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X-linked adrenoleukodystrophy (X-ALD) is a rare metabolic disorder caused by variants in the ABCD1 gene that lead to an accumulation of very long chain fatty acids (VLCFAs) in tissue. The buildup of VLCFAs can cause adrenal insufficiency (AI), inflammatory demyelinating cerebral disease, and spinal cord disease. Early diagnosis is critical because allogeneic hematopoietic stem cell transplantation (HSCT) can slow or even halt cerebral disease progression if performed at an early stage of leukodystrophy, before neurologic symptoms manifest. (HSCT has no effect on AI. ) Laboratory testing for the diagnosis of X-ALD involves measurement of VLCFAs; the detection of ABCD1 gene variants confirms the diagnosis. Following diagnosis, monitoring is necessary to identify patients for whom treatment is indicated because the disease course is variable.
Quick Answers for Clinicians
Newborn screening for X-linked adrenoleukodystrophy (X-ALD) is recommended nationwide but has not yet been implemented in all states. See Newborn Screening for more information.
Two frequently seen manifestations of X-linked adrenoleukodystrophy (X-ALD) in males are childhood cerebral adrenoleukodystrophy (CCALD) and adult spinal cord disease, which is also called adrenomyeloneuropathy (AMN). A third form of X-ALD is the “Addison disease-only” phenotype. CCALD, a neuroinflammatory disease that progresses rapidly, occurs in approximately 40% of children with X-ALD, generally between 2 and 10 years of age, and can be fatal or severely debilitating. Progressive spinal cord disease affects all men with X-ALD and typically presents between 20 and 30 years of age. Addison disease-only X-ALD manifests as primary adrenocortical insufficiency, often in childhood, but typically progresses to neurologic disability in adulthood. Adrenal insufficiency (AI) occurs in 80% of all patients with X-ALD.
It was once thought that women were asymptomatic carriers, but 60-80% of women with X-linked adrenoleukodystrophy (X-ALD) will also develop progressive spinal cord disease, although the disease occurs at an older age and develops more slowly in women than in men. Only 1% of women with X-ALD will develop adrenal insufficiency (AI) and/or cerebral disease.
Hematopoietic stem cell transplantation (HSCT) must be performed early in the development of leukodystrophy; males with pathogenic ABCD1 gene variants therefore must undergo ongoing assessment, including evaluation of adrenocortical function and magnetic resonance imaging (MRI) of the brain, to determine if HSCT is indicated. HSCT can slow or arrest the progression of leukodystrophy but will not influence whether the patient develops adrenal insufficiency (AI). See Monitoring for more information.
Adrenal insufficiency (AI) may be the initial presentation of X-linked adrenoleukodystrophy (X-ALD), and 21-hydroxylase antibody testing may confirm or exclude an autoimmune etiology of AI. In X-ALD, 21-hydroxylase antibody test results will be normal. Therefore, although 21-hydroxylase antibody testing is not part of the typical workup for suspected X-ALD, males with AI and normal 21-hydroxylase antibody test results should be tested for X-ALD using very long chain fatty acid (VLCFA) profile testing.
Indications for Testing
Laboratory testing for X-ALD is used to:
- Screen infants (as part of newborn screening panels in some states)
- Diagnose X-ALD in:
- Infants with positive newborn screening results
- Boys with signs of childhood cerebral adrenoleukodystrophy (CCALD), such as attention deficit disorder/hyperactivity, and increasing cognitive, visual, behavioral, and motor impairment, particularly with adrenocortical dysfunction
- Males with signs of adrenomyleoneuropathy, such as leg stiffness or weakness, sexual dysfunction, sphincter impairment, or adrenocortical dysfunction
- Males with AI and normal 21-hydroxylase antibody testing (VLCFA profile)
- Detect carrier status or disease in family members of a patient diagnosed with X-ALD
- Monitor for disease progression and to guide treatment in patients diagnosed with X-ALD
Laboratory Testing
Newborn Screening
Newborn screening for X-ALD involves measurement of C26:0-LPC, a derivative of a VLCFA marker, in dried blood spots. Neonates with increased levels of C26:0-LPC are referred for confirmatory tests. Some states perform DNA sequencing to detect ABCD1 gene variants before referring the patient for confirmatory tests. See Genetic Testing below.
Diagnosis
Initial Testing
VLCFA concentrations are typically increased in male patients with X-ALD, regardless of disease status 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 males, and has a high sensitivity for the disease. In 15-20% of females with X-ALD, VLCFA concentrations will be normal, and genetic testing must be performed for a definitive diagnosis.
Genetic Testing
All patients with X-ALD have an ABCD1 gene variant; genetic testing therefore is typically used to definitively diagnose the disease and to identify female carriers. This testing is particularly indicated in females because only about 85% will demonstrate elevated VLCFA concentrations.
Testing of family members is recommended after a diagnosis of X-ALD. However, the detection of variants is not prognostic because there is no genotype-phenotype correlation (ie, the particular variant does not correlate with disease severity or disease course), even among family members. In addition, up to 19% of patients with X-ALD have been reported to carry de novo ABCD1 variants.
Monitoring
Monitoring is necessary in patients with X-ALD to detect disease progression and identify patients for whom treatment is indicated. It includes testing for AI (measurement of morning cortisol and adrenocorticotropic hormone [ACTH]) and periodic evaluation for cerebral white matter demyelination via magnetic resonance imaging (MRI).
Risk for AI in males with X-ALD is age dependent. Testing for the development of AI is recommended every 4-6 months for patients ≤10 years of age and annually for patients 11-40 years of age. In patients ≥40 years, the risk of developing AI is lower; testing is recommended if clinically indicated but does not need to occur at the same frequency as in younger populations. AI is rare in women with X-ALD. See the ARUP Consult Adrenal Insufficiency topic for additional information on laboratory testing.
ARUP Laboratory Tests
Liquid Chromatography-Tandem Mass Spectrometry
Quantitative Electrochemiluminescent Immunoassay
Quantitative Electrochemiluminescent Immunoassay
References
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NORD - X-Linked Adrenoleukodystrophy
National Organization for Rare Disorders. Rare Disease Database: X-linked adrenoleukodystrophy. Updated 2019; accessed May 2020.