Canavan Disease

From Bioinformatikpedia

<figure id="ASPA">

Crystal structure of aspartoacylase (2O4H - PDB-file).

</figure> Canavan Disease (ICD-10 E75.2) is an autosomal recessive disorder, in which a dysfunctional enzyme causes severe brain damage. It is also known under a variety of other names describing the chemical basis or phenotype of the disease. Examples are "Spongy Degeneration Of Central Nervous System", "Aspartoacylase (ASPA) Deficiency", or "Aminoacylase 2 (ACY2) Deficiency"[1]. The trivial name, Canavan Disease, originates from the name of Myrtelle Canavan (1879 – 1953)[2], an American physician, who first described the disease in 1931. There is no cure and almost all patients die within the first decade of their life. The mild / juvenile type is less severe. The treatment is based on the symptoms and is supportive.


Canavan Disease is an autosomal recessive genetic defect of the ASPA (aspartoacyclase) gene on chromosome 17 (for the crystal structure of the ASPA protein see <xr id="ASPA">Figure</xr>). With this pattern of heritage a newborn of a couple where both parents are carriers of the defective genome has a 25% chance neither being born suffering from Canavan Disease nor being born a carrier. For some time children born of Ashkenazi Jewish ancestry had a higher prevalence of having Canavan Disease while in the last years this prevalence is sinking due to ongoing prenatal screening programs. Other ethnic groups where Canavan Disease has a higher penetrance are for example populations of Saudi Arabian ancestry.
According to Genetics Home about one in 6400 to 13500 of the Ashkenazi Jewish are affected. No further information about prevalences in other populations was found. However the different populations have also different frequencies regarding the mutation they are based on. For further information see section Disease Causing Mutations.


Canavan Disease has a variety of different phenotypes ranging across all body parts. Here is a short overview:

  • Head
    • macrocephaly (increased head circumference)
    • mental retardation and impairment (losing mental skills)
    • losing ability to move head
  • Eyes
    • becoming blind
    • nystagmus (greek: νυσταζω nytaxoo "sleep, nod", german: "Augenzittern")
  • Ears
    • becoming deaf
  • Mouth
    • problems with swallowing
    • losing communicational abilities (cannot talk, stay quiet)
  • Body
    • paralysis
    • seizures
    • problems moving the muscles

Children suffering from Canavan Disease usually die within the first decade. In the mild/juvenile form of Canavan Disease, the children usually have some developmental delay and some speech problems.

Disease Mechanism

<figure id="KEGG">

Alanine, Aspartate and Glutamate Metabolism (source: KEGG) highlighting disease associated enzymes of Canavan Disease.

</figure> Canavan Disease belongs to the group of leukodystrophies. The etymological origin are the greek words: λευκος leukos "white", δυς dys "bad, wrong" and τροφη trophae "feeding, growth". This is a genetic induced metabolic disorder, which affects the white matter of the nervous system. If the white matter is not properly grown, the myelin, which surrounds the nerve cells for protection, is degraded. This is especially true for Canavan Disease. The visible phenotypes are a result of a genetic defect that negatively affects the growth of the myelin sheath covering the nerve fibers. An improperly build myelin sheath, results in a reduced ability to transmit the electric signal along the nerve fibers, eventually losing it completely and finally the degradation of whole nerve cells.
The cause for the malfunctioning myelin sheath growth is a genetic defect of the aspartoacylase (ASPA) gene. The product of the gene, the enzyme aspartoacylase is crucial in the degradation process of N-acetyl-L-aspartate (NAA) which is present at much higher levels than normal in patients suffering from Canavan Disease. Normally ASPA would degrade NAA into smaller fragments which are required prerequisites for the production of the myelin sheath (see <xr id="KEGG">Figure</xr> for an overview where APSA is located in the metabolic map). Therefore the missing / defective ASPA is reason for the defective build up process of myelin. The degradation of the nerve cells / white brain matter has the consequence that empty spaces are arising which are filled with brain fluid leading to even more degradation of nerve cells and signal transduction problems.


There are a couple of possibilities how and when an affected patient is diagnosed with Canavan Disease. The time points are prenatal, postnatal, and when a mild or juvenile form of Canavan Disease is already present. Nevertheless one of the most important things to know before is if both parents carry one copy of the disease causing gene. This can simply be done by DNA testing.

Prenatal Diagnosis

There are several types of prenatal testing possibilities depending on whether the carrier status of both parents is known or not. For couples where it is only known that one of the parents is a carrier and the remaining parents status is not known, normally testing is done by measuring the concentration of N-acetyl-L-aspartic acid (NAA) in the amniotic fluid within the time between the 16th and 18th week of pregnancy. Another possibility is molecular genetic testing. Following this method an analysis of DNA extracted from fetal cells is done. These fetal cells are obtained either between the tenth to 12th week of pregnancy by chorionic villus (“proto-”placental tissue that has the same genetic material as the fetus) sampling or between the 15th and 18th week by amniocentesis, also known as amniotic fluid testing (AFT). However for the molecular genetic testing both disease causing genes of the parents have to be identified first.

Neonatal / Infantile Diagnosis

Postnatal testing for Canavan Disease can be done in several ways. One possibility is to test for a raised N-acetyl-L-aspartic acid (NAA) concentration in urine, blood and cerebrospinal fluid (CSF) (comparable to prenatal testing with the carrier status of one parent unknown). Other possibilities may be cultivating skin fibroblasts and test them for reduced aspartoacylase activity, perform neuroimaging of the brain and look for spongy degeneration, or test the gene itself for a defect in the newborn child. However it takes between three to nine months after birth until most of the symptoms become apparent.

Mild / Juvenile Diagnosis

Diagnosing a patient with Canavan Disease if he or she is suffering from a mild or juvenile form, is a bit more challenging, as the postnatal diagnosis methods, except testing the gene itself, will not yield in a satisfactory result or may even overlook the disease completely. The concentration of NAA may be elevated only slightly and not as significant such that a proper diagnosis can be made. The same being true for the results of neuroimaging, and the mild developmental delay that is a result of Canavan Disease which can simply be unrecognized.


Right now there is no cure for Canavan Disease, but there are treatments depending on the symptoms, which work in a supportive manner.

Prenatal Treatment

There is a possibility of prenatal screening to check whether or not someone is a carrier of the disease (as described in the section before). Other prenatal treatments are under investigation and depend on animal models.

Neonatal / Infantile Treatment

Since Canavan Disease also affects the metabolism there is need to control the nutrition and hydration. This includes specialized food to compensate missing metabolites and nutrients as well as different ways of feeding / providing nutrition to the child to prevent problems arising from swallowing difficulties and other physical disabilities. To improve those physical disabilities and muscle problems, it is recommended that children need physical therapy. Additionally there are anti-epileptic drugs against seizures and spastic behavior.

Mild / Juvenile Treatment

Since mild and juvenile Canavan patients only have some delays in the development and speech, a speech therapy may be useful. Further deep medical care is not necessary.

Future Work

There are some clinical trials and animal models under investigation to find a cure for Canavan Disease.

Gene Therapy

There were several studies in the gene therapy, using viral and non viral vectors to transfer genes into the patients that were thought to improve the course of the disease. However none of the children showed an improvement and the disease showed a development similar to an untreated patient.

Lithium Citrate as Pharmaceutical

Since N-acetyl-L-aspartate (NAA) is one important factor in the biochemical background of Canavan Disease, where the NAA level is too high, lithium citrate may be able to reduce the NAA concentration. Rat models have shown that treating a rat with lithium citrate resulted in a reduced level of NAA. Furthermore if the drug is administered to a human the same effect can be observed with a return to elevated NAA concentration when the lithium citrated is washed out of the body after roughly 2 weeks. However so far no larger controlled clinical studies have been conducted, but lithium citrate shows a potential treatment that is worth pursuing.

Animal Models

Several gene models in knockout mice and rats have been studied, with lithium citrate and an enzyme replacement therapy showing the best result so far and therefore being the most promising at the moment.

Aspartoacylase (ASPA)

<figure id="AspaKegg">

The hydrolyzation of N-acetyl-L-aspartate (C01042) catalyzed by aspartoacylase to acetyl (C00033) and aspartate (C00049). (source: KEGG)



Aspartoacylase is the enzyme that hydrolyzes N-acetyl-L-aspartate into acetate and L-aspartate, which are essential for the build-up process of the myelin sheath (chemical reaction displayed in <xr id="AspaKegg">Figure</xr>). Crystallized ASPA exists as a homodimer however it is assumed that the in-vivo form only works as a monomer. The active site of ASPA contains a zinc ion which acts catalytic in the hydrolyzation process and is only accessible through a channel like surface fold of the protein. This channel like structure serves two purposes. On the one hand it hinders polypeptides to enter and bind at the active site, therefore ASPA does not function as protease. On the other hand and more importantly it is assumed, that the positive electrostatic potential that is present on the channel serves as a form of transport mechanism to properly carry the negatively charged substrate (NAA) to the hydrolyzing site. Furthermore, the binding pocket is highly specific to N-acetyl-L-aspartate with a far lower hydrolyzing activity towards other N-acetyl-amino complexes like N-acetylglutamate.

Gene Position and Mutations

The ASPA gene is located on chromosome 17 on the p-arm (upper part, short arm) band 1 subband 3 subsubband 2 (short 17p13.2) (see <xr id="Location">Figure</xr>). <figure id="Location">

Chromosome 17 with highlighted position of ASPA-gene. (source: Genecards)


Reference Sequence
Disease Causing Mutations

The disease causing mutations can be found in <xr id="DisCausMut">Table</xr> and <xr id="AllelicVar">Table</xr> below. Very interesting in this Table is the frequency of some mutations across different populations. <figtable id="DisCausMut">

Summary of Molecular Genetic Testing Used in Canavan Disease
Gene Symbol Test Method Mutations Detected Mutation Detection Frequency by Test Method Test Availability
Ashkenazi Jewish Non-Ashkenazi Jewish
ASPA Targeted mutation analysis Panel p.Glu282Ala, p.Tyr231X 98% 3% Clinical Testing
p.Ala305Glu 1% 30%-60%
Sequence analysis Sequence variants N/A 87%
Deletion / duplication analysis Large genomic deletions/duplications
comprising one or more exons
N/A Unknown (<10%)
Disease causing Mutations in Canavan Disease. (source: NCBI)


<figtable id="AllelicVar">

Selected ASPA Pathologic Allelic Variants
DNA Nucleotide Change Protein Amino Acid Change Reference Sequence
c.433-2A>G - NM_000049.2
c.693C>A p.Tyr231X
c.854A>C p.Glu285Ala
c.863A>G p.Tyr288Cys
c.914C>A p.Ala305Glu
Disease causing Mutations in Canavan Disease. (source: NCBI)



The written text is based on a summary of different sources:
Canavan Disease: