• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The ABCD1 gene is associated with X-linked adrenoleukodystrophy (X-ALD) (MedGen UID: 57667).

The ABCD1 gene encodes a protein that is a member of the ATP-binding cassette transporter superfamily. The ABCD1 protein is a component of a peroxisomal transporter and plays a role in the catabolism of very long chain fatty acids.

OMIM: 300371

Clinical condition
ABCD1 is the gene associated with X-linked adrenoleukodystrophy (X-ALD) and adrenomyeloneuropathy (AMN; OMIM 300100). Mutations in the ABCD1 gene prevent the breakdown of very long-chain fatty acids (VLCFAs) and lead to their accumulation in the cells of the body.

X-ALD is the most common peroxisomal disorder and is characterized by a spectrum of cognitive, movement, and hormonal disorders (National Library of Medicine. Genetics Home Reference: X-linked adrenoleukodystrophy. https://ghr.nlm.nih.gov/condition/x-linked-adrenoleukodystrophy. Accessed August 2017). The build-up of VLCFAs mainly affects the adrenal glands leading to adrenal insufficiency as well as destruction of the nerve myelin sheaths leading to demyelination. The clinical presentation is extremely variable and may vary even within the same family (Saudubray J-M, et al.; PMID: 28601575). Females in families with X-ALD can be asymptomatic or very mildly affected, and thus genetic testing before pregnancy is recommended for carrier detection and accurate genetic counseling (PMID: 28601575).

The three main phenotypes seen in affected males include:

  • Childhood cerebral form presenting between 4 and 8 years of age
  • AMN presenting in the late 20s
  • Adrenal insufficiency (Addison’s disease), which can present between the ages of 2 years and adulthood but typically manifests by 7.5 years of age (PMID: 20301491)

The adrenocortical insufficiency can precede the neurologic symptoms by many years in some affected males (PMID: 22889154).

The childhood cerebral form is the most severe form, affecting 40% of patients with X-ALD (Saudubray J-M, et al.). Affected males present with attention deficit disorder, hyperactivity, and behavioral changes, followed by severe visual and hearing impairment, cerebellar ataxia, and quadriplegia. Early symptoms often include a decline in school performance and a misdiagnosis of attention deficit disorder (PMID: 22889154). Seizures are also not uncommon (Saudubray J-M, et al.).

The progressive neurodegenerative symptoms lead to a vegetative state and death within a few years (Saudubray J-M, et al.). The rate of progression may be rapid in some affected individuals and is attributed to a severe neuroinflammatory process (PMID: 22889154; National Library of Medicine. Genetics Home Reference: X-linked adrenoleukodystrophy. https://ghr.nlm.nih.gov/condition/x-linked-adrenoleukodystrophy. Accessed August 2017). Presentation in adolescence and adulthood is less common, with a more slowly progressive course and psychiatric manifestations (PMID: 22889154). Approximately 90% of young males with neurologic symptoms have adrenal insufficiency (PMID: 20301491).

The AMN form presents as a progressive paraparesis with bowel and bladder incontinence and sexual dysfunction. Approximately 70% of adult men with AMN have adrenal insufficiency (PMID: 20301491). About 50% of females develop AMN with milder manifestations and later age of onset than affected males (Moser HW, et al.), with the majority developing symptoms in their 40s and 50s (PMID: 22889154). Symptoms in females with AMN include sensory ataxia, fecal incontinence, and leg pain, while cerebral involvement is rare (PMID: 22889154).

The adrenocortical insufficiency or an Addisonian crisis may be the presenting symptom in males preceding the neurologic manifestations. It has been suggested that males with Addison’s disease get tested for X-ALD as well as alert family members that they are at risk for X-ALD and need genetic counseling and ABCD1 genetic testing.

As of February 2016, the Advisory Committee on Heritable Disorders in Newborns and Children has recommended that X-ALD be added to the Recommended Uniform Screening Panel (RUSP). Early diagnosis leading to timely treatment has been shown to improve the neurodevelopmental course of the disorder. However, the inclusion of X-ALD on the RUSP has been controversial due to the fact that the available treatments for this disorder are limited (see the management section below). Also, genetic counseling following a positive newborn screening result for X-ALD can be complicated due to the variability of the condition. It is currently impossible to predict the clinical course for pathogenic variants found in ABCD1, which can lead to a tremendous level of anxiety for the affected families.

Differential diagnosis
For the cerebral childhood form, other types of leukodystrophy, such as Krabbe disease and metachromatic leukodystrophy, may be considered. Juvenile neuronal ceroid lipofuscinosis may also present with similar psychological and personality changes (PMID: 20301491).
Patients with the AMN form resemble those with progressive multiple sclerosis, progressive hereditary spastic paraplegia, and adult onset ataxia (PMID: 20301491, PMC5421786). Some infections and environmental causes of chronic myeloneuropathy have features similar to AMN.
Addison’s disease can be an isolated entity, but affected males should be tested for X-ALD. Presentation of Addison’s disease in females with X-ALD is rare (PMID: 20301491).

Gene information
The ABCD1 (adenosine triphosphate-binding cassette D1) gene produces the adrenoleukodystrophy protein (ADLP), which is located in the membrane of the peroxisomes and transports VLCFAs into the peroxisomes where they undergo beta-oxidation. Mutations in ABCD1 prevent the breakdown of VLCFA leading to their accumulation, which is toxic to the adrenal glands and the myelin of the neural sheaths (National Library of Medicine. Genetics Home Reference: X-linked adrenoleukodystrophy. https://ghr.nlm.nih.gov/condition/x-linked-adrenoleukodystrophy. Accessed August 2017)).

ABCD1 shows X-linked recessive inheritance.

Treatment with corticosteroid replacement is essential for affected males with adrenal insufficiency (PMID: 20301491). Early detection is important in X-ALD both for the hormone treatment and also for the consideration of hematopoietic stem cell transplantation (HSCT). Due to these factors, a recommendation has been made to add screening of X-ALD to the uniform screening panel for state newborn screening programs (PMID: 25724074, 27337030). HSCT has been used in males with very early symptoms and in some asymptomatic individuals to improve neurodevelopmental outcome (PMID: 28274546, 28418523). MRI surveillance of affected males is recommended for detection of early cerebral disease (PMID:20301491). For many years, Lorenzo’s oil has been shown to lower plasma concentrations of hexacosanoic fatty acid (C26:0) in X-ALD patients, but its clinical effectiveness remains controversial (PMID: 17901554, 26836218).

Yearly endocrinologic evaluation is recommended for males who do not have Addison’s disease (PMID: 22889154). For males without neurologic deficits, close MRI surveillance may reveal abnormalities before clinical symptoms are noted (PMID: 22889154). HSCT could be undertaken as early as possible after MRI changes are noted. The efficacy of HSCT in affected adult males and the increased mortality risk associated with the procedure complicate the assessment of its usefulness.
Supportive care for affected boys includes physical therapy and psychological and educational evaluations and strategies (PMID: 20301491). Individuals with AMN need close monitoring, so supportive care can be initiated in a timely manner (PMID: 22889154).

Additional References

  • National Library of Medicine. Genetics Home Reference: X-linked adrenoleukodystrophy. https://ghr.nlm.nih.gov/condition/x-linked-adrenoleukodystrophy. Accessed August 2017.
  • Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. X-linked adrenoleukodystrophy. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chapter 131. New York, NY: McGraw-Hill. 2015.
  • Saudubray J-M, et al., eds. Inborn Metabolic Diseases Diagnosis and Treatment. 6th ed. Berlin, Germany: Springer; 2016.

Review date: August 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ABCD1 NM_000033.3