Canavan Disease 2012

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When spring unfolds the beechen leaf, and sap is in the bough

when light is on the wild-wood stream, and wind is on the brow

when stride is long, and breath is deep, and keen the mountain air

come back to me! Come back to me! And say my land is fair.



The Canavan Disease is a rare genetic, degenerate disorder of the brain. It is always fatal, with patients dying after weeks or the first decades of their life, depending on the type of Canavan disease. Other names or descriptions include spongy degeneration of the brain or Aspartoacylase deficiency.

It is named after Myrtelle Canavan, who described the Disease for the first time in 1931. (

Up to now, there is no final cure for Canavan Disease and treatment mainly focuses on managing the symptoms.


Canavan disease is officially classified as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). In this classification rare diseases mean to affect less than 200,000 people in the US population.(

Yet Canavan disease appears more often in certain ethnic groups of eastern and central European Jewish descent. Out of these Jewish communities, the Ashkenazi Jews form the largest community. Today they account for approximately up to 80 percent of Jews worldwide.

  • Carrier Frequency:2% of the Ashkenazi are carriers of Canavan disease, which means that 1 out of 40 persons carriers a mutated allele.
  • Disease Frequency: Studies suggest that 1 per 6,400 - 13,500 people of the Ashkenazi Jewish community in the US suffer from Canavan disease and

Statistics for non-Ashkenazi groups are unknown.

Phenotype: Signs and symptoms

Typical symptoms that occur in Canavan patients after the first weeks of life include:

  • macrocephaly (abnormally large head)
  • limited motoric abilities that decrease as the disease progresses. These include:
    • not being able to crawl, sit, walk, or talk
    • weak neck muscles that cause poor head control
    • hypotonia in general
  • mental retardation
  • abnormal muscle tone (e.g., stiffness or floppiness)

These symptoms may be followed by:

  • seizures
  • hypotonia leading to paralysis
  • blindness
  • deafness

Classification and Types

Canavan Disease belongs to a group of disorders called Leukodystrophies. Leukodystrophies are metabolic disorders that are characterized by dysfunction of the white brain matter. With respect to Canavan disease, the dysfunction of white matter expresses as a spongy degeneration and a swelling of glial cells.

White Matter

The central nervous system an be divided into two components:

  • white matter
  • grey matter

The white matter is formed by glial cells and myelinated axons whereat myelin itself makes up the majority of the white matter. Myelin is produced by glial cells and is composed of water, lipids and proteins. It forms layers called myelin sheaths around axons and functions as a dialectric material for speeding up signal transduction.

In contrast, grey matter includes neuronal cell bodies and unmyelinated axons. As you can see in figure (File:WhiteMatter.jpg) white and grey matter can easily be distuinguished in brains conserved in formaldehyde


There are three types of Canavan disease, that correlate to severity:

  • Neonatal(severe): Onset is at birth and children die only within few weeks of life.
  • Infantile(severe): Onset of the disease is at a few months of life. Life expectancy ranges from some years into teen-age depending on medical care and clinical course of the disease. This is the most common type of Canavan. The children may appear normal in early life but developmental delays become more obvious over time.
  • Juvenile(mild): Onset after the age of five and patients might survive until adolescence. These children usually have only a slighlty delayed speech and motoric development and often may attend regular school.


The Canavan disease belongs to the classes of single gene disorders, i.e., there is a single gene that, if mutated, causes the disease.

For the Canavan disease, the responsible gene lies on The ASPA gene is located on the short (p) arm of chromosome 17 at position 13.3. More precisely, the ASPA gene is located from base pair 3,377,403 to base pair 3,402,699 on chromosome 17. (

The Canavan Disease is inherited in an autosomal recessive pattern, i.e., if both parents are heterozygous for a mutation that causes the Canavan disease, there is a 25% chance that a child will be affected, a 50% chance that the child will be a heterozygous carrier for the disease, and a 25% chance that it is neither affected nor a carrier.

Biochemical disease mechanism

The ASPA gene codes for Aspartoacylase (EC This enzyme catalyses the breakdown of N-Acetyl-L-Aspartate (NAA) to L-Aspartate and Acetate. This reaction is a hydrolysis and thus requires a water molecule. In figure (???) you can see the reaction schema.

N-Acetyl-L-aspartate + H2O <--> Acetate + L-Aspartate

Acetate is a molecule needed for myelin formation in the glial cells. Therefore, loss-of-function-mutations in the enzyme Aspartoacylse, will result in a deficient myelin production.[1]

NAA is one of most abundant amino acid derivatives in the human brain, next to glutamate. It is known, that NAA is necessary for correct development and maintenance of white matter. Despite the function of NAA as an important distributor of acetate molecules for myelin production, its exact role in the brain remains unclear.

Furthermore the ASPA mutations lead to pleiotropic effects, resulting in a series of genomic interaction in the brain. For example, low levels of glutamate and GABA have been registered.[2]

An interesting fact is the compartimentalization of the components of the above stated reaction. NAA is synthesized from L-aspartate and Acetyl-CoA in the neuronal cells of the grey matter. In contrast, Aspartoacylase is only expressed in glial cells of the white matter. Therefore, in order for the Aspartoacylase reaction to happen, NAA needs to be transported from neuronal cells to glial cells of the white matter. (see figure ????)

Due to the decreased turnover of NAA, this compound accumulates in the brain, as well as in cerebral fluids and plasma of Canavan patients. That is why elevated amounts of NAA in the excreted urin are a further indication for the disease.


- > 50 bekannt. omim und entrez fuer (neutrale) muts

Current knowledge about mutations associated with the disease. - Separate into disease causing and neutral mutations. -- These sequence pages will be the starting point for collecting prediction results and result discussions.

Note: Until further notice you only need to care about the reference sequence pages. -- At a later stage we will assign mutations we expect you to work on. Then, it will make sense to create on page per mutation that is assigned to you.

Reference sequence

Which sequence does not cause the disease and is most often found in the population.

Neutral mutations

Disease causing mutations

Effect of mutations

siehe folien, die armen axons ohne myelin


  • prenatal: NAA, mut ana
  • postnatal: NAA, neuroimg, mut ana

NAA urine war irgendeine Chromatographie, nur kurz erwähnen oder beim echten wikipedia verlinken



Canavan Disease


[1]Aryan M.A. Namboodiri, Arun Peethambaran, Raji Mathew, Prasanth A. Sambhu, Jeremy Hershfield, John R. Moffett, Chikkathur N. Madhavarao, Canavan disease and the role of N-acetylaspartate in myelin synthesis, Molecular and Cellular Endocrinology, Volume 252, Issues 1–2, 27 June 2006, Pages 216-223

[2] Sankar Surendran, Kimberlee Michals-Matalon, Michael J Quast, Stephen K Tyring, Jingna Wei, Ed.L Ezell, Reuben Matalon, Canavan disease: a monogenic trait with complex genomic interaction, Molecular Genetics and Metabolism, Volume 80, Issues 1–2, September–October 2003, Pages 74-80