Difference between revisions of "Canavan Disease 2012"
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==== Effect of mutations ====
==== Effect of mutations ====
Revision as of 15:58, 22 August 2012
The Canavan Disease is a rare, genetic, degenerate disorder of the brain that is caused by a dysfunctional enzyme. 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 <ref name=myrtelle> http://www.morbus-canavan.com/canavansdisease.htm </ref>. Up to now, there is no final cure for Canavan Disease and treatment mainly focuses on managing the symptoms.
- 1 Prevalence
- 2 Phenotype: Signs and symptoms
- 3 Classification and Types
- 4 Heredity
- 5 Biochemical disease mechanism
- 6 Mutations
- 7 Diagnosis
- 8 Treatment
- 9 Tasks
- 10 References
Canavan disease is officially classified as a "rare disease" by the Office of Rare Diseases (ORD) <ref name="ORD">rarediseases.info.nih.gov/</ref> of the National Institutes of Health (NIH)<ref name="nih">http://www.nih.gov/</ref>. In this classification rare diseases mean to affect less than 200,000 people in the US population <ref name="rare_disease"> http://rarediseases.info.nih.gov/RareDiseaseList.aspx </ref>.
However, 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: has been determined by different studies
- 1:40 (2%), meaning 1 out of 40 persons carries a mutated allele. Screening for the two most common alleles in 1995.<ref> Kronn D, Oddoux C, Phillips J, Ostrer H. Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population. Am J Hum Genet. 1995;57:1250–2 </ref> <ref>Matalon R, Michals K, Kaul R. Canavan disease: from spongy degeneration to molecular analysis. J Pediatr. 1995;127:511–7.</ref>
- 1:58, screening for the three most common alleles in 2001<ref>Sugarman EA, Allitto BA. Carrier testing for seven diseases common in the Ashkenazi Jewish population: implications for counseling and testing. Obstet Gynecol. 2001;97:S38–S39.</ref>
- 1:57, screening for the three most common alleles in 2004 <ref> Feigenbaum A, Moore R, Clarke J, Hewson S, Chitayat D, Ray PN, Stockley TL. Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay. Am J Med Genet A. 2004;124A:142–</ref>
- 1:82, screening for the three most common alleles in 2008 <ref>Fares F, Badarneh K, Abosaleh M, Harari-Shaham A, Diukman R, David M. Carrier frequency of autosomal-recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? Prenat Diagn. 2008;28:236–41.</ref>
- Disease Frequency: Studies suggest that 1 per 6,400 - 13,500 people of the Ashkenazi Jewish community in the US suffer from Canavan disease.
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<ref name="ncbi_canavan"> http://www.ncbi.nlm.nih.gov/books/NBK1234/ </ref><ref name="can_foundation"> http://www.canavanfoundation.org/canavan.php </ref><ref name="can_wikipedia"> http://en.wikipedia.org/wiki/Canavan_disease</ref> :
- 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:
- hypotonia leading to paralysis
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.
The central nervous system can 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 1 the grey and white 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 such that the gene product loses its function, causes the disease.
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 (18.104.22.168) that belongs to the desuccinylase / Aspartoacylase family. The protein probably acts as a homodimer formed by two 55kDa monomeres with 313 aminoacids. The structure of human aspartoacylse was first solved in 2006 <ref> Ensemble Refinement of Protein Crystal Structures: Validation and Application, Levin, Elena J.; Kondrashov, Dmitry A.; Wesenberg, Gary E.; Phillips, George N., Structure (London, England : 1993) doi:10.1016/j.str.2007.06.019 (volume 15 issue 9 pp.1040 - 1052) </ref> and is shown in <xr id="aspa_struct"/>.
The N-terminal domain of aspartoacylase resembles a protein fold of zinc-dependent hydrolases related to carboxypeptidases A. It was also found that the protein coordinates a Zinc ion.
The C-terminal part of Aspartoacylse forms a globular domain. The interface between the two domains forms the catalytic site, that is also similar to that of carboxypeptidases. In the figure on the right, you can see the structure of the protein taken from the PDB (ID: 2I3C).
More detailed structural information can be found here: []
Aspartoacylase 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 <xr id="aspa_react"/>, you can see the reaction schema.
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 <ref name="myelin_deficiency"> 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 </ref>.
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 <ref name="pdb_structure" /> <ref name="NAA"> Ronald E. Viola, The impact of structural biology on neurobiology, PNAS 2007 104: 399-400 </ref>.
Furthermore, the ASPA mutations lead to pleiotropic effects, resulting in a series of genomic interactions in the brain. For example, low levels of glutamate and GABA have been registered. <ref name="pleiotropic"> 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 </ref> 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.
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 <xr id="aspa_comp" />).
The ASPA gene lies on the short (p) arm of chromosome 17 at position 13.3 (see <xr id="aspa_location"/>). More precisely, the ASPA gene is located from base pair 3,377,403 to base pair 3,402,699 on chromosome 17. It thus comprises 29kb and has six exons and five introns.<ref>http://ghr.nlm.nih.gov/gene/ASPA</ref>
There are two splice variants of Aspartoacylase (see <xr id="aspa_splice" />):
The gene product for both splice variants is the same (Uniprot: P45381):
>sp|P45381|ACY2_HUMAN Aspartoacylase OS=Homo sapiens GN=ASPA PE=1 SV=1 MTSCHIAEEHIQKVAIFGGTHGNELTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKK CTRYIDCDLNRIFDLENLGKKMSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTS NMGCTLILEDSRNNFLIQMFHYIKTSLAPLPCYVYLIEHPSLKYATTRSIAKYPVGIEVG PQPQGVLRADILDQMRKMIKHALDFIHHFNEGKEFPPCAIEVYKIIEKVDYPRDENGEIA AIIHPNLQDQDWKPLHPGDPMFLTLDGKTIPLGGDCTVYPVFVNEAAYYEKKEAFAKTTK LTLNAKSIRCCLH
dbSNP lists over 500 variants of Aspartoacylase for humans.
There are more than 55 mutations known in the ASPA gene that cause the Canavan Disease.
Two mutations, namely Glu285Ala and Tyr231X, are responsible for 98% of disease-causing alleles in the Ashkenazi Jewish population, and 3% of alleles in non-Ashkenazi Jewish populations. One mutation, Ala305Glu, accounts for 30%-60% of disease-causing alleles in non- Ashkenazi Jewish populations and approximately 1% of alleles in the Ashkenazi Jewish populations <ref name="ncbi_canavan"> http://www.ncbi.nlm.nih.gov/books/NBK1234/ </ref>.
Of these mutations, the Glu285Ala mutation results in a leftover enzyme activity of 2.5%, while the other two lead to a complete loss of function<ref name="mutations_results"> Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R., Canavan disease: mutations among Jewish and non-Jewish patients,PMID: 8023850 [PubMed - indexed for MEDLINE] PMCID: PMC1918221 </ref>.
Effect of mutations
If aspartoacylase does not function properly, N-acetyl L-aspartate (NAA) cannot be broken down and accumulates in the brain. The exact mechanisms are not fully understood yet, but with accumulating NAA that is not broken down, the myelin sheaths isolating the axons and supporting brain signal transduction, can either not be built or maintained.
Not all mutations leading to the Canavan disease have the same amount of effect on the protein. However, all those listed above as disease-causing mutations lead to a loss of function to at least some extent.
The disrupted signal transduction, caused by the incomplete myelin sheaths, leads to the severe symptoms that characterise the Canavan Disease.
- Via amniocentese either the amount of NAA can be measured in the amniotic fluids, or genetic testing can be performed
- For measuring the concentration of NAA in the amniotic fluids, methods like stable-isotope dilution,GC-MS or liquid chromatography tandem mass spectrometry are used. NAA concentration in the amniotic fluid in controls was measured with 0.30-2.55 µmol/L, whereas it showd values over 8 µmol/L in an affected pregnancy [Bennett et al 1993].
- If the genotype of the parents is known, and both parents are carriers of an mutated ASPA allele, targeted mutational testing can be performed.
Using enzymatic activity assays may not be a relieable diagnostic measure, because of the low or undetectable aspartoacylase activity in direct or cultured normal chorionic villi and in normal cultured amniocytes. The activity of the enzyme mainly depends on culture conditions. <ref name=ncbi> http://www.ncbi.nlm.nih.gov/books/NBK1234/ </ref>
- In neonatale and infantile CD patients, high concentration of NAA can be found in the urine. Patients with the mild, juvenile type of CD only have slightly elevated NAA levels in the urine. Therefore, urine tests are not suffiecient to diagnose CD in those patients. For measuring the concentration of NAA in the urine, gas chromatography-mass spectrometry (GC-MS) is used.
- Via neuroimaging studies, Leukodystrophy might be detected. In dependence on the progress of the disease, spongy degenerations of the white brain matter can be found.
- Again, mutation analysis can be performed. If the parental alleles are known, targeted muation analyses is the method of choice. Otherwise, sequence analysis of the ASPA gene can be done to screen the gene for allelic variants. <ref name="ncbi"/>
The Canavan disease is characterised by a progressive disorder of the brain, and there is no final cure for it. Treatment is therefore mostly symptomatic and tries to slow down the results of the dysfunctional protein.
- Physical Therapy: Physical therapy is prescribed in order to maintain the highly limited motoric abilities that often decrease as the disease progresses.
- Speech Therapy: Most Canavan Disease-patients are not able to talk. However, basic communication is sometimes possible, and is being trained.
Gene Therapy is the only form of therapy that is able to halt the progression of the disease and can, to some extend, undo some of its consequences. The Canavan Disease was the first Leukodystrophie to be treated with Gene Therapy <ref name="jacobscure"> http://jacobscure.org/canavan-research.php </ref>. A number of different viruses have been used as vectors to transport a healthy copy of the ASPA gene into the patient's white brain matter. Patients suffering from the Canavan Disease have been treated with Gene Therapy and have showed varying degrees of improvement, ranking from improved motoric abilities to regained vision. <ref> http://www.biotechnologie.de/BIO/Navigation/DE/Foerderung/foerderbeispiele,did=130222.html</ref>
- Collect information on the individual disease
- Sequence alignments (sequence searches and multiple alignments)
- Sequence-based analyses
- Homology based structure predictions
- Mapping point mutations
- Sequence-based mutation analysis
- Structure-based mutation analysis
- Molecular Dynamics Simulations
- Normal mode analysis -- see Animated Gifs section for hints how to get an animated gif for the wiki
- Molecular Dynamics Simulations Analysis
- KEGG Pathway: Aspartoacylase(HSADD00250)
- PDB: 2O53, 2I3C
- OMIM: 608034
- Uniprot: P45381
- GO annotation: P45381
- Pfam: PF04952