X-Linked Adrenoleukodystrophy Testing

  • 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
  • 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
  • Useful molecular test to confirm diagnosis or carrier status for X-ALD
  • Detects most pathogenic variants
  • Sequencing does not detect deletions and duplications
Related Tests

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