Adrenoleukodystrophy (ALD) is a progressive, genetic disorder that primarily affects the nervous system and the adrenal glands, impacting males. The condition is characterized by the body’s inability to properly break down very long-chain fatty acids (VLCFAs). This leads to their accumulation in the brain, spinal cord, and adrenal glands, causing inflammation and damage to the myelin sheath, the protective covering of nerve cells. Early diagnosis of ALD is paramount because the window for effective intervention is narrow, allowing treatment to halt or slow the disease’s progression.
Recognizing the Need for Testing
A physician considers ALD testing when a patient presents with neurological or adrenal symptoms, or if there is a known family history. Clinical presentation varies widely depending on the form and the patient’s age. Childhood Cerebral ALD (CCALD), the most severe form, usually appears in boys between four and ten, marked by rapid neurological decline.
CCALD signs may be subtle, including behavioral issues, difficulty in school, vision loss, or hearing impairment, often leading to misdiagnosis. The adult-onset form, Adrenomyeloneuropathy (AMN), typically presents in men in their twenties or later with a slower progression. AMN symptoms involve stiffness and weakness in the legs, gait disturbances, and issues with bladder or bowel control. Primary adrenal insufficiency can also be the first or only symptom, manifesting as muscle weakness, fatigue, or skin darkening.
Biochemical Confirmation and Neuroimaging
The initial step in diagnosis involves biochemical testing of the blood to measure very long-chain fatty acids (VLCFAs). The inability to properly metabolize these lipids, specifically the saturated fatty acid C26:0, is the defining biochemical hallmark of the disorder. Elevated concentrations and ratios (C26:0 to C22:0 and C24:0 to C22:0) are indicative of ALD in males.
Measurement of plasma VLCFAs is a reliable diagnostic tool for over 99.9% of affected males, regardless of symptoms. This test is less reliable in female carriers, however, with approximately 15 to 20% showing normal VLCFA levels. A normal VLCFA result in a female does not eliminate the need for further genetic analysis if ALD is suspected.
Neuroimaging, particularly Magnetic Resonance Imaging (MRI) of the brain, is crucial for assessing the extent and severity of the cerebral form. The MRI detects demyelination and inflammatory lesions, which appear as symmetrical white matter abnormalities, often starting in the posterior parieto-occipital region. Radiologists use the standardized Loes score to quantify the severity of brain damage. This 34-point scale evaluates the location and extent of white matter abnormalities and atrophy, and a higher score determines eligibility for therapies like hematopoietic stem cell transplantation.
Genetic Analysis and Newborn Screening
The definitive diagnosis of ALD is established through genetic analysis, which identifies a pathogenic mutation in the ABCD1 gene. This gene, located on the X chromosome, provides instructions for producing the ALD protein, necessary for transporting VLCFAs into peroxisomes for breakdown. Identifying a mutation confirms the underlying cause of the disorder and is the most reliable method for identifying female carriers, where biochemical tests may be inconclusive.
Genetic testing is important in family planning and for screening asymptomatic relatives. Since the disease is X-linked, a mother who is a carrier has a 50% chance of passing the mutation to her children. The unpredictable nature of ALD means individuals with the same ABCD1 mutation can have vastly different clinical presentations.
Newborn screening (NBS) represents the earliest opportunity for ALD detection and has been adopted in many areas to facilitate timely intervention. The screening process utilizes tandem mass spectrometry to measure the biomarker C26:0-lysophosphatidylcholine (C26:0-LPC) in a dried blood spot sample. Elevated levels of this biomarker strongly suggest the presence of the ABCD1 gene mutation.
Early identification through NBS is beneficial because it allows for immediate, proactive monitoring with regular neurological exams and brain MRIs before symptoms appear. Detecting the disease before irreversible neurological damage occurs (often before the Loes score reaches 10) significantly improves the success of treatments, such as stem cell transplantation. NBS shifts the diagnostic focus from reacting to symptoms to preemptive identification.