The ABCD1 gene is located on the X chromosome at position Xq28. This gene plays a role in various cellular processes. It consists of 10 exons and spans approximately 21 kilobases of genomic DNA.
The Role of the ABCD1 Gene
The ABCD1 gene provides instructions for creating adrenoleukodystrophy protein (ALDP). ALDP is found within the membranes of peroxisomes. Peroxisomes are small, sac-like structures inside cells that process various molecules.
The primary function of ALDP is to transport very long-chain fatty acids (VLCFAs) into peroxisomes. Once inside, VLCFAs are broken down through beta-oxidation. This breakdown is important for maintaining cellular health, particularly in the brain and adrenal glands.
ALDP acts as an ATP-binding cassette (ABC) transporter, using energy from ATP to move molecules across membranes. It functions as a “half-transporter,” requiring a “partner-half” to form a functional unit for fatty acid import. Proper transport and breakdown of VLCFAs are important for the normal functioning of various tissues.
ABCD1 Gene and X-linked Adrenoleukodystrophy (X-ALD)
Mutations in the ABCD1 gene are directly linked to X-linked adrenoleukodystrophy (X-ALD). Over 650 different mutations have been identified. These genetic changes can prevent ALDP production in about 75% of individuals, or result in non-functional ALDP.
When ALDP is deficient or non-functional, VLCFAs are not properly broken down and accumulate in the body’s tissues. This accumulation occurs in areas like the brain, spinal cord, and adrenal glands. The buildup of these fats harms myelin, the fatty layer insulating nerves, and the adrenal glands.
VLCFA accumulation can trigger an inflammatory response in the brain, leading to myelin breakdown. This demyelination impairs nerve communication, contributing to neurological problems. Damage to the adrenal cortex can also cause a shortage of hormones, leading to adrenocortical insufficiency.
Understanding X-ALD Phenotypes
X-ALD presents with a wide range of phenotypes, even within the same family. The disease primarily affects males, though approximately 80% of female carriers may develop symptoms later in life. Severity and age of onset vary considerably and are not predictable by the specific ABCD1 gene mutation or VLCFA levels.
Childhood Cerebral ALD (CCALD) is a severe form that appears between ages 4 and 10. Early symptoms include behavioral changes (e.g., hyperactivity, disruptive behavior) and cognitive deficits (e.g., problems with thinking, processing information). This form progresses rapidly, leading to a decline in school performance, vision and hearing loss, and motor deficits, often resulting in a vegetative state and early death if untreated.
Adrenomyeloneuropathy (AMN) presents in adult males, often in their 20s to 40s. Its primary symptoms include progressive stiffness and weakness in the legs, bladder dysfunction, and abnormal sensory perception. AMN progresses more slowly than CCALD, over years or decades, though its severity can vary, with some individuals eventually requiring walking aids.
Addison-Only X-ALD is characterized primarily by adrenal insufficiency, which can occur years or decades before any neurological symptoms appear. This form involves a shortage of adrenal hormones and can be the first sign of X-ALD in boys and adult males. While neurological symptoms may not be present initially, individuals remain at risk for developing other forms of the disease over time.
Diagnosing X-ALD
Diagnosing X-ALD involves several methods, often beginning with newborn screening in some regions. Newborn screening identifies elevated levels of C26:0 lysophosphatidylcholine, a specific very long-chain fatty acid, in a small blood sample from a baby’s heel. This initial screening can detect the condition before symptoms appear, which is important for early intervention.
Blood tests are a key diagnostic marker, measuring VLCFA levels, particularly C26:0 and the ratio of C26:0 to C22:0. Elevated VLCFA levels are found in nearly all affected males and about 85% of female carriers. This biochemical test is often the first step in confirming a suspected diagnosis.
Genetic testing, specifically DNA analysis, confirms the diagnosis by identifying mutations in the ABCD1 gene. This testing pinpoints the exact genetic change responsible for the disorder. Genetic testing also aids in carrier detection and can be used for prenatal diagnosis.
Magnetic Resonance Imaging (MRI) of the brain plays a role in detecting brain lesions, particularly in cerebral forms of X-ALD. MRI can reveal demyelination and inflammation in the white matter, even before overt neurological symptoms are evident. Adrenal function tests also assess for adrenal insufficiency, a common feature of X-ALD.