X-linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a rare X-linked metabolic disorder. Early diagnosis is critical because allogeneic transplant has the potential to halt disease progression, but is only effective if administered prior to the onset of neurological symptoms.

  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References

Indications for Testing

  • Infants with an abnormal newborn screening test for X-linked adrenoleukodystrophy (X-ALD)
    • Consider very long-chain fatty acids (VLCFA) profile
  • At-risk family members of an affected individual
    • Consider molecular testing and/or VLCFA profile
  • Males presenting with cognitive and neurological symptoms with white matter lesions on brain MRI
    • Consider VLCFA profile
  • Males with adrenal insufficiency and normal 21-hydroxylase antibody testing
    • Consider VLCFA profile

Laboratory Testing

  • Diagnostic testing
    • VLCFA and branched-chain fatty acids (BCFA) profile
      • First-line test for an individual with suspected X-ALD or adrenomyeloneuropathy
      • Elevated VLCFA in males is significant
      • 85% of heterozygous female carriers will have elevated VLCFA
    • Molecular testing (ABCD1)
      • Recommended for diagnostic confirmation in individuals with clinical and/or biochemical presentation of X-ALD
  • Additional testing
    • 21-hydroxylase antibody testing
      • May confirm or exclude autoimmune etiology
      • Results will be normal in X-ALD
        • Males with adrenal insufficiency and normal 21-hydroxylase antibody testing should be tested for X-ALD with VLCFA profile

Imaging Studies

  • Brain MRI – will show demyelination in cerebral white matter

Differential Diagnosis

  • Screening for X-ALD was added to the Health and Human Services' Recommended Uniform Screening Panel (RUSP) for infants in 2016; however, this recommendation has not been universally adopted in the U.S.

Epidemiology

  • Incidence – ~1/20,000
  • Most common peroxisomal disorder

Genetics

  • ABCD1 gene (contains 10 exons)
  • X-linked inheritance  
  • Neurological symptoms are present in nearly 100% of males by adulthood
  • Most variants specific to a particular family (“private variants”)
    • ~7% of individuals with X-ALD have a de novo variant

Pathophysiology

  • X-ALD is caused by variants in the ABCD1 gene which causes a deficiency in adrenoleukodystrophy protein (ALDP), a peroxisomal ATP-binding cassette subfamily D member (ABCD1) transporter protein
  • ALDP assists in creating a passage into peroxisomes for very long-chain fatty acids (VLCFA), where they subsequently undergo beta-oxidation to medium-chain fatty acids
  • In the presence of this defect, VLCFA accumulate in cells
  • 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

Clinical Presentation

  • Multiple forms of X-ALD exist with different phenotypes and presentation (even within families)
    • Cerebral form
      • Presents in childhood (typically 4-8 years)
      • Most common symptoms
        • Ataxia
        • Hearing loss
        • Hyperactivity
        • Loss of ability to speak or swallow
        • Paralysis
        • Seizures
        • Spasticity
        • Visual impairment
      • Neurological disturbances progress rapidly, ending with death
      • Primary adrenocortical insufficiency may precede neurological symptoms
    • Adrenomyeloneuropathy form
      • Presents between 20-30 years of age
      • Symptoms
        • Progressive spastic paraparesis – often in combination with impaired adrenocortical function
        • Neurological disturbances occur over decades
    •  “Addison disease only” form
      • Presents between childhood and adulthood
      • Symptoms
        • Adrenal insufficiency due to adrenocortical impairment
    • Female carriers of a pathogenic variant
      • Can present with progressive spastic paraparesis
      • 18% under age 40 and 88% by age 60 develop neurological symptoms
      • Adrenal function tends to be normal
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

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

Adrenoleukodystrophy, X-Linked (ABCD1) Sequencing and Deletion/Duplication 2011906
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

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

Not evaluated

  • Variants in genes other than ABCD1
  • Regulatory region variants
  • Deep intronic variants

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

Limitations 

Diagnostic errors can occur due to rare sequence variations

Not evaluated

  • Variants in genes other than ABCD1
  • Regulatory region variants
  • Deep intronic variants

Sequencing will not detect deletions and duplications; however, ABCD1 Deletion/Duplication testing is available upon request

Please contact an ARUP Genetic Counselor for assistance

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

General References

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

Cappa M, Bizzarri C, Vollono C, Petroni A, Banni S. Adrenoleukodystrophy Endocr Dev. 2011; 20: 149-60. PubMed

Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta. 2012; 1822(9): 1465-74. PubMed

Koike R, Onodera O, Tabe H, Kaneko K, Miyatake T, Iwasaki S, Nakano M, Shizuma N, Ikeguchi K, Nishizawa M. Partial deletions of putative adrenoleukodystrophy (ALD) gene in Japanese ALD patients. Hum Mutat. 1995; 6(3): 263-7. PubMed

Kok F, Neumann S, Sarde CO, Zheng S, Wu KH, Wei HM, Bergin J, Watkins PA, Gould S, Sack G. Mutational analysis of patients with X-linked adrenoleukodystrophy. Hum Mutat. 1995; 6(2): 104-15. PubMed

Matsukawa T, Asheuer M, Takahashi Y, Goto J, Suzuki Y, Shimozawa N, Takano H, Onodera O, Nishizawa M, Aubourg P, Tsuji S. Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes. Neurogenetics. 2011; 12(1): 41-50. PubMed

SJ S, AB M, al. e. X-Linked Adrenoleukodystrophy. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2016. Seattle, WA [Updated: Apr 2015; Accessed: Jan 2017]

Takano H, Koike R, Onodera O, Sasaki R, Tsuji S. Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy. Arch Neurol. 1999; 56(3): 295-300. PubMed

Wang Y, Busin R, Reeves C, Bezman L, Raymond G, Toomer CJ, Watkins PA, Snowden A, Moser A, Naidu S, Bibat G, Hewson S, Tam K, Clarke JT, Charnas L, Stetten G, Karczeski B, Cutting G, Steinberg S. X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol Genet Metab. 2011; 104(1-2): 160-6. PubMed

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

Medical Reviewers

Content Reviewed: 
April 2017

Last Update: October 2017