GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: genedx@genedx.com
www.genedx.com
Test Information Sheet
ASPA Gene Analysis in Canavan Disease
Mendelian Inheritance in Man Numbers: 271900 –Canavan Disease; 608034- ASPA gene
Clinical features:
Canavan disease (CD) is a neurodegenerative leukodystrophy that typically presents as a neonatal/infantile (severe)
form with onset of symptoms at 2-4 months that include poor head control, macrocephaly, truncal hypotonia, and
developmental delay. Severe CD is associated with delayed motor skills and the inability for these children to sit,
stand, walk or talk. Many severe patients also have optic atrophy. Over time, spasticity develops and sleep
disturbance, seizures and feeding difficulties may be present. Spongy degeneration of the white matter is present,
with swollen astrocytes and elongated mitochondria. The life expectancy of patients with the severe form is
variable with survival reported from months to past the teen years.1 A much more rare mild/juvenile form of CD
also exists that is characterized by mild developmental delay that may go unrecognized. CD occurs in all ethnic
groups, but it is most common in the Ashkenazi Jewish population where the carrier rate has been estimated at 1 in
40 to 1 in 82.1
Inheritance pattern: Autosomal Recessive
Genetics and biochemical features:
CD is caused by mutations in the ASPA gene that encodes the aspartoacylase (ASPA) enzyme that hydrolyzes Nacetyl aspartic acid (NAA) to aspartate and acetate in oligodendrocytes. Deficient ASPA activity results in the
accumulation of NAA in the brain. Patients with severe CD are usually diagnosed by the presence of increased
levels of NAA in urine, while in patients with mild CD NAA levels in urine may only be mildly elevated;
therefore, the diagnosis of mild CD may depend upon identification of disease-causing mutations in the ASPA
gene. Measurement of ASPA enzyme activity is possible in skin fibroblasts (activity is not detectable in
leukocytes) but the reliability of this test has been questioned since enzyme activity is affected by culture
conditions.1 The ASPA gene is located on chromosome 17pter-p13 and has 6 exons.
Reasons for referral:
1. Confirmation of biochemical diagnosis
2. Diagnosis of a mild disease presentation
3. Carrier testing
4. Genetic counseling
5. Prenatal diagnosis in at risk pregnancies
Test method:
Mutation analysis of the ASPA gene is performed on genomic DNA from the submitted specimen using bidirectional sequence analysis of coding exons and corresponding intron/exon boundaries. In addition, targeted
array CGH analysis with exon-level resolution (ExonArrayDx) is performed concurrently to evaluate for a deletion
or duplication of one or more exons of this gene. A mutation/deletion is confirmed by repeat analysis using
sequencing, restriction fragment analysis, quantitative PCR or oligo-array comparative genome hybridization
(ExonArrayDx), as appropriate.
Test sensitivity:
In 23 patients with CD, sequence analysis and deletion/duplication testing of the ASPA gene identified mutations
on greater than 95% of alleles (44/46).2
Information Sheet on Canavan Disease
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Mutation spectrum:
At this time, more than 70 mutations have been identified in the ASPA gene including missense, nonsense, splicing,
small deletions/insertions and large deletions. In one study of 23 non-Ashkenazi Jewish patients from diverse
ethnic backgrounds, large deletions that would not be detected by sequence analysis were identified in over 10% of
ASPA alleles (5/46).2 Two mutations, p.Glu285Ala and p.Tyr231Stop, account for 98% of disease-causing alleles
in the Ashkenazi Jewish population, and a p.Ala305Glu mutation accounts for 20%-60% of disease-causing alleles
in non-Ashkenazi Jewish patients.3, 4 Most other mutations appear to be private or confined to small geographic
areas.2 Individuals homozygous for p.Glu285Ala, p.Tyr231Stop or p.Ala305Glu usually have a severe CD
phenotype as do individuals who are either homozygous or compound heterozygous for a large deletion.1 Mild CD
has been associated with the presence of at least one “mild” mutation: p.Tyr288Cys, p.Arg71His or p.Pro257Arg.1
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 1-5 mL whole blood in EDTA (1-2mL for infants). Ship overnight at ambient
temperature, using a cool pack in hot weather. Specimens may be refrigerated for one week prior to shipping.
 Buccal Brushes: CANNOT be accepted for this test.
 Prenatal Diagnosis: For prenatal testing for a known mutation in the ASPA gene, please refer to the specimen
requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship specimen overnight
at ambient temperature, using a cool pack in hot weather.
Required Forms:
Sample Submission (Requisition) Form – complete all pages
Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the “Canavan Disease” page on
our website: www.genedx.com
References: 1. Matalon, R. and Michals-Matalon, K. (Updated [August 11, 2011]) Canavan Disease. In: GeneReviews
at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington,
Seattle. 1997-2011. Available at http://www.genetests.org. 2. Zeng et al., (2006) Molec Genet Metab 89 :156-163.
3. Kaul et al., (1994) Am J Hum Genet 55 :34-41. 4. Zeng et al., (2002) J Inherit Metab Dis 25 :557-570.
Information Sheet on Canavan Disease
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