Adrenoleukodystrophy, X-Linked

Adrenoleukodystrophy, X-linked; X-ALD (includes Adrenomyeloneuropathy and Addison Disease only phenotypes)
	Gene:	ABCD1; chrXq28

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. Information on females with ABCD1 mutations.
	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; automatically reflexed to MLPA for deletion detection if needed
	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 99% for MLPA probes analyzed.
	Sample Requirements:	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 on a blood 83891 x 1; 83898 x 10; 83904 x 20; 83909 x 20; 83912 x 1 MLPA: $541for routine testing on blood 83896 x 5; 83900 x 1; 83909 x 1; 83914 x 1; 83912 x 1 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 very rare for female carriers to exhibit adrenal insufficiency. Women may present with progressive paraparesis, incontinence, and sensory disturbances involving the lower limbs. It is not uncommon to be misdiagnosed as having multiple sclerosis. More severe or earlier onset disease is most likely due to skewed X-inactivation. 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. Female carriers may have normal or equivocal plasma VLCFA levels, so DNA testing is the most reliable means of testing available. You have the option of having the patient's result forwarded to Dr. Gerald Raymond at Kennedy Krieger Institute. This may allow de-identified association of the patient result with existing X-ALD family pedigrees, anonymous update of the ABCD1 mutation database, opportunities for inclusion in clinical research, or clinical consultation. If you would like the report and your contact information forwarded, please check the appropriate box on the requisition form.

	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.
Helpful Links
	Sample Requirements Requisition and Billing forms Clinical information in X-ALD and related disorders Link to the General Test Information page for a discussion of the uses and limitations of genetic testing Patient and Family Page for general resources on genetic testing.