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  • Test code: 06209
  • 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
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Invitae X-linked Adrenoleukodystrophy (X-ALD) Test

Test description

The Invitae X-linked Adrenoleukodystrophy (X-ALD) Test analyzes the ABCD1 gene. Pathogenic variants in ABCD1 lead to X-ALD, which is caused by a deficiency of adrenoleukodystrophy protein (ALDP) and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues.

This test is indicated for any individual in whom X-ALD is suspected based on clinical or laboratory findings, including positive newborn screening. Treatment may benefit some affected individuals, so early diagnosis is important.

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Primary panel (1 gene)
Add-on Peroxisomal Acyl-CoA Oxidase (ACOX1) Deficiency Gene (1 gene)

Patients with ACOX1 deficiency have the same pattern of biochemical abnormalities as patients with X-ALD such as elevated very long chain fatty acids with normal phytanic acid, pristanic acid, pipecolic acid, plasmalogens, and THCA/DHCA ratio. Given the significant biochemical overlap between X-ALD and ACOX1 deficiency, analyzing the ACOX1 gene may be appropriate. This gene can be included at no additional charge.

ACOX1

Add-on Elevated Very Long Chain Fatty Acids Genes (13 genes)

Patients with other peroxisomal disorders can have elevations of very long chain fatty acids, similar to patients with X-ALD, despite having additional biochemical abnormalities that distinguish these disorders. Given the biochemical overlap between X-ALD and other disorders that may cause elevated very long chain fatty acids, analyzing these genes may be appropriate. These genes can be included at no additional charge.

HSD17B4 PEX1 PEX10 PEX12 PEX13 PEX14 PEX16 PEX19 PEX2 PEX26 PEX3 PEX5 PEX6

  • X-linked adrenoleukodystrophy (X-ALD)
    • childhood cerebral adrenoleukodystrophy (CCALD)
    • adolescent cerebral adrenoleukodystrophy (AdolCALD)
    • adult cerebral adrenoleukodystrophy (ACALD)
    • adrenomyeloneuropathy (AMN) with cerebral disease
    • adrenomyeloneuropathy (AMN) without cerebral disease
    • addison disease (AD) only
    • X-linked adrenoleukodystrophy (X-ALD) in females

X-ALD is a peroxisomal disease characterized by a deficiency of adrenoleukodystrophy protein (ALDP) and resultant accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. Clinical phenotype of affected males varies greatly. There are three cerebral adrenoleukodystrophy (CALD) subtypes, two adrenomyeloneuropathy (AMN) subtypes, an Addison disease (AD) only subtype, and a heterozygous female presentation of X-ALD.

Childhood, adolescent, and adult CALD (CCALD, AdolCALD, and ACALD) onset at different times, but are rapidly progressive and are all characterized by behavioral and cognitive disorders, extensive white matter lesions notable on brain MRI, and often AD. CCALD often leads to total disability within 3 years of onset. With older the onset, as in AdolCALD and ACALD, it becomes more likely for affected individuals to experience myelopathy and peripheral neuropathy. AMN develops in most patients when they reach adulthood and is most commonly characterized by myelopathy, axonal sensory-motor peripheral neuropathy with paraparesis, and AD. Those with AMN and cerebral disease also show rapid progression, behavioral and cognitive disorders, and white matter lesions notable on brain MRI. When AMN manifests without cerebral disease, progression is slower and brain MRI is either normal or shows only subtle abnormalities. Those affected with AD only experience adrenocortical insufficiency and absence of other features. In many cases, individuals live with an AD only phenotype throughout much of their childhood and adult life, and then go on to develop other features of X-ALD. Most heterozygous females with pathogenic ABCD1 variants do develop features of AMN between the ages of 40 and 60 years. Features are typically slowly progressive, milder than in affected males, and are often restricted to peripheral neuropathy; myelopathy, white matter lesions on brain MRI, and AD are rare.

In 2016, the US Department of Health and Human Services added X-ALD to the list of disorders recommended to be included in state newborn screening panels. Children with CCALD benefit from early treatments (such as hematopoietic stem cell transplantation and adrenal hormone replacement therapy) and monitoring, making early diagnosis of the condition highly important.

For individuals with features of X-ALD, pathogenic sequence variants or deletion/duplication events in the ABCD1 gene are identified in 99% of individuals.

X-ALD is inherited in an X-linked recessive manner. The majority of heterozygous females experience features of the disease by the age of 60 years.

X-ALD is panethnic and its prevalence is estimated to be approximately 1 in 21000 males. The prevalence of heterozygosity for pathogenic X-ALD variants in females is estimated to be approximately 1 in 14000.

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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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
ACOX1 NM_004035.6
HSD17B4 NM_000414.3
PEX1 NM_000466.2
PEX10 NM_153818.1
PEX12 NM_000286.2
PEX13 NM_002618.3
PEX14 NM_004565.2
PEX16 NM_004813.2
PEX19 NM_002857.3
PEX2 NM_000318.2
PEX26 NM_017929.5
PEX3 NM_003630.2
PEX5 NM_001131025.1
PEX6 NM_000287.3