The signs of Canavan disease usually appear when the children are between 3 and 6 months of age. They include developmental delay (significant motor slowness), enlargement of the head (macrocephaly), loss of muscle tone (hypotonia), poor head control, and severe feeding problems. As the disease progresses, convulsions (seizures), shrinkage of the nerve to the eye (optic atrophy) and often blondness, heartburn (gastrointestinal reflux) and deterioration of swallowing develop.
Canavan disease is caused by a deficiency of the enzyme aspartoacylase. This leads to increased excretion of a substance (its substrate) called N-acetylaspartic acid (NAA) in the urine. The diagnosis of Canavan disease is made by finding an increased level of urinary NAA (by organic acid analysis).
As in Tay-Sachs disease (another severe progressive genetic disorder of the CNS), Canavan disease is inherited as an autosomal recessive condition. Both parents silently carry a single Canavan gene and each of their children runs a 1 in 4 risk of receiving both of their Canavan genes and, therefore, having this dread disease.
As in Tay-Sachs disease, Canavan disease is more prevalent among individuals of Eastern European Jewish (Ashkenazi) background. It is estimated that the carrier frequency in the Ashkenazi Jewish population is approximately 1 per 40. Thus, the risk from an affected offspring in this population approximates 1 in 6,400 births.
Unlike Tay-Sachs disease, however, there do not appear to be any other high-risk ethnic populations, although Canavan disease has been reported occasionally in individuals of non-Ashkenazi Jewish background.
Molecular genetic (DNA) studies have revealed two specific mutations (changes) in the gene for aspartoacylase on chromosome 17. These two mutations account for approximately 97% of the mutations causing Canavan disease in the Ashkenazi Jewish population. (One is a mutation in codon 285 of the aspartoacylase gene, and the other is a mutation in codon 231.)
Genetic screening of Ashkenazi Jewish individuals for Canavan disease carriers can be done by checking for these two mutations. Screening for Canavan disease carriers requires molecular diagnostic methods. Simple enzyme tests, as commonly used in Tay-Sachs screening, cannot be used for Canavan disease because the activity of the deficient enzyme, aspartoacylase, is not detectable in blood. Testing for the most common Canavan disease mutations -- there are actually three of them -- will identify about 97% of Ashkenazi Jewish carriers (and 40-50% of the non-Jewish carriers).
When both parents are carriers of Canavan disease mutations, prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis can be done by DNA testing. (In couples where one or both members have unknown mutations, biochemical analysis of NAA levels in the amniotic fluid can be used reliably. Elevated NAA levels can be used to detect an affected fetus.)
The Committee on Genetics of the American College of Obstetricians and Gynecologists (ACOG) has recommended that Ashkenazi Jews be offered screening to determine if they are carriers of Canavan disease. Because ACOG recommendations tend to set the standards of practice in obstetrics and gynecology, it seems highly likely that Ashkenazi Jews in the U.S. will be routinely offered carrier screening for Canavan disease in regard to pregnancy planning.
Alternative names for this disease include Canavan-Van Bogaert-Bertrand disease, and several names of a biochemical nature (aspartoacylase deficiency, ASPA deficiency, ASP deficiency, aminoacylase 2 deficiency, and ACY2 deficiency).