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Adrenoleukodystrophy, X-linked Test

(includes Adrenomyeloneuropathy and Addison Disease only phenotypes)
Genes:
ABCD1

Syndrome Information

Clinical Description

ABCD1 mutation may cause one of three primary phenotypes.  Copies of the patient's biochemical analysis are extremely helpful in result interpretation.  

X-ALD is a neurodegenerative disorder associated with elevated plasma very long chain fatty acids (VLCFA).  A significant proportion of boys present with adrenal insufficiency in childhood.  Early involvement of the central nervous system manifests as behavioral changes (including attention deficit hyperactivity disorder), vision and hearing impairment, or seizures.  Brain MRI yields characteristic evidence of demyelination of the parieto-occipital, most commonly, or frontal regions. This disorder can be rapidly progressive and patients may reach a vegetative state within 6 months to 2 years of onset.

Adrenomyeloneuropathy (AMN): Neurological features develop in the third or fourth decade.  AMN is principally a progressive demyelinating disease of the spinal cord, but 25-50% may eventually develop cerebral disease.  Presenting symptoms may be progressive paraparesis, incontinence, sexual dysfunction or behavioral changes.

Addison Disease: Males with primary adrenocortical insufficiency should be tested to rule out the possibility of an ABCD1 defect, as males with ABCD1 defects often present with adrenal symptoms.  For males with a known ABCD1 defect and/or elevated plasma VLCFA, measuring cortisol and ACTH levels is recommended so that adrenal insufficiency can be identified and treated prophylactically.

Inheritance Pattern

X-linked Recessive

Genotype-Phenotype Correlation

None; known intra- and inter-familial variability

Test Information

Test Method

Bidirectional sequencing of the coding regions and intron-exon boundaries of ABCD1; 
A
utomatically reflexed to MLPA for deletion/duplication detection if sequencing is negative.

Clinical Utility

Identification of causative mutations in known or highly suspicious cases of X-ALD, or AMN with elevated plasma VLCFA levels; rule-out an ABCD1 defect in the presence of equivocal clinical presentation and/or plasma VLCFA levels; targeted carrier testing of relatives of proband; predictive prenatal testing when familial mutation is  known.

Clinical Sensitivity

Sequencing will identify a mutation in 99% of males (point mutations and indirect evidence of deletions) and 93% of females (point mutations only).  Deletions directly identified by MLPA analysis account for 6% of mutations.  

Analytic Sensitivity

Sequencing:  Greater than 97% for nucleotides analyzed.  All reports will indicate if a certain percentage of nucleotides were not called or were analyzed in a single direction.  

MLPA: Greater than 95% for MLPA probes analyzed.

Sample Requirements

3-6ml whole blood in EDTA (purple topped) tubes. (see Pediatric or Adult blood sample algorithms for additional information)

We prefer whole blood for all tests. For tests utilizing MLPA, we are only able to accept whole blood drawn in EDTA (purple or lavender top) tubes and Qiagen Puregene extracted DNA.

Turn Around Time

Sequencing: 4 weeks
MLPA: 4 weeks

Fee and CPT Codes

Sequencing:  $1158 for routine testing
CPT Code: 81405

MLPA: $541 for routine testing
CPT Code: 81479

Please contact the lab to arrange testing for known mutations on blood or prenatal samples.

Special Considerations

We request that copies of the patient's biochemical analysis be submitted with the sample.

ABCD1 Mutations in Females:  Up to 50% of female carriers of ABCD1 mutations develop a milder form of AMN in the fifth to sixth decades of life.It is extremely rare for a female to develop childhood cerebral disease and so it has only been associated with defective ABCD1 genes on both X chromosomes. You have the option of having the patient's result forwarded to Dr. Ali Fatemi at Kennedy Krieger Institute.

INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.