Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)
- Biochemical test to measure concentration of very long-chain fatty acids (VLCFAs) C22-C26, pristanic acid, and phytanic acid
- Initial test to screen for disorders of peroxisomal biogenesis and/or function, including X-ALD and Zellweger syndrome
- Confirmatory test for abnormal newborn screening suggestive of X-ALD
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
- Preferred molecular test to:
- Confirm diagnosis of X-ALD following abnormal results from VLCFA profile test
- Determine carrier status in females when familial variant is unknown
- Detects 99% of pathogenic variants
X-linked adrenoleukodystrophy (X-ALD) is a rare X-linked metabolic disorder caused by variants in the ABCD1 gene that cause a deficiency in adrenoleukodystrophy protein (ALDP) and subsequent accumulation of very long-chain fatty acids (VLCFAs). VLCFA accumulation occurs in plasma and all tissue types, but primarily affects the adrenal cortex and white matter of the brain and spinal cord, resulting in a range of clinical outcomes.
Adrenal insufficiency may be the initial presentation of X-ALD, and 21-hydroxylase antibody testing may confirm or exclude an autoimmune etiology. In X-ALD, 21-hydroxylase antibody testing results will be normal; therefore, males with adrenal insufficiency and normal 21-hydroxylase antibody testing should be tested for X-ALD (VLCFA profile).
- VLCFA and branched-chain fatty acid (BCFA) profile is the first-line test for an individual with suspected X-ALD or adrenomyeloneuropathy
- Molecular testing (ABCD1) is recommended for diagnostic confirmation in individuals with clinical and/or biochemical presentation of X-ALD
Neurologic symptoms are present in nearly 100% of males by adulthood.
- Most are specific to a particular family (“private variants”)
- ~4-19% of individuals with X-ALD have a de novo variant
For more information on the disease including testing strategy, disease overview, and genetics, visit the X-Linked Adrenoleukodystrophy topic in ARUP Consult.
Biochemical testing (VLCFAs and BCFAs)
Molecular testing (ABCD1)
- Clinical sensitivity
- Analytical sensitivity/specificity: 99%
- Pathogenic variant detected
- Confirms X-ALD in males and carrier status in females
- No variant detected
- X-ALD is less likely but not excluded
- Inconclusive: variants of unknown clinical significance may be identified
- Exons 7-10 are not evaluated by deletion/duplication analysis due to the presence of pseudogenes
- Breakpoints of large deletions/duplications will not be determined
- Diagnostic errors can occur due to rare sequence variations
- Variants in genes other than ABCD1, regulatory region variants, and deep intronic variants are not evaluated
Huffnagel IC, Dijkgraaf MGW, Janssens GE, et al. Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis. 2019;14(1):30.
Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta. 2012;1822(9):1465-1474.
Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet. 2015;8:109-121.
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.