Canavan Disease (Aspartoacylase Deficiency) via the ASPA Gene

Canavan disease (Aspartoacylase deficiency) is a neonatal/infantile disease characterized by macrocephaly, lack of head control, hyperextension of legs and flexion of arms, blindness and severe developmental delays usually noted by age three to five months. As children get older, hypotonia becomes severe and failure to achieve independent sitting, ambulation, or speech become apparent. Hypotonia eventually changes to spasticity. Assistance with feeding becomes necessary. Life expectancy is usually into the teens. Mild/juvenile Canavan disease is characterized by mild developmental delay that can go unrecognized. Head circumference may be normal (Matalon and Michals-Matalon 2011).

Canavan disease occurs in all ethnic groups, but has a high prevalence in individuals of Ashkenazi Jewish origin with a carrier rate of about 1 in 40. It is inherited as an autosomal recessive disorder.

The ASPA gene is the only gene with mutations known to be causative for Canavan disease. ASPA codes for the enzyme aspartoacylase, which breaks down N-acetyl-L-aspartic acid (NAA) into aspartic acid (an amino acid that is a building block of many proteins) in the brain. The cycle of production and breakdown of NAA appears to be critical for maintaining the brain's white matter, which consists of nerve fibers covered by myelin, that insulates and protects nerves. Mutations in the ASPA gene reduce or eliminate the activity of aspartoacylase, which prevents the normal breakdown of NAA. Buildup of NAA also leads to progressive destruction of existing myelin around nerve cells. Nerve fibers without this protective covering malfunction and die, damaging the brain and causing the serious signs and symptoms of Canavan disease.

More than 55 mutations in the ASPA gene are known to cause Canavan disease. Two specific mutations cause most cases of the disease in the Ashkenazi Jews; Glu285Ala or E285A and Tyr231Ter or Y231X. The Ala305Glu or A305E mutation is common in individuals who are not of Ashkenazi Jewish origin.

Molecular genetic testing by sequencing of ASPA will detect 87% of disease-causing mutations in individuals of Non-Ashkenazi Jewish origin. The founder mutations in individuals of Ashkenazi Jewish ancestry will also be detected.

This test provides full coverage of all coding exons of the ASPA gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).