What Is Adult Cerebral Leukodystrophy (ACLD)?
Also known as X-linked adrenoleukodystrophy, it is a hereditary condition that affects the nervous system and the adrenal gland. It damages the myelin sheath (wrapped around the nerve cells in the brain) and the adrenal cortex (that surrounds the adrenal gland), leading to neurological problems and adrenal insufficiency, respectively.
The fundamental unit of the brain and the nervous system is the neuron; it sends and receives signals from and to the brain. It has three main parts- dendrites, an axon, and a cell body. A useful analogy is to think of the neuron as a tree. The cell body with its dendrites looks like the crown of the tree with its branches, the axon represents the trunk, and the axon terminal looks like the roots of the tree. The dendrites receive the nerve impulse, the cell body processes them, and the axon carries the processed information to the next neuron.
Bundles of axons combine to form the white matter in the brain and the cell body with its dendrites and form gray matter. The axons are coated with myelin which is a mixture of proteins and lipids; it insulates the axon while transmitting nerve impulses. Without myelin, the signals between the nerve cells are not transmitted properly and will lead to neurological symptoms.
The adrenal glands are a pair of glands that sit on the top of each kidney and produce sex hormones, cortisol, etc., which are vital for health and proper development. The adrenal cortex is the outer layer of the cells of the adrenal glands; in some patients with ACLD, the adrenal cortex does not function properly, leading to adrenal insufficiency. This leads to abnormalities in blood pressure, heart rate, sexual development, and reproduction.
What Causes ACLD?
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It is an X-linked recessive disorder that is caused due to mutations (changes) in the ABCD1 gene. Because it is an X-linked disorder, males develop more serious complications than females.
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X-linked inheritance means the genes causing the trait or the disorder are located in the X-chromosome. An X-linked recessive disorder means for the gene to actually express itself, the X chromosome present in the individual should always be recessive.
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Females have 2 X chromosomes (XX), and males have 1Y and 1X chromosomes (XY).
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The ABCD1 gene mutation in the X chromosome will cause ACLD in a female if both the X chromosomes are recessive; if one X is dominant and the other X is recessive, she will be a carrier of the mutation but will not actually be affected by ACLD.
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Similarly, in a male, the ABCD1 mutation will cause ACLD if the X chromosome in their XY composition is recessive.
What Happens in ACLD?
A normal ABCD1 gene contains instructions for making a protein called X-linked adrenoleukodystrophy protein, or simply ADLP. This protein is necessary to transport very long-chain fatty acids (which are a type of fat molecule) to their destination, where they will be metabolized or broken down.
In patients with ABCD1 mutation, there is a deficiency of ADLP, which will reduce the transportation of very long-chain fatty acids. As a result, these fatty acids will not get metabolized and will build up in the brain and the adrenal cortex.
Accumulation of these fatty acids in the brain will trigger an inflammatory reaction that ultimately damages the myelin sheath leading to neurological symptoms. In the adrenal cortex, the excess fatty acids will destroy the hormone-producing cells leading to adrenal insufficiency.
What Are the Signs and Symptoms of ACLD?
It affects adult men at any time between their late twenties to their early fifties. The symptoms are similar to those seen in childhood cerebral adrenoleukodystrophy; they are-
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Different behavioral problems include attention deficit disorder.
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Regression of previously acquired skills.
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Cognitive deficit- It translates to impairment in the mental process of the patient pertaining to how an individual should act in the world.
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Difficulty in understanding speech and language.
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Deterioration in writing skills.
The symptoms at the later stage of the condition are-
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Diminished vision.
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Gait difficulty.
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Weakness and stiffness of the limbs.
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Convulsions and seizures.
In the advanced stage, the symptoms are-
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Blindness.
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Deafness.
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Inability to move.
The condition will further progress, resulting in a vegetative stage and death within 2-3 years from the onset of the symptoms. If the condition also affects the adrenal cortex, the symptoms are as follows-
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Fatigue.
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Unintended weight loss.
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Nausea.
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Vomiting.
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Gastrointestinal issues.
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Morning headaches.
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Low blood pressure.
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Low blood sugar levels.
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Hyperpigmented skin.
How Is ACLD Diagnosed?
After reviewing the medical and family history of the patient with the patient's family, the clinician will request the following tests-
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Blood tests to check for levels of very long-chain fatty acids.
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Magnetic resonance imaging (MRI) to observe lesions in the nerves.
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Vision screening will help to estimate the prognosis of the condition.
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Skin biopsy and fibroblast cell culture to check for increased levels of very long-chain fatty acids.
How Is ACLD Treated?
There are two types of treatment-
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Standard Therapy- This includes managing neurological symptoms and adrenal insufficiency by allogeneic hematopoietic stem cell transplantation (HSCT) and corticosteroid therapy, respectively. It is done in individuals who are in their early course of the condition with no neurological symptoms. In HSTC, the patient will receive hematopoietic stem cells from a healthy person known as the donor, who will prevent the progression of neurological conditions in patients with ACLD.
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Investigational Therapy- This includes gene therapy which is yet to be approved. It is a procedure where the defective gene is removed and replaced with a normal gene that will produce sufficient ADLP. This will prevent the development and progression of the condition. Theoretically, this will be the cure for ACLD, but studies regarding its effectiveness and its long-term safety are still going on.
Another investigational therapy is Lorenzo’s oil which has reduced neurological symptoms in some children but has not been experimented on adults with cerebral leukodystrophy.
Conclusion:
ALCD is a neurodegenerative condition with a poor prognosis. Diagnosis plays an important role because the symptoms of ALCD often mimic multiple sclerosis, which will deviate the treatment plan and lose precious time. Treatment includes a multidisciplinary team that can handle long-term medical and emotional challenges.
