With adrenoleukodystrophy, sometimes called ALD, adreno- refers to the adrenal glands,
while -leuko-, means white, and -dystrophy refers to tissue degradation. So, adrenoleukodystrophy
is a rare genetic condition, caused by a mutation in the ABCD1 gene, located in the X-chromosome,
that leads to the progressive loss of white matter in the nervous system, and the degradation
of adrenal glands.
Generally, genes tell our bodies how to make proteins. In this case, the ABCD1 gene directs
the body to produce adrenoleukodystrophy protein or ALD protein. ALD protein is a transporter
that is found embedded in the membranes of vesicles found in cells that break down specific
forms of fatty acids, called peroxisomes. Its function is to import into peroxisomes,
a group of fats, naturally present in the human body and in our diets, called very long-chain
fatty acids or VLCFAs. Once inside the peroxisomes, these molecules are broken down into shorter
forms of fatty acids.
Now, in adrenoleukodystrophy, there’s a mutation in the ABCD1 gene which leads to
a defective ALD protein. Without a working ALD protein, VLCFAs have no way of entering
the peroxisomes to be broken down, so they accumulate inside cells. This build up of
VLCFAs is thought to be damaging to our nerve cells and the glial cells that support them,
the cells in our adrenal glands that produce steroid hormones, the cells in the testicles,
and some of our immune cells.
Adrenoleukodystrophy is inherited in an X-linked fashion. This means that the ABCD1 gene is
found on the X-chromosome. Males who carry a ABCD1 gene mutation on their X chromosome
will have the condition. 85% of females who carry a ABCD1 gene mutation on one of their
X chromosomes present higher levels of VLCFAs and half experience symptoms.
Now, adrenoleukodystrophy has variable expressivity, which means that the symptoms between each
person with the condition can differ greatly, even within the same family. For this reason,
an affected person can develop four main types of adrenoleukodystrophy. The four main types
are the childhood cerebral type, called ccALD, the adult cerebral type, called acALD, the
adrenomyeloneuropathy or AMN type, and adrenal insufficiency-only type. It’s important
to note that while in the cerebral forms of ALD, there is a rapidly progressive inflammation
of the brain resulting in destruction of the brain’s white matter, the AMN type is due
to a slowly progressive degeneration of the long nerve fibers in the spinal cord and the
peripheral nerves. Despite extensive research it remains unknown why some people develop
one versus the other form of this disease. Currently, there is also no way to predict
who will develop which form.
In the childhood cerebral type, the affected children develop normally for the first few
years but neurological symptoms typically begin in early school years. These symptoms
may include new onset behavioral problems, learning disabilities, seizures, vision loss,
deafness, loss of speech, and trouble coordinating movements.
In the adrenomyeloneuropathy type, the most common form, there are both adrenal and neurological
problems. It usually begins in early adulthood. Symptoms may include stiffness, weakness,
clumsiness in the limbs, pain in the hands and feet, muscle spasms, urinary problems,
and erectile dysfunction.
In the adult cerebral type, men who often already have AMN symptoms will also start
experiencing behavioral changes, memory and cognitive issues, similar to people with dementia,
slurring of speech, and inability to take care of themselves.
In the adrenal insufficiency-only type, there’s adrenal deficiency but no neurological problems.
Symptoms may appear at any time between childhood and adulthood and include decreased appetite,
increased pigment in the skin, low blood pressure, muscle weakness, and vomiting.
While males can develop all forms of this disease, about half the females who carry
the ABCD1 mutation will develop AMN symptoms typically during middle age. Cerebral forms
and adrenal insufficiency are very rare in females.
Now, the diagnosis of adrenoleukodystrophy may be suspected in people with adrenal insufficiency
even in absence of neurological symptoms. Diagnosis starts with a blood test that measures
the amount of VLCFAs. Then genetic testing is done to confirm the diagnosis. After diagnosis,
a brain MRI is done to evaluate the extent of the disease.
Now because adrenoleukodystrophy is caused by a genetic mutation, there’s no known
overall cure, but treatments for the different forms do exist. For ccALD, it’s important
to catch it early with screening because hematopoietic stem cell transplant, also called bone marrow
transplant, can be done, but it’s only effective if done during the early stages of the disease.
Due to this, newborn babies are now being tested for ALD in several countries and several
states in the US. For the adult forms of the disease, management focuses on treating adrenal
insufficiency with supplementation of the missing steroid hormones. Symptoms like muscle
stiffness, pain, and gait problems can be treated with medications and physical therapy.
Alright, as a quick recap, adrenoleukodystrophy, or ALD, is a rare genetic condition caused
by a mutation in the ABCD1 gene located in the X-chromosome that leads to the progressive
loss of white matter in the nervous system and the degradation of adrenal glands. It
has variable expressivity, which means that there are different forms of the disease.
The symptoms are neurological or related to adrenal insufficiency. It's diagnosed with
a blood test that detects VLCFAs levels and a genetic test. Treatment involves glucocorticoids
to counter the adrenal insufficiency, hematopoietic bone marrow transplantation for the childhood
cerebral form, and symptom specific medications and physical therapy for the adult forms.