X-Linked Adrenoleukodystrophy Testing

See Testing Strategy

Very Long-Chain and Branched-Chain Fatty Acids Profile 2004250
Method: Liquid Chromatography-Tandem Mass Spectrometry

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

Adrenoleukodystrophy, X-Linked (ABCD1) Sequencing and Deletion/Duplication 2011906
Method: 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

Detect most pathogenic variants

Adrenoleukodystrophy, X- Linked (ABCD1) Sequencing 2011902
Method: Polymerase Chain Reaction/Sequencing

Useful molecular test to confirm diagnosis or carrier status for X-ALD

Detects most pathogenic variants

Sequencing does not detect deletions and duplications

Related Test
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing is known

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).

Testing Strategy

Diagnostic Testing

  • 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

Disease Overview

Incidence

1/14,700 live births 

Genetics

Gene

ABCD1

Structure

ABCD1 gene, contains 10 exons 

Inheritance

X-linked

Penetrance

Neurologic symptoms are present in nearly 100% of males by adulthood.

Variants

  • 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®.

Test Interpretation

Biochemical testing (VLCFAs and BCFAs)

  • Elevated VLCFAs in males
  • ~85% of heterozygous female carriers will have elevated VLCFAs 

Molecular testing (ABCD1)

Sensitivity/Specificity

  • Clinical sensitivity
    • Sequencing of ABCD1: ~97% 
    • Deletion/duplication of ABCD1: ~3% 
  • Analytical sensitivity/specificity: 99%

Results

  • Positive
    • Pathogenic variant detected
    • Confirms X-ALD in males and carrier status in females
  • Negative
    • No variant detected
    • X-ALD is less likely but not excluded
  • Inconclusive: variants of unknown clinical significance may be identified

Limitations

  • 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
References 
  1. Huffnagel IC, Dijkgraaf MG, Janssens GE, van Weeghel M, van Geel BM, Poll-The BT, Kemp S, Engelen M. Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis. 2019; 14(1): 30. PubMed
  2. Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta. 2012; 1822(9): 1465-74. PubMed
  3. Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis. Appl Clin Genet. 2015; 8: 109-21. PubMed
  4. Raymond G, Moser A, Fatemi A. X-Linked Adrenoleukodystrophy. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Updated: Feb 2018; Accessed: May 2019]
  5. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad H, Stratakis CA, Torpy DJ. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101(2): 364-89. PubMed
Related Information 
X-Linked Adrenoleukodystrophy

Last Update: June 2019