A
unique homozygous mutation came to light in the ABCA1 gene during a molecular investigation
(Hiwot, Tarekegn, and Andrew Cook, 2021)
Due to the misdiagnosis, treatment with miglustat no longer continued. The woman
subsequently suffered severe neurological symptoms; memory loss, slow thinking processes, and
skin sores. After seven months, miglustat treatment began again with results of neurological
stabilization and improvement in cutaneous involvement. These findings point to miglustat as a
potential treatment option for Tangier, an incurable condition. The known side effects of
miglustat include: “diarrhea, weight loss, gastrointestinal upset, nausea and vomiting, anorexia,
constipation, headache, tremor, dizziness, weakness, visual problems, dry mouth, paresthesia,
peripheral neuropathy, ataxia, and memory loss” (NCBI, 2018). The mechanisms through which
miglustat improves at least some clinical signs of Tangier disease need to be studied further.
Tangier illness had an incidence rate of 35 in Japan and 109 in other countries by 2020,
indicating that it is not a prevalent disease. However, the incidence of defective ABCA1 gene
variants in the general population remains unclear. According to a recent study that used the
Exome Aggregation Consortium database, 1 in 400 persons in the general population is a
heterozygote for a loss-of-function mutation in the ABCA1 gene based on allele frequencies. As
a result, a sizable proportion of instances may go undiagnosed (Koseki, Masahiro, et al., 2021).
Although Tangier disease is rare, the study, first published in 2014 on the results of
miglustat's positive effects on the neurological symptoms of TD, is promising. However,
research should consider the treatment's side effects when considering each case. Although the
benefits of miglustat occurred accidentally, it is an opportunity that should be seized.

Works Cited
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Berberich, Amanda J, and Robert A Hegele. “A Modern Approach to Dyslipidemia.”

Endocrine Reviews, Oxford University Press, 13 July 2022,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277652/.

Colaco, Alexandria, et al. “Mechanistic Convergence and Shared Therapeutic Targets in

Niemann-Pick Disease.” Journal of Inherited Metabolic Disease, John Wiley &
Sons, Inc., May 2020,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317544/#:~:text=NPC%20is
%20caused%20by%20defects,neurological%20course%20of%20the%20disease.

GARD. “Tangier Disease - about the Disease.” Genetic and Rare Diseases Information
Center, U.S. Department of Health and Human Services,
https://rarediseases.info.nih.gov/diseases/7731/tangier-disease.

Hiwot, Tarekegn, and Andrew Cook. “Investigating the Role of Miglustat in the
Management of a Patient with Tangier Disease.” ISRCTN, 7 Jan. 2021,
https://www.isrctn.com/ISRCTN17945917.

Koseki, Masahiro, et al. “Current Diagnosis and Management of Tangier Disease.”

Journal of Atherosclerosis and Thrombosis, Japan Atherosclerosis Society, 1 Aug.
2021, https://www.jstage.jst.go.jp/article/jat/28/8/28_RV17053/_article.

“Miglustat.” National Center for Biotechnology Information, U.S. National Library of

Medicine, 5 Mar. 2018, https://www.ncbi.nlm.nih.gov/books.