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X-Linked Adrenoleukodystrophy
(ALD)
By Megan Martinez and Shelbi Green
Nature of ALD: Overview
• ALD is an X-linked peroxisomal disorder characterized by
the demyelination of the central nervous system and
degradation of adrenal function (Aubourg, 1993).
• Caused by the inability of peroxisomes to degrade verylong chain fatty acids (VLCFAs).
• VLCFAs build up in the tissues of the body, especially the
brain and adrenal glands (Mosser, 2010).
The Peroxisomes and β-Oxidation
Peroxisomes: digestive organelles in all
eukaryotic cells that carry oxidative
enzymes that are involved in the
break down of fatty acids by
oxidation.
Fatty Acids: necessary and vital
components of all cells (i.e.
triglycerides for energy storage).
VLCFAs: very hydrophobic fatty acids with
tails longer than 22 carbons. They are
normal components in membranes
such as the myelin sheath.
VLCFAs Oxidation: too long to be broken
down in the mitochondria.
Therefore, are broken down in the
peroxisomes in a series of chemical
reactions called the β-oxidation cycle
which the VLCFAs are broken down
by the successive removal of two
carbons (Mosser, 2010).
ALD Protein
• ALD Protein: the cause of the peroxisome’s inability to
oxidize VLCFAs is the absence of a protein named the
ALD protein (ALDP).
• It was shown that the expression of the ALDP in ALD
patient cells restored normal β-oxidation of VLCFAs
(Shinnoh et al, 1995).
• ALDP function: transports VLCFAs across the
peroxisomal membrane. When it does not fuction
properly, VLCFA accumulates in the cytosol and does
not get degraded.
• ALDP deficiency has two effects:
– Impairs β oxidation of VLCFAs
– Allows the VLCFAs waiting in the cytosol to become
substrates for further elongation.
Consequences of Excess VLCFAs
Demyelination: the
destruction of myelin
impairs the conduction
of signals in affected
neurons.
Adrenal Insuffiency:
damage to the adrenal
glands causes their
inability to produce the
necessary amount of
steroid homones
Cause of ALDP deficiency: Mutation
ALDP deficiency is
caused by a
mutation in the ATPbinding cassette,
sub-family
D (ABCD1) gene
which is located on
the long arm of the X
chromosome at
position 28 (Xq28)
Pattern of Inheritance: X-Linked
Recessive
The ABCD1 gene is
located on the Xchromosome, and the
mutation causing ALDP
deficiency is a recessive
allele.
Disorder is passed from
mother to son and
daughter are carriers.
History of ALD
• 9 documented cases of ALD between 1910-1963.
• Disease was elusive and unknown, but by 1963 was suspected to be Xlinked recessive because only male patients had been documented. Very
little was known about the disease except that it involved degeneration of
the white matter in the CNS and adrenocortical insufficiency.
• Major breakthrough was made in 1972 Schaumburg and Johnson
observed that adrenal cells of ALD patients contained characteristic lipid
inclusions (fat droplets), and showed that these fat droplets consisted of
cholesterol esters that contained VLCFAs (Engelen & Kemp, 2010).
• 1986: Lorenzo’s Oil
• 1988: First successful bone marrow transplant
• 1993: ABCD1 mutation identified allowing for improvements in diagnosis
and genetic counseling
• 2006: advancement in VLCFA screening in blood tests
• 2007: two 7-year-old boys successfully treated using gene therapy
• 2010: discovery ALDP transports VLCFAs across the peroxisomal
membrane
ALD Diagnosis and Facts
• The most common leukodystrophy affecting 1:17,000
(Engelene & Kemp, 2010).
• Affects all ethnic groups
• Progressive demyelination and adrenocortical
insuficiency eventually leads to long-term coma
(vegetative state) usually within 2 years of the first
neurological symptoms.
• Patient can live up to 10 years in this state (Englene &
Kemp, 2010).
Lorenzo Odone, the
inspiration for the film
Lorenzo’s Oil three days
before his death in May
2008.
Untreated ALD
• If ALD goes untreated
– Myelin sheaths of the nerve cells continues to
degrade leading to failure of adrenal glands, brain
damage and in sever cases, vegetation or even
death.
Demyelination of ALD
Healthy myelin
Damaged Myelin
Untreated ALD
Healthy Brain
Brain damaged by ADL
Current Treatment of ALD
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Dietary therapy
Transplant
Gene therapy
Adrenal insufficiency
Dietary therapy
• Dietary restrictions of very-long-chain fatty
acids lead to the discovery of Lorenzo's oil
Transplant Therapy
• Allogeneic Hematopoietic Stem Cell
Transplants
Gene therapy
• Appropriate vectors are selected and modified
to express wild type ABCD1 and then
transplanted into the patients
Adrenal insufficiency
• Hormone replacement is standard treatment for ALD
patients demonstrating adrenal insufficiency, but it
cannot resolve any of the neurological symptoms.
Recent Research
• A gene therapy trial in two ALD patients showed
results that strongly suggest that hematopoietic stem
cells were transduced in the patients and that gene
therapy of hematopoietic stem cells can provide
clinical benefits in ALD.
References
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Amorosi, C., Myskóva, H., Monti, M., Argaraña, C., Morita, M., Kemp, S., & ... de
Ramírez, A. (2012). X-Linked Adrenoleukodystrophy: Molecular and Functional
Analysis of the ABCD1 Gene in Argentinean Patients. Plos ONE, 7(12), 1-8.
Aubourg, P., Mosser, J., Douar, AM., Sarde, CO., Lopez, J., Mendel, JL. (1993).
Adrenoleukodystrophy gene: Unexpected homology to a protein involved in
peroxisome biogenesis. Biochimie, 75(3-4), 293-302.
Cartier N., Hacein-Bey-Abina S., Bartholomae C.C., Veres G. (2009). Hematopoietic
Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy.
Science Journal, 326:818-823
Engelen, M., Kemp, S. (2010). History of X-ALD. X-ALD Database.
Moser, HW. (2010). X-linked Adrenoleukodystrophy database. Kennedy Krieger
Institute.
Shinnoh N., Yamada T., Yoshimura T., Furuya H., Yoshida Y., Suzuki Y., Shimozawa
N., Orii T., Kobayashi T. (1995). Adrenoleukodystrophy: the restoration of
peroxisomal beta-oxidation by transfection of normal cDNA. Biochem Biophys Res
Commun 210(3), 830-6.