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X-linked Adrenoleukodystrophy

History
X-linked adrenoleukodystrophy (X-ALD) is a genetic disease involving peroxisomal
metabolism resulting in the accumulation of saturated very long chain fatty acids (VLCFAs).
Cells most vulnerable to X-ALD are neurons and adrenal cells. The long-term accumulation of
these fatty acids inside cells can cause demyelination in neurons of the brain, peripheral nerve
malfunctioning, and adrenal abnormalities (6). Siemerling and Creutzfeld were the first to
characterize the manifestation of adrenal degeneration, demyelination of neurons, and infiltration
into lymph nodes in a medical case that is viewed as the first undeniable report of X-ALD. In
1963 genetic studies of X-ALD began through family pedigrees and in 1970, the name was
coined by Michael Blaw (1).
As information on the disease from clinical cases, medical research into the disease
accelerated. It was discovered in 1976 that patients with X-ALD develop an accumulation of
VLCFAs in the cells of the brain and adrenal cortex (6). Further research showed that VLCFs
were present in other cell lines including plasma and skin fibroblasts. However, it wasn’t until
1984 that it was understood that a mutation in the Xq28 locus caused a defect in the beta-
oxidation of VLCFAs in peroxisomes (6).
Continued research on X-ALD found the genetic source of the mutation: gene ABCD1 on
the X chromosome (3). This finding confirmed earlier studies that focused on pedigrees that
showed an increased occurrence of the disease in males. X-ALD was later divided into subsets
based on physical symptoms and age of diagnosis: childhood cerebral, adrenomyeloneuropathy,
and adrenal insufficiency. Interestingly, within a family individuals can express different forms
of the disease while having equivalent genotypes; the cause is currently unclear (4). Theraputic
breakthroughs will be discussed in later sections. Further discussion of X-ALD will focus on the
childhood cerebral subset.
The medical literature on X-ALD shows that the disorder is present in all populations and
does not suggest there is a geographical association (6). There is also no personal connection to
the disease.
Cellular Etiology
As a rare disease, the cellular mechanism behind X-ALD is not completely understood
but biochemical research into the disorder has yielded promising findings. As stated earlier, the
disease is caused by mutations in the ABCD1 gene encoding ALDP, a peroxisomal
transmembrane protein that facilitates VLCFA transport into the peroxisome for beta-oxidation
(1). The mutation inhibits effective transport creating an accumulation of VLCFAs in cells
including neurons, adrenal cells, and myoblasts. However, studies have been unable to explain
why family members with the same genetic mutation manifest different subsets of the disease
(1). Research by Van de Beek and colleagues demonstrated a novel feature of X-ALD in cerebral
childhood cases: endoplasmic reticulum stress (5). Endoplasmic reticulum stress is dependent on
fatty acid chain length and concentration in the cell. While the entire cellular mechanism is not
understood, there is evidence that the accumulation of fatty acid chains in the cell cause
endoplasmic reticulum stress, mitochondrial malfunctions, and oxidative stress via increased
levels of free radicals (5).
Risk factors include inheritance from a parent with increased prevalence of the disease in
males due to the location of the mutation on the X chromosome. However, the genetics of the
disease is complex due to the occurrence in women. Evidence does not support an X-linked
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recessive characterization. It is observed that cellular stress from the disorder in cerebral
childhood cases causes periventricular demyelination, inflammation of cells, and cerebral
cavitation (6). The sustained long-term damage to the central nervous system induces behavioral
problems, poor vision, impaired cognition, poor motor control, and reduced executive
functioning between the ages of four and eight years old (4). The disorder is typically diagnosed
through the former symptoms and confirmed with brain imaging, genetic screening, and
biochemical analysis. The disease progresses rapidly with the onset of behavioral symptoms
characterized by significant loss of neurological function resulting in death within two to three
years after diagnosis (6). The rapid observable deterioration of executive functioning can lead to
anxiety and depression in patients. Development of cerebral childhood X-ALD is also associated
with dementia within months of exhibiting physical symptoms (6).
Treatment
Current treatment strategies are for managing symptoms and are not curative nor
preventive. An important part of treatment is reducing the consumption of VLCFAs and
cholesterol. Restricting dietary fat helps albeit minimally. Similarly, using cholesterol and lipid
lowering drugs has shown some ability to slow the progression of the disease but not enough to
be significant on their own (1). By reducing the amount of exogenous fat absorbed in the body
from diet, the synthesis and accumulation of VLCFAs can be slowed. This partially reduces
endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and tissue
inflammation but reduces diet variety as a side-effect.
Research has focused on pharmacologically increasing other proteins involved in fatty
acid transport such as ABCD2-encoded ALDRP which has been shown to compensate for the
ABCD1 mutation as an alternative mode of treatment (1). ALDRP is structurally similar to
ALDP and also functions as a peroxisomal ABC-transporter. Overexpression of the protein
alleviates some of the deficiency caused by the disease but basal levels are insufficient to reduce
disease symptoms. Current pharmacological agents are in the clinical trial phase and have not yet
been approved for wide-spread usage (1). The side-effects of these agents are still being studied.
A published mortality rate is not known due to the rare occurrence of the disease.
However, most cases result in a vegetative state and eventual death six-months to two years after
the onset of physical symptoms (6). A few cases of survival have been documented in clinical
trials with the progression of the disease halted but neurological damage was not reversed. Early
detection is integral to managing the disease and increasing the comfort of the patient. Access to
a family doctor and a pediatrician for annual checkups is essential for diagnosing the disease
early. Families of a lower socioeconomic status are less likely to have access to a primary care
physician and will be financially pressed to afford medical care including conventional drugs and
experimental treatments.
There is an alternative treatment that has produced results in treating cerebral childhood
X-ALD and stabilizing patient conditions. Lorenzo’s oil is a solution of oleic acid and erucic
acid alleviates the severity of symptoms but does not repair demyelination nor reverse the effects
of the disease (6). It is unclear how the solution works but it has been shown to be effective in
treating young children before the onset of symptoms (6). The drug is still considered to be
experimental and the cost is a barrier for low-income families.
Looking to the Future
Despite a half-century of research and study of X-ALD, our understanding of the disease
is incomplete with gaps in how VLCFA accumulations directly cause cerebral inflammation and
demyelination, as well as the relationship between genotype, phenotype, and environmental cues.
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It is not understood how the mutation in the ABCD1 gene inhibiting ADLP function manifests
into multiple phenotypes affecting different organ systems including the central nervous system,
the adrenal cortex, and the testes.
An available cure for X-ALD may be on the horizon with current research suggesting
possible curative therapies in the next few decades. Once findings are tested and verified,
therapies must remain accessible medically and financially for patients of varying socioeconomic
backgrounds. The current struggles with research include finding available funding for projects
and clinical trials. Research grants available for the disease are limited due to the rare occurrence
of the disease. Public attention and funding is given to more ubiquitous disorders including
breast cancer, diabetes, and cardiovascular disease. Nonetheless, researchers are on the brink of
developing safe and effective novel treatments.
While the cellular mechanisms responsible for the disease are still being studied,
researchers have found promising curative therapies. Lenti-D gene therapy is at the forefront of
research for treating X-ALD with exciting experimental results (2). When performed in the early
stages of cerebral adrenoleukodystrophy, the therapy is effective at stopping the progression of
the disease and stabilizing cognitive states with potential of repairing low-grade neuronal
damage. Results of the trial indicate that the Lenti-D treatment is safe with 15 of the 17 patients
demonstrating gene therapy efficacy (2). This gene therapy that offers genetic correction of the
ABCD1 gene allows for functional ALDP and disease stabilization. It is currently one of the best
experimental treatments that may prove to be curative with additional studies. The treatment is
more effective than traditional therapies and reduces the risks created by hematopoietic stem-cell
transplant via bone marrow that include infection, compromised immune function, and surgical
complications (2).
References
1. Berger J, Gärtner J. 2006. X-linked adrenoleukodystrophy: clinical, biochemical and
pathogenetic aspects. Biochimica et Biophysica Acta. 1763(12): 1721-1732.

2. Eichler F, Duncan C, Musolino PL, Orchard PJ, Oliveira S, Thrasher AJ, Armant M,
Dansereau C, Lund TC, Miller WP, et al. 2017. Hematopoietic stem-cell gene therapy for
cerebral adrenoleukodystrophy. The New England J. of Med. 377(17): 1630-1638.

3. Genetic and Rare Diseases Information Center [Internet]. Gaithersburg (MD): National
Institute of Health; [cited 2018 Jan. 15]. Available from:
https://rarediseases.info.nih.gov/diseases/5758/x-linked-adrenoleukodystrophy.

4. Steinberg SJ, Moser AB, Raymond GV. 1999. X-Linked adrenoleukodystrophy synonym:
x-ald. GeneReviews.

5. Van de Beeka M, Ofmana R, Dijkstraa I, Wijburgb F, Engelenb M, Wandersa R, Kemp S.


2017. Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy. BBA
- Mol. Basis of Disease. 1863(9): 2255-2265.

6. Van Geel B, Assies J, Wanders Ronald, Barth P. 1997. X linked adrenoleukodystrophy:


clinical presentation, diagnosis, and therapy. J of Neurol, Neurosu, and Psychiatry. 63: 4-14.