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X-Linked Adrenoleukodystrophy. ARUP Consult®. Retrieved October 30, 2025, https://arupconsult.com/content/x-linked-adrenoleukodystrophy

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X-Linked Adrenoleukodystrophy

Last Literature Review: September 2025 Last Update:

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X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an estimated incidence of approximately 1 in 17,000 births.  This inherited metabolic condition primarily affects the brain, spinal cord, and adrenal glands.  X-ALD is caused by pathogenic variants in the ABCD1 gene, located on the X chromosome, which lead to the toxic accumulation of very long-chain fatty acids (VLCFAs) in fluids and tissues. ,  Clinical manifestations vary widely; even identical pathogenic variants can result in different phenotypes.  X-ALD affects both male and female individuals, although male individuals typically experience earlier onset and more severe symptoms.  The disorder presents with three main phenotypes that can manifest in isolation or concurrently: primary adrenal insufficiency (PAI), adrenomyeloneuropathy (AMN), and progressive cerebral forms. The cerebral form most commonly presents in childhood (childhood cerebral ALD, or CCALD) but can also manifest during adolescence or in adulthood.  Without treatment, individuals with CCALD are at risk for severe disability and death within a few years from the onset of brain lesions.  Early diagnosis enables timely intervention, such as hematopoietic stem cell transplantation (HSCT) in those with CCALD or clinical management to avoid life-threatening crises in those with adrenal insufficiency.  Diagnostic evaluation includes measurement of VLCFA levels and genetic confirmation of pathogenic ABCD1 variants. ,  Following diagnosis, ongoing monitoring is critical due to the variable disease course and is used to identify candidates for treatment. 

Quick Answers for Clinicians

Are newborns in the United States screened for X-linked adrenoleukodystrophy?

Newborn screening for X-linked adrenoleukodystrophy (X-ALD) is included in the Recommended Uniform Screening Panel (RUSP) from the Advisory Committee on Heritable Disorders in Newborns and Children  but has not yet been implemented in all U.S. states.  The Association of Public Health Laboratories (APHL) maintains state profiles with information on which conditions are included in each state’s newborn screening panel.  For more information on newborn screening, refer to the Newborn Screening section.

How does X-linked adrenoleukodystrophy manifest clinically in male patients?

Male patients with X-linked adrenoleukodystrophy (X-ALD) typically experience earlier onset and more severe symptoms than female patients. The most severe form of X-ALD, childhood cerebral adrenoleukodystrophy (CCALD), typically presents between 6 and 12 years of age  and affects approximately one-third of male individuals with X-ALD. It initially presents with cognitive deficits and behavioral problems that can be attributed to conditions such as attention-deficit/hyperactivity disorder (ADHD). However, the disease progresses rapidly, causing neurologic decline. CCALD is lethal without timely hematopoietic stem cell transplantation (HSTC).  Most male individuals with X-ALD develop primary adrenal insufficiency, which also requires timely intervention to avoid the risk of life-threatening adrenal crises. Adrenomyeloneuropathy (AMN) is the most common form of adult-onset X-ALD. 

How does X-linked adrenoleukodystrophy manifest clinically in female patients?

Female individuals with a pathogenic ABCD1 variant were historically considered asymptomatic carriers of X-linked adrenoleukodystrophy (X-ALD). Although approximately one-third remain asymptomatic throughout their lives, female individuals can develop adrenomyeloneuropathy (AMN) in adulthood; onset typically occurs in the fifth decade of life. The exact mechanism remains unclear, but it is hypothesized that a skewed X-inactivation preserving the normal allele may explain why some female individuals remain asymptomatic. Adrenal insufficiency and childhood cerebral adrenoleukodystrophy (CCALD) are rare in female patients. 

When should suspected adrenal insufficiency in male patients raise concern for X-linked adrenoleukodystrophy?

Testing for X-linked adrenoleukodystrophy (X-ALD) via a very long-chain fatty acid (VLCFA) plasma profile should be considered in male patients with adrenal insufficiency and negative results for 21-hydroxylase autoantibodies or other organ-specific antibodies.  Adrenal insufficiency has multiple etiologies, but normal 21-hydroxylase antibody testing increases concern for X-ALD.

Indications for Testing

Laboratory testing for X-ALD is used to:

  • Screen newborns in states that include X-ALD in newborn screening panels
  • Diagnose X-ALD in:
    • Infants with abnormal newborn screening results
    • Male patients with white matter lesions characteristic of X-ALD on brain magnetic resonance imaging (MRI) scans
    • Male patients with neurologic or behavioral symptoms concerning for CCALD, including changes in attention, learning, behavior, speech, vision, walking, or coordination 
    • Male and female patients with symptoms of chronic myelopathy and normal MRI 
    • Male patients with PAI and negative 21-hydroxylase autoantibodies 
    • Patients at risk for X-ALD based on familial relationship with an affected individual 
  • Monitor for disease progression and guide treatment in patients diagnosed with X-ALD

Laboratory Testing

Newborn Screening

Newborn screening is a public health program designed to identify certain conditions that manifest in infancy or early childhood and enable early intervention to reduce morbidity and mortality. Although each U.S. state determines its own panel of screened disorders, all programs use a dried blood spot collected from a newborn’s heel shortly after birth for testing. X-ALD was initially recommended for newborn screening panels to identify male newborns with CCALD who need HSCT. However, screening also detects male newborns with other X-ALD phenotypes, female newborns who may develop symptoms later in life, and some newborns diagnosed with other disorders. 

Newborn screening for X-ALD involves measurement of lysophosphatidylcholine (LPC) containing hexacosanoic acid (C26:0), or C26:0-LPC, a derivative of a VLCFA marker.  Neonates with increased levels of C26:0-LPC are referred for confirmatory testing. Some states perform DNA sequencing to detect ABCD1 gene variants before referring the patient for confirmatory testing.  Refer to the Genetic Testing section for more information.

Elevated concentrations of C26:0-LPC are also observed in other conditions besides X-ALD. The most notable among these are peroxisome biogenesis disorders within the Zellweger spectrum. 

Diagnosis

Diagnostic confirmation of X-ALD involves a combination of biochemical and molecular genetic testing. 

Biochemical Testing

Biochemical testing for X-ALD involves plasma measurements of VLCFA and branched-chain fatty acids. Ideally, specimens should be collected after fasting, or in newborns and children, collection may occur before feeding or a couple of hours after a meal.

Biochemical testing should precede genetic testing in symptomatic male patients.  VLCFA concentrations are typically increased in affected male individuals, regardless of symptoms or patient age. Three specific VLCFAs are useful in diagnostic testing: behenic acid (C22:0), tetracosanoic acid (C24:0), and hexacosanoic acid (C26:0). Measurement of VLCFAs in plasma (specifically C26:0, the ratio of C26:0 to C22:0, and the ratio of C24:0 to C22:0) can be used to diagnose X-ALD in male patients and has a high sensitivity for the disease.  In 15-20% of female patients with X-ALD, VLCFA concentrations will be normal; therefore, genetic testing must be performed for definitive diagnosis. 

Genetic Testing

Genetic testing is used to identify pathogenic ABCD1 variants for a definitive diagnosis of X-ALD.  Testing for ABCD1 variants is recommended as the first-tier test for asymptomatic male individuals and all female individuals suspected of having X-ALD and should also be ordered for all symptomatic male patients who have a positive biochemical result. 

It is important to note that de novo variants or variants of uncertain significance (VUS) are common. In these cases, genetic testing results should be considered in the context of other clinical findings.  In vitro fibroblast culture can be useful for assessing the pathogenicity of a variant, particularly in asymptomatic male individuals with biochemical markers that fall between the upper limit of normal and the lower limit typically associated with disease. , 

When an individual with X-ALD is found to carry a pathogenic ABCD1 variant, genetic counseling is recommended to discuss inheritance and coordinate testing of potentially affected blood relatives. Although prognostic abilities are limited due to the lack of a well-established genotype-phenotype correlation, detection of a familial variant can identify other relatives at risk for X-ALD and help assess recurrence risk.

Other Considerations

Individuals with an abnormal newborn screen for X-ALD, abnormal biochemical test, and a VUS or benign ABCD1 variant should be evaluated for related diseases such as Zellweger spectrum disorder, ACOX1 deficiency, CADDS, ACBD5 deficiency, and Aicardi-Goutières syndrome. 

Monitoring

Monitoring is necessary for patients with X-ALD to detect disease progression and identify patients for whom treatment is indicated.

Male Patients With X-ALD

Male patients should undergo monitoring for adrenal insufficiency and cerebral disease after a diagnosis of X-ALD. Testing for adrenal insufficiency should include morning cortisol and adrenocorticotropic hormone (ACTH), starting at 6 months of age. In children younger than 10 years, testing should be repeated every 3 to 6 months and annually thereafter.

Testing for cerebral disease requires a periodic brain MRI, with a baseline scan at 2 years of age. When possible, adrenal insufficiency screening should parallel brain MRI.  Refer to the ARUP Consult Adrenal Insufficiency topic for additional information on laboratory testing for this condition.

Screening for myeloneuropathy is recommended for individuals older than 18 years and in parallel with other testing. Screening for gonadal insufficiency is not recommended unless symptoms develop. 

Female Patients With X-ALD

Routine screening for adrenal insufficiency and cerebral disease is not recommended in female patients. Screening for myeloneuropathy is recommended for individuals older than 18 years. 

ARUP Laboratory Tests

Initial Test
Monitoring Tests

References