Adrenoleukodystrophy (ALD) is a rare, inherited disorder that primarily affects the nervous system and the adrenal glands. This progressive condition belongs to a group of genetic diseases called leukodystrophies, which damage the myelin sheath, the protective insulation around nerve cells in the brain and spinal cord. ALD affects males more severely than females, typically leading to a decline in neurological function and, in some forms, life-threatening hormonal issues.
Genetic Basis and Cellular Mechanism
The underlying cause of ALD is a mutation in the ABCD1 gene, which is located on the X chromosome, making it an X-linked genetic disorder. This gene provides instructions for creating the Adrenoleukodystrophy Protein (ALDP), a transporter protein found in the membrane of peroxisomes. The function of ALDP is to help transport very long-chain fatty acids (VLCFAs) into the peroxisome, a tiny organelle within the cell, so they can be broken down.
A defective ALDP prevents the proper transport and subsequent breakdown of these VLCFAs, causing them to accumulate throughout the body. This buildup is particularly toxic in the central nervous system, adrenal glands, and testes. The accumulation of VLCFAs, specifically saturated fatty acids like cerotic acid, triggers an inflammatory response that damages the myelin sheath.
The resulting demyelination disrupts the communication between nerve cells, impairing bodily functions and leading to the characteristic neurological symptoms of ALD.
Recognizing the Different Forms
ALD presents with a wide range of clinical severity and age of onset, categorized into three main phenotypes. Childhood Cerebral ALD (CCALD) is the most devastating form, typically appearing in boys between the ages of four and ten. Affected children experience a rapidly progressive loss of cognitive and motor functions, often presenting with behavioral problems, vision loss, hearing issues, and difficulty with language comprehension.
Adrenomyeloneuropathy (AMN) is the adult-onset form, usually beginning between the ages of 21 and 35, and it progresses much more slowly. This form primarily involves the spinal cord and peripheral nerves, leading to symptoms like leg stiffness, gait disturbances, and bladder dysfunction. While milder than CCALD, men with AMN can eventually develop cognitive problems similar to the cerebral form.
The third major presentation is Addison-only, which involves adrenal insufficiency without any initial neurological symptoms. The adrenal glands fail to produce enough steroid hormones, such as cortisol, which can cause symptoms like muscle weakness, fatigue, weight loss, and darkening of the skin. Approximately 1 in 10 individuals with ALD may present with only this hormonal issue, though they remain at risk for developing neurological symptoms later.
Diagnostic Procedures and Screening
Diagnosis of ALD begins with a high index of suspicion based on a patient’s neurological symptoms or a history of adrenal insufficiency, especially in young males. A key diagnostic test involves a blood sample to measure the plasma levels of very long-chain fatty acids. Elevated VLCFA levels are a distinct biochemical signature of the disorder and a strong indicator of ALD.
Genetic sequencing is used to confirm the diagnosis by identifying a specific mutation in the ABCD1 gene. This genetic confirmation is also important for identifying female carriers and other family members who may not yet be symptomatic. Neuroimaging, specifically Magnetic Resonance Imaging (MRI) scans, are used to look for signs of demyelination and white matter damage.
The severity of brain damage seen on the MRI is often rated using a Loes score, which helps monitor disease progression and determine the appropriate treatment window. Early detection is significantly enhanced by newborn screening programs, which are now available in many regions. Screening detects elevated VLCFA levels in newborns, allowing for diagnosis and intervention before symptoms of CCALD appear.
Management and Therapeutic Options
Treatment for ALD depends on the specific form of the disease and the stage of progression. For early-stage Childhood Cerebral ALD, the most effective intervention is Hematopoietic Stem Cell Transplantation (HSCT), which aims to stop the inflammatory process that causes demyelination. HSCT involves replacing the patient’s faulty blood-forming cells with healthy donor cells that can produce the functional ALDP.
This therapeutic option is most beneficial when performed before significant neurological damage has occurred, often requiring a diagnosis through newborn screening and regular monitoring. Gene therapy represents a newer approach, using a patient’s own stem cells genetically modified to correct the defective ABCD1 gene.
Management of the adrenal insufficiency component, which can occur in any form of ALD, involves highly effective hormone replacement therapy using corticosteroids. Dietary interventions like Lorenzo’s Oil have shown limited effectiveness in halting the progression of established cerebral disease, though they may help normalize VLCFA levels and potentially delay onset in asymptomatic boys.