Difference between revisions of "Tay-Sachs Disease 2011"

From Bioinformatikpedia
(→‎Summary)
m (moved Tay-Sachs Disease to Tay-Sachs Disease 2011: Make room for 2012 :))
 
(56 intermediate revisions by 2 users not shown)
Line 1: Line 1:
 
== Summary ==
  
== Summary ==
−
The Tay-Sachs disease (TSD) is a rare autosomal, recessive genetic disorder which is caused by accumulation of lipids in the brain. This leads to the cell death of those neurons. There exist three different variations of the TSD. The most common one is the Infantile Tay-Sachs disease which affects death of the children under the age of 5. The two other variants are the Juvenile and Adult/Late Onset TSD, which are less aggressive. The disease causes a deterioration of mental and physical abilities. Sadly, there currently exists no treatment.
 +
The Tay-Sachs disease (TSD) is a rare autosomal, recessive genetic disorder which is caused by accumulation of lipids in the brain. This leads to the cell death of those neurons. There exist three different variations of the TSD. The most common one is the Infantile Tay-Sachs disease which results in death of the children under the age of 5. The two other variants are the Juvenile and Adult/Late Onset TSD, which are less aggressive. The disease causes a deterioration of mental and physical abilities. Sadly, there currently exists no treatment.
   
 
== Phenotype ==
  
== Phenotype ==
−
Phenotypic description of the disease.
 
   
  +
'''Infantile Tay-Sachs disease:'''
−
(Describe this in your own words, avoid plagiarism. Summarise the information from different sources.)
  
  +
  +
The most common and aggressive form of TSD is the infantile TSD, which has a wide range of different symptoms and leads to the early death of the affected children.
  +
The most common symptoms are:
  +
* normal development in the first six month after birth
  +
* "cherry-red" macula
  +
* paralysis
  +
* dementia
  +
* blindness
  +
* deafness
  +
* muscle atrophy
  +
* startle response to sound stimuli
  +
* inability to coordinate muscle movement (child can't roll over and sit)
  +
* death in the second or third year
  +
  +
  +
'''Juvenile and Adult TSD:'''
  +
  +
This forms of the Tay-Sachs disease occur later in lifetime. These two forms were not always recogniced as variants of the TSD. The symptoms of these forms are less aggressive. Often the patients become wheelchair users and have some psychiatric and physical limitation, which can be handled with drugs.
  +
   
 
=== Cross-references ===
 
=== Cross-references ===
 
See also description of this disease in
  
See also description of this disease in
  +
*[http://en.wikipedia.org/wiki/Tay–Sachs_disease Wikipedia]
−
* specific link to Wikipedia
  
  +
*[http://www.ncbi.nlm.nih.gov/omim/272800 OMIM]
−
* specific link to HGMD
  
  +
*[http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm NINDS ]
−
* specific link to OMIM
  
  +
*[http://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v%3Aproject=medlineplus&query=Tay+Sachs+disease&x=0&y=0 MedlinePlus]
−
... (see [[Resource data|databases in "resources"]])
  
  +
*[http://www.ncbi.nlm.nih.gov/pubmed?term=Tay%20Sachs%20disease PubMed]
   
 
== Biochemical disease mechanism ==
  
== Biochemical disease mechanism ==
  +
The affecting protein in the TSD is the Beta-Hexosaminidase, which is a heterodimer consisting of two subunits alpha (encoded by the gene HEXA) and beta (encoded by the gene HEXB). The alpha subunit processes the hydrolysis of the GM2 gangliosides (which are fatty acid derivatives) to the GM3 gangliosides (compare Figure 1 and Figure 2). This means the enzyme gradates the lipids in the brain and in other tissues.
−
The example protein is involved in the example pathway...
  
  +
If the enzyme is defect it results in the accumulation of GM2 gangliosides in the neurons, which results the death of those cells.
   
  +
{| class="centered"
−
Ideally, include a graphical pathway representation like this one: [[Image:SphingolipidMetabolism.png|frame|Sphingolipid Metabolism (source: KEGG) highlighting disease associated enzymes]]
  
  +
| [[Image:hsa00604.png|thumb|center|Figure 1: KEGG-Pathway Glycosphingolipid biosynthesis highlighting TSD associated enzyme Beta-Hexosaminidase A (http://www.genome.jp/tmp/mark_pathway130536834226114/hsa00604.png)]]
−  
  +
| [[Image:hexa_pathway.png‎ |thumb|Figure 2: Catalytic mechanism for Beta-Hexosaminidase A.. '''''Disclaimer:''' This file is redistributed from [M. Joanne Lemieux, Brian L. Mark, Maia M. Cherney, Stephen G. Withers, Don J.
−
(see above: own words, no plagiarism)
  
  +
Mahuran3, and Michael N. G. James . Crystallographic Structure of Human β-Hexosaminidase A:
  +
Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis. J Mol Biol. Author Manuscript 2010;] . All rights belong to the creator.'']]
  +
|}
   
 
<br style="clear: both" />
  
<br style="clear: both" />
 
=== Cross-references ===
  
=== Cross-references ===
  +
* [http://www.uniprot.org/uniprot/P06865 Uniprot]
−
* link to KEGG
  
  +
* [http://www.ncbi.nlm.nih.gov/gene/3073 PubMed]
−
* link to MetaCyc
  
  +
* [http://www.genome.jp/dbget-bin/www_bget?hsa:3073 KEGG]
−
... see [[Resource data|databases in "resources"]]
  
  +
* [http://en.wikipedia.org/wiki/HEXA Wikipedia]
  +
* [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910082/?tool=pubmed PubMed]
   
 
== Mutations ==
  
== Mutations ==
  +
Only mutations in the HEXA gene can result in the TSD, whereas mutations in the HEXB gene result in other metabolic diseases. Mutations in the HEXA gene lead to amino acid substitutions in the Beta-Hexosamidase A protein (visualized in Figure 3), which leads to the TSD.
−
Current knowledge about mutations associated with the disease. - Separate into disease causing and neutral mutations.
  
  +
Today, there are more than 120 known mutations which cause the TSD disease. These mutations suppress the activity of the Beta-Hexosamidase A which causes the failure of the GM2 gangliosides degradation. Furthermore, this leads to the toxic accumulation of those lipids which results in the cell death of the involved neurons.
  +
The TSD is normally very rare, but there is a strong prevalence for it in the Eastern European Jewish, Cajun and French Canadian population.
  +
Most of the mutations in HEXA lead to the TSD, because they delete the enzyme function completely, which cause the infantile form of TSD. There are other mutations, which only reduce the enzyme-activity and therefore, cause the Juvenile or Adult TSD.
  +
  +
[[Image:2gjx_bio_r_500.jpg|thumb|Figure 3: Beta-Hexosaminidase A (http://www.pdb.org/pdb/images/2gjx_bio_r_500.jpg)]]
   
 
=== Reference sequence ===
  
=== Reference sequence ===
   
  +
* [[Beta-hexosaminidase subunit alpha|amino acid sequence]]
−
Which sequence does not cause the disease and is most often found in the population.
 
−
* [[example_sequence|Create a page for the reference sequence.]] -- These sequence pages will be the starting point for collecting prediction results and result discussions.
  
   
 
=== Neutral mutations ===
  
=== Neutral mutations ===
  +
* [http://i12r-studfilesrv.informatik.tu-muenchen.de/wiki/index.php/Mapping_SNPs_HEXA#Silent_Mutations Neutral mutations].
−
* [[example_sequence|Create one page per mutated sequence]].
  
   
 
=== Disease causing mutations ===
  
=== Disease causing mutations ===
  +
* [http://i12r-studfilesrv.informatik.tu-muenchen.de/wiki/index.php/Mapping_SNPs_HEXA#Mutations_annotated_in_both_databases Disease causing mutations].
−
* [[example_sequence|Create one page per mutated sequence]].
  
  +
  +
== Tasks ==
  +
  +
  +
=== Sequence Alignments ===
  +
  +
* [[Sequence Alignments HEXA|Sequence Alignments]]
  +
  +
=== Sequence-based predictions ===
  +
  +
*[[Sequence-based predictions HEXA|Sequence-based predictions]]
  +
  +
=== Homology Modelling ===
  +
  +
*[[homology-modelling HEXA | Homology Modelling]]
  +
  +
=== Mapping SNPs ===
  +
  +
* [[ Mapping SNPs HEXA | Mapping SNPs]]
  +
  +
=== Sequence-based mutation analysis ===
  +
  +
* [[Sequence-based mutation analysis HEXA | Sequence-based mutation analysis]]
  +
  +
=== Structure-based mutation analysis ===
  +
  +
* [[Structure-based mutation analysis HEXA | Structure-based mutation analysis]]
  +
  +
=== Molecular Dynamics Simulations ===
  +
  +
* [[Molecular Dynamics Simulations HEXA | Molecular Dynamics Simulations]]
  +
  +
=== Normal mode analysis ===
  +
  +
* [[Normal mode analysis HEXA | Normal mode analysis]]

Latest revision as of 11:20, 13 April 2012

Summary

The Tay-Sachs disease (TSD) is a rare autosomal, recessive genetic disorder which is caused by accumulation of lipids in the brain. This leads to the cell death of those neurons. There exist three different variations of the TSD. The most common one is the Infantile Tay-Sachs disease which results in death of the children under the age of 5. The two other variants are the Juvenile and Adult/Late Onset TSD, which are less aggressive. The disease causes a deterioration of mental and physical abilities. Sadly, there currently exists no treatment.

Phenotype

Infantile Tay-Sachs disease:

The most common and aggressive form of TSD is the infantile TSD, which has a wide range of different symptoms and leads to the early death of the affected children. The most common symptoms are:

  • normal development in the first six month after birth
  • "cherry-red" macula
  • paralysis
  • dementia
  • blindness
  • deafness
  • muscle atrophy
  • startle response to sound stimuli
  • inability to coordinate muscle movement (child can't roll over and sit)
  • death in the second or third year


Juvenile and Adult TSD:

This forms of the Tay-Sachs disease occur later in lifetime. These two forms were not always recogniced as variants of the TSD. The symptoms of these forms are less aggressive. Often the patients become wheelchair users and have some psychiatric and physical limitation, which can be handled with drugs.


Cross-references

See also description of this disease in

Biochemical disease mechanism

The affecting protein in the TSD is the Beta-Hexosaminidase, which is a heterodimer consisting of two subunits alpha (encoded by the gene HEXA) and beta (encoded by the gene HEXB). The alpha subunit processes the hydrolysis of the GM2 gangliosides (which are fatty acid derivatives) to the GM3 gangliosides (compare Figure 1 and Figure 2). This means the enzyme gradates the lipids in the brain and in other tissues. If the enzyme is defect it results in the accumulation of GM2 gangliosides in the neurons, which results the death of those cells.

Figure 1: KEGG-Pathway Glycosphingolipid biosynthesis highlighting TSD associated enzyme Beta-Hexosaminidase A (http://www.genome.jp/tmp/mark_pathway130536834226114/hsa00604.png)
Figure 2: Catalytic mechanism for Beta-Hexosaminidase A.. Disclaimer: This file is redistributed from [M. Joanne Lemieux, Brian L. Mark, Maia M. Cherney, Stephen G. Withers, Don J. Mahuran3, and Michael N. G. James . Crystallographic Structure of Human β-Hexosaminidase A: Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis. J Mol Biol. Author Manuscript 2010;] . All rights belong to the creator.


Cross-references

Mutations

Only mutations in the HEXA gene can result in the TSD, whereas mutations in the HEXB gene result in other metabolic diseases. Mutations in the HEXA gene lead to amino acid substitutions in the Beta-Hexosamidase A protein (visualized in Figure 3), which leads to the TSD. Today, there are more than 120 known mutations which cause the TSD disease. These mutations suppress the activity of the Beta-Hexosamidase A which causes the failure of the GM2 gangliosides degradation. Furthermore, this leads to the toxic accumulation of those lipids which results in the cell death of the involved neurons. The TSD is normally very rare, but there is a strong prevalence for it in the Eastern European Jewish, Cajun and French Canadian population. Most of the mutations in HEXA lead to the TSD, because they delete the enzyme function completely, which cause the infantile form of TSD. There are other mutations, which only reduce the enzyme-activity and therefore, cause the Juvenile or Adult TSD.

Figure 3: Beta-Hexosaminidase A (http://www.pdb.org/pdb/images/2gjx_bio_r_500.jpg)

Reference sequence

Neutral mutations

Disease causing mutations

Tasks

Sequence Alignments

Sequence-based predictions

Homology Modelling

Mapping SNPs

Sequence-based mutation analysis

Structure-based mutation analysis

Molecular Dynamics Simulations

Normal mode analysis

Retrieved from "https://i12r-studfilesrv.informatik.tu-muenchen.de/wiki/index.php?title=Tay-Sachs_Disease_2011&oldid=16191"