X-Linked Adrenoleukodystrophy Testing

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