Difference between revisions of "Tay-Sachs Disease 2012"

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(moved Tay-Sachs Disease to Tay-Sachs Disease 2011: Make room for 2012 :))
 
(Initial upload, lots commented out)
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By Alice Meier and Jonas Reeb
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#REDIRECT [[Tay-Sachs Disease 2011]]
  
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<!-- Prefix all uploads with TSD_ -->
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<!-- Append to all Pages TSD -->
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<!-- No 'we' if possible :) -->
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<!-- When uploading figures put the caption in the comment section. That allows for using thumbnails. When one clicks to see the full version, the caption is still visible and there is no need to go back and forth -->
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== Summary ==
  +
  +
Tay-Sachs disease (TSD) is a form of GM2 gangliosidosis. Failure to degrade gangliosides leads to accumulation of these products in the brain's nerve cells and usually to death of the patient.
  +
  +
== Phenotype ==
  +
=== Infantile TSD ===
  +
TSD can be further classified into the three forms, infantile, juvenile and adult TSD. The most common and classical form of TSD is the infantile variant.
  +
A phenotypic feature common to all variants is the "cherry red" macula. Since HexA deficiency leads to GM2 accumulation in nerve cells, this also applies to the retinal ganglion cells. In the vertebrate eye, these are positioned between
  +
the light source and the rod and cone cells that actually register the light. However, since the macula is the point of highest acuity, it is usually depleted of ganglion cells to improve the achieved resolution [Suvarna2008]. This allows a view onto the outer retinal
  +
layers, where the red color simply stems from the blood flow. For the rest of the retina the accumulated GM2 in ganglion nerve cells leads to a decreased transparency and altered color. Therefore the red spot seen in the macula is in fact the
  +
only portion of the retina that has the normal color. This phenotypic trait however is not exclusive to TSD. Other storage diseases like Gaucher's disease or Adult Niemann Pick disease also cause a red macula [Suvarna2008].
  +
  +
Other common phenotypes are blindness, closely related with the above mentioned effects that cause the red spot, as well as a disturbance of gait, general detoriations of motor functions and seizures [Jeyakumar2002]. A startled response
  +
to sound has been reported as an early detection method as well [Schneck1964]. <!-- deafness is also listed on some sites, but i cannot find any publication mentioning it -->
  +
<!-- see if the book has anything else -->
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=== Other forms of TSD ===
  +
Juvenile and adult TSD are rare. Effects like a deterioration of motor functions and general weakness are present, albeit less strong as in the infantile form. In the adult other prominent features like blindness and seizures
  +
are not exhibited anymore [Jeyakumar2002]. While patients with juvenile TSD, showing symptoms as early as one year of age usually die at an age of around 15 years [Maegawa2006], the adult variant of TSD is often non-fatal [ref! book? TODO].
  +
<!-- there are more fine grained distinctions including a B1 variant, apparently dating back to http://www.sciencedirect.com/science/article/pii/S0006291X88809458, however the distinction is not entirely clear to me
  +
also see here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683169
  +
and here for more finegrained distinctions: http://emedicine.medscape.com/article/951943-overview -->
  +
  +
Nonetheless there is no cure for any TSD variant [Desnick2001]. Although the adult variant might not lead to death, current treatment can only slow the disease's progress [Maegawa2007].
  +
<!-- Replacing the enzyme is diffcult due to the blood-brain barrier and -->
  +
  +
== Prevalence ==
  +
In the general population TSD is rare with 1 case in 201000 live births and a carrier frequency of 1 in 300 people [Maegawa2006]. However, in Ashkenazi Jews (1 in 30) and eastern Quebec French Canadians (1 in 14)
  +
the carrier frequency is much higher. Carrier screenings have been set up successfully over 30 years ago to reduce births of infants with TSD in the Jewish community [Charrow2004,Schneider2009].
  +
  +
== Genetic basis ==
  +
TSD is caused by mutations in ''HEXA'' on chromosome 15. ''HEXA'' codes for the alpha subunit of the alpha/beta heterodimer beta-Hexosaminidase A. The beta subunit is coded for by ''HEXB''.
  +
''HEXA'' is a recessive gene, therefore TSD only occurs in patients that carry a defective copy of ''HEXA'' on both autosomal chromosomes.
  +
  +
== Biochemical Basis ==
  +
=== GM2 ===
  +
GM2 is a ganglioside and therefore composed of a glycosphingolipid with at least one sialic acid attached to the sugar chain. A more specific name of GM2 is β-D-GalNAc-(1→4)-[α-Neu5Ac-(2→3)]-β-D-Gal-(1→4)-β-D-Glc-(1↔1)-N-octadecanoylsphingosine.
  +
From this one can derive, that the sialic acid in this case is α-Neu5Ac. <xr id=fig:tsd_gm2/> shows GM2 with annotated subunits. <!--that explain the name.-->
  +
  +
<figure id="fig:tsd_gm2">
  +
[[Image:TSD GM2 ganglioside.png|thumb|<caption>Shown is the sceletal formula of the ganglioside GM2. Names of sugars are highlighted in green, the single sialic acid in orange and the components of the sphingolipid in blue.
  +
Red numbers denote the numbering of C atoms. The purple lightning symbol highlights the glycosidic bond broken by Hex A. The figure was adapted from [http://en.wikipedia.org/wiki/File:GM2_ganglioside.png Wikipedia]</caption>]]
  +
</figure>
  +
  +
<!--*GM2
  +
** is a ganglioside
  +
** G: anglioside
  +
** M: onosialic
  +
** 2: nd discovered
  +
** β-D-GalNAc-(1→4)-[α-Neu5Ac-(2→3)]-β-D-Gal-(1→4)-β-D-Glc-(1↔1)-N-octadecanoylsphingosine
  +
** Structure: See the adjusted GM2_ganglioside.png, set original link, if used
  +
-->
  +
  +
=== Hexosaminidase ===
  +
Beta-Hexosaminidase A (Hex A) is an essential enzyme for the degradation of GM2. In presence of the cofactor GM2-activator protein (GM2AP) the alpha subunit of Hex A catalyzes the removal of β-D-GalNAc from GM2, resulting
  +
in GM3 that is then further processed until sphingosine remains (''cf.'' KEGG pathway [[http://www.genome.jp/kegg-bin/show_pathway?hsadd00604+3073+3074+C04884 hsa00604]]). <!-- or the one from Jeyakumar2002, depending on what we use in the end -->
  +
  +
The details of the catalytic process have been proposed in [Lemieux2006] and are outlined in <xr id="fig:tsd_hexa_catalysis">. As can be seen, no residues of GM2AP are directly involved in the process. The task of GM2AP is the delivery
  +
of GM2 to Hex A. The residues of Hexosaminidase that stabilize the complex and carry out the nucleophilic attack might be interesting targets for a later analysis.
  +
<figure id="fig:tsd_hexa_catalysis">
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[[Image:TSD TODO|frame|<caption>asdasd</caption>]] <!-- Probably do own shorten and annotate: GalNac Scope, C numbering, glycosidic bond , what else might be intersting. Decide on whether to reproduce or what of the original caption-->
  +
</figure>
  +
  +
From the same publication two high resolution structures are available in the PDB entries [[http://www.rcsb.org/pdb/explore/explore.do?structureId=2GK1 2GK1]] and [[http://www.rcsb.org/pdb/explore.do?structureId=2GJX 2GJX]].
  +
  +
While Hex A is the only relevant structure for TSD, homodimeric isozymes of two beta subunits (Hex B) and two alpha subunits (Hex S) also exist [ref TODO].
  +
  +
  +
hier das bild vom diseasepathway eigenes oder das aus der publication, die stukturen, etc. siehe artikel TODO (or above same section)
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  +
=== Nomenclature ===
  +
  +
Since there is contradicting nomenclature used in the literature in the following ''HEXA'' and ''HEXB'' always refer to the genes and their respective sequences.
  +
Hexosaminidase A and B denote the respective isozymes, ''i.e.'' the alpha/beta and beta/beta heterodimers. This might be abbreviated to Hex A and Hex B. If no further description is given, the text is referring to Hex A.
  +
Lastly, the subunits are always explicitly referred to as such.
  +
  +
== Distinction to other sphingolipidoses ==
  +
  +
While TSD was the first reported [Tay1881,Sachs1887], it is strongly related with two other gangliosidoses: Sandhoff disease and the AB variant are also both autosomal recessive diseases, affect the degradation of GM2, lead to comparable phenotypes and
  +
usually have a fatal outcome [Jeyakumar2002]. <xr id="tbl:tsd_types_overview"/> gives an overview of the three types of GM2 gangliosidosis.
  +
<!-- and figure x shows how they are related in the general lipid biosynthesis pathway -->
  +
  +
<figtable id="tbl:tsd_types_overview">
  +
{| class="wikitable"
  +
|+ The three major types of GM2 gangliosidosis. The column Alt. Name denotes the name based on the scheme introduced by Sandhoff et al. [Sandhoff1971]. It describes the types of hexosaminidase isozymes that remain functional. Further names used
  +
in the literature are noted as well. The gene column shows the defective gene and the chromosome it is found on.
  +
|-
  +
! Name
  +
! Alt. Names
  +
! Gene
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! OMIM
  +
|-
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| TSD
  +
| Variant B, Type I GM2-gangliosidosis
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| 15:''HEXA''
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| [http://www.omim.org/entry/272800 272800]
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|-
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| Sandhoff disease
  +
| Variant 0, Type II GM2-gangliosidosis
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| 5:''HEXB''
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| [http://www.omim.org/entry/268800 268800]
  +
|-
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| AB variant
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| Variant AB
  +
| 5:''GM2A''
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| [http://www.omim.org/entry/272750 272750]
  +
|}
  +
</figtable>
  +
  +
*Other shingolipidoses: (that others cover!) also see overview picture src: http://apps.who.int/classifications/icd10/browse/2010/en#/E75.0
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** adapted version in folder
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{{Quote|Overview of sphingolipidoses covered in the practical. Highlighted in red are gangliosidoses while green marks sphinolipidoses covered by other students. Compound names are cyan and enzymes denoted in plain black.
  +
Picture has been adapted from http://en.wikipedia.org/wiki/File:Sphingolipidoses.svg. Addition of AB variant based on Lemieux2006a.
  +
}} <!-- Note that AB is in brackets since it should not apply to Hex B, since it only has beta subunits but maybe see papers for this again, who knows -->
  +
<!-- Maybe merge or substitute this with the one from Jeyakumar2002 -->
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** Gaucher
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** Fabry
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<!-- ***Other sphingolipidoses don't need another section, just mention it whereever the picture is put in. But maybe change heading-->
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  +
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<!--
  +
== allesmoegliche sammlung ==
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* but many mutations! (see http://www.rostlab.org/services/snpdbe/dosearch.php?id=disease&val=tay-sachs)
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From wiki:
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{{Quote|GM2-gangliosidosis, AB variant is extremely rare. In contrast with both Tay-Sachs disease and Sandhoff disease,
  +
in which many mutant polymorphic alleles have been discovered, including pseudodeficiency alleles, very few GM2A mutations have been reported.}}
  +
  +
*Function
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** So again beta-hexosaminidase consists of an alpha and beta subunit that build a heterodimer. Failure of either of the two will lead to
  +
problems in GM2 degradation
  +
**A: only A can cleave the GalNac, for more details why see here: http://en.wikipedia.org/wiki/Hexosaminidase#Lysosomal_A.2C_B.2C_and_S_isozymes
  +
*** Residues: ARG178, GLU462
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**B:
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*** Residues: GLU491, ASP452
  +
** Sources for residues: \citep{Lemieux2006a}
  +
  +
* Hexosamines: (e.g. NANA, right?, def. GlaNAc!)
  +
** amino sugars = amine group added to a hexose
  +
  +
* Hexosaminidase:
  +
** enzyme that degrades N-acetyl-D-hexosamine residues in N-acetyl-beta-D-hexosaminides.
  +
  +
**Mutations
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***Mark2003a: 100 in HEXA!
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*** also check function/residues if it fits and find more functional residues
  +
  +
  +
any useful kegg pathways? couldn't find any
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  +
What exactly is the reaction catalyzed by the beta subunit?
  +
should be more or less the same but for certain reasons in GM2 only alpha can do it
  +
-->
  +
== Mutations ==
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<figtable id="tbl:tsd_hexa_mutations">
  +
{| class="wikitable"
  +
|+ List of known ''HEXA'' mutations. It was adapted from the curated UniProtKB:Swissprot article[REF]. [MORe DBS + refs] were checked as well but did not contain additional information... add the terminating ones! and then really make a short googling
  +
|-
  +
! scope="col"| Mutation
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! scope="col"| Effect
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! scope="col"| Reference
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! scope="col"| dbSNP
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! scope="col"| Comment
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|-
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| <font face="monospace" size=4>P25S</font>
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| TSD (late infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>L39R</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>L127F</font>
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| TSD
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>L127R</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>R166G</font>
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| TSD (late infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>R170Q</font>
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| TSD (infantile)
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|
  +
|
  +
| ;; inactive or unstable protein
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|-
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| <font face="monospace" size=4>R170W</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>R178C</font>
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| TSD (infantile)
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|
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|
  +
| ;; inactive protein
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|-
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| <font face="monospace" size=4>R178H</font>
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| TSD (infantile)
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|
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|
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| ;; inactive protein
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|-
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| <font face="monospace" size=4>R178L</font>
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| TSD (infantile)
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|
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| [http://www.ncbi.nlm.nih.gov/snp/?term=rs28941770 rs28941770]
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|
  +
|-
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| <font face="monospace" size=4>Y180H</font>
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| TSD
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|
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| [http://www.ncbi.nlm.nih.gov/snp/?term=rs28941771 rs28941771]
  +
|
  +
|-
  +
| <font face="monospace" size=4>V192L</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>N196S</font>
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| TSD
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>K197T</font>
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| TSD
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>V200M</font>
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| TSD
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|
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| [http://www.ncbi.nlm.nih.gov/snp/?term=rs1800429 rs1800429]
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|
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|-
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| <font face="monospace" size=4>H204R</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>S210F</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>F211S</font>
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| TSD (infantile)
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|
  +
|
  +
|
  +
|-
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| <font face="monospace" size=4>S226F</font>
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| TSD
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|
  +
|
  +
|
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|-
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| <font face="monospace" size=4>R247W</font>
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| TSD
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|
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|
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| in HEXA pseudodeficiency
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|-
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| <font face="monospace" size=4>R249W</font>
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| TSD
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|
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|
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| in HEXA pseudodeficiency
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|-
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| <font face="monospace" size=4>G250D</font>
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| TSD (juvenile)
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|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>G250S</font>
  +
| TSD
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>R252H</font>
  +
| TSD
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|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>R252L</font>
  +
| TSD
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>D258H</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>G269D</font>
  +
| TSD
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>G269S</font>
  +
| TSD
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|
  +
|
  +
| ; late onset; inhibited subunit dissociation
  +
|-
  +
| <font face="monospace" size=4>S279P</font>
  +
| TSD (late infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>S293I</font>
  +
| TSD
  +
|
  +
| [http://www.ncbi.nlm.nih.gov/snp/?term=rs1054374 rs1054374]
  +
| in
  +
|-
  +
| <font face="monospace" size=4>N295S</font>
  +
| TSD
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>M301R</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>D314V</font>
  +
| TSD
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>I335F</font>
  +
| TSD
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>V391M</font>
  +
| TSD
  +
|
  +
|
  +
| ; mild; associated with spinal muscular atrophy
  +
|-
  +
| <font face="monospace" size=4>N399D</font>
  +
| TSD
  +
|
  +
| [http://www.ncbi.nlm.nih.gov/snp/?term=rs1800430 rs1800430]
  +
| in
  +
|-
  +
| <font face="monospace" size=4>W420C</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
| ;; inactive protein
  +
|-
  +
| <font face="monospace" size=4>I436V</font>
  +
| TSD
  +
|
  +
| [http://www.ncbi.nlm.nih.gov/snp/?term=rs1800431 rs1800431]
  +
| in
  +
|-
  +
| <font face="monospace" size=4>G454S</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>G455R</font>
  +
| TSD (late infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>C458Y</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>W474C</font>
  +
| TSD
  +
|
  +
|
  +
| ; subacute
  +
|-
  +
| <font face="monospace" size=4>E482K</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>L484Q</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>W485R</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>R499C</font>
  +
| TSD (infantile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>R499H</font>
  +
| TSD (juvenile)
  +
|
  +
|
  +
|
  +
|-
  +
| <font face="monospace" size=4>R504C</font>
  +
| TSD (infantile)
  +
|
  +
| [http://www.ncbi.nlm.nih.gov/snp/?term=rs28942071 rs28942071]
  +
|
  +
|-
  +
| <font face="monospace" size=4>R504H</font>
  +
| TSD (juvenile)
  +
|
  +
|
  +
| ;; inhibited subunit dissociation
  +
|}
  +
</figtable>
  +
  +
no mapping done, since that is task 5!
  +
  +
<!-- To add:
  +
Neutrals from here:
  +
Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., & Thomas, G. H. (1992). Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals. American journal of human genetics, 50(4), 834-41.
  +
Deleted? and stop from here: -->
  +
<!--|-
  +
! A137!
  +
| TSD
  +
| [Akli1991]
  +
|-
  +
! A178C
  +
| TSD
  +
| [Akli1991]
  +
|-
  +
! S210F
  +
| TSD
  +
| [Akli1991]
  +
|-
  +
! A393!
  +
| TSD
  +
| [Akli1991]
  +
|-
  +
! A504C
  +
| TSD
  +
| [Akli1991]-->
  +
<!-- add where we took it from, e.g. swissprot, so it can be mapped back to an actual sequence
  +
Wikipedia ones
  +
thes:
  +
Add manually FT VARIANT 304 304 Missing (in GM2G1; infantile; Moroccan
  +
Add manually FT VARIANT 320 320 Missing (in GM2G1; late infantile).
  +
Add manually FT VARIANT 347 352 Missing (in GM2G1).
  +
neutrals extra after the TSD causing ones, but in same table
  +
gm2 gangliosidoses database
  +
  +
c.1278.insTATC 1278 insTATC Insertion Frameshift
  +
'Three mutations account for >95% of alleles segregating among obligate carriers or patients: 1278ins4 (-80%), IVS12+1G--C (-16%), and the adult-onset, chronic allele, 805G-+A (3%) (Myerowitz'
  +
  +
also check here http://www.hexdb.mcgill.ca/?Topic=HEXAdb&Page=Sequence&Section=Full
  +
  +
  +
Two Ashkenazi mutations associated with classic infantile onset disease (1278ins4 and 1421+1G>C) account for 95 to 98% of the mutant alleles in this group [5]. Another mutation (G269S) is typically associated with a neurological disorder with later onset and slower progression (chronic GM2 gan- gliosidosis or late-onset Tay–Sachs disease). In addition, in chronic GM2 gangliosidosis, psychomotor regression may be mild or absent, and psychiatric disturbances (schizophrenia, psychotic depression) are prominent,
  +
occurring in  40% of patient
  +
  +
noone lists neutral ones? (dbsnp does) -->
  +
  +
== Tasks ==
  +
* Task 2: [[Sequence Alignments TSD|Sequence Alignments]]
  +
* Task 3: [[Proteinsequence-based predictions TSD|Proteinsequence-based predictions]]
  +
* Task 4: [[Homology modelling TSD|Homology modelling]]
  +
* Task 5: [[SNPs, databases TSD|SNPS, databases]]
  +
* Task 6: [[Sequence-based mutation analysis TSD|Sequence-based mutation analysis]]
  +
* Task 7: [[Structure-based mutation analysis TSD|Structure-based mutation analysis]]
  +
* Task 8: [[MD simulation TSD|MD simulation ]]
  +
* Task 9: [[Normal mode analysis TSD|Normal mode analysis]]
  +
* Task 10: [[MD simulation analysis TSD|MD simulation analysis]]
  +
  +
== Templates ==
  +
<!-- === Wanted ===
  +
http://en.wikipedia.org/wiki/Template:Annotated_image
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http://en.wikipedia.org/wiki/Template:Cite_book
  +
  +
http://www.mediawiki.org/wiki/Extension:ParserFunctions
  +
http://www.mediawiki.org/wiki/Extension:Cite
  +
http://www.mediawiki.org/wiki/Extension:CrossReference
  +
  +
http://openwetware.org/wiki/Wikiomics:Biblio#Installation biblio alone is nice already I guess, the merged version has to be obtained by contacting some guy
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http://www.mediawiki.org/wiki/Extension:Bibtex
  +
  +
Wikipedia exports:
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Template:Reflist
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Template:Citation
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Template:Cite_book
  +
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http://www.mediawiki.org/wiki/Extension:Bibtex + Biblio but not really important, oh whatever
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Reassuring....: https://bugzilla.wikimedia.org/show_bug.cgi?id=8167
  +
  +
Getting templates to work:
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-->
  +
=== Ref books etc ===
  +
<!--Oh look a reference.<ref>Johnson, S. (2001). "[http://www.george-eby-research.com/html/wide-mag-deficiency-path.pdf The multifaceted and widespread pathology of magnesium deficiency]". ''Medical Hypotheses'' 56(2):163–170. Harcourt Publishers Ltd. DOI:10.1054/mehy.2000.1133 PMID:11425281</ref> -->
  +
  +
Or, better,:
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<ref>{{cite book
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| last = Mumford
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| first = David
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| authorlink = David Mumford
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| title = The Red Book of V...
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| publisher = [[Springer-Verlag]]
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| series = Lecture Notes ...
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| volume = 1358
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| edition = 2nd expanded
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| location = Berlin
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| date = 1999
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| page = 198
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| doi = 10.1007/b62130
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| isbn = 354063293X
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}}
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</ref>
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=== Ref images ===
  +
Multiple work but might need some manual tweaking, see commented out code. Using only a single images works. See <xr id=fig:singleimg/>.
  +
<!-- Figure <xr id="fig:Agent_Life_Cycle#1"/> illustrates the standard agent's life-cycle.
  +
...
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Figure <xr id="fig:Agent_Life_Cycle#2"/> illustrates the finer agent's life-cyle,
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...
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<figure id="fig:Agent_Life_Cycle">
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<div style="float: left;">
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<subfigure>
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[[Image:Ts.jpg|frame|<caption>Standard Agent's Life-Cycle</caption>]]
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</subfigure>
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</div><div style="float: left;">
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<subfigure>
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[[Image:Ts.jpg|frame|<caption>Finer Agent's Life-Cycle</caption>]]
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</subfigure>
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</div>
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<center><small><caption>Life Cycles of Agent</caption></small></center>
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</figure>
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-->
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blabla bal
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<figure id="fig:singleimg">
  +
[[Image:Ts.jpg|frame|<caption>Standard Agent's Life-Cycle</caption>]]
  +
</figure>
  +
  +
== References ==
  +
{{reflist}}

Revision as of 12:28, 13 April 2012

By Alice Meier and Jonas Reeb


Summary

Tay-Sachs disease (TSD) is a form of GM2 gangliosidosis. Failure to degrade gangliosides leads to accumulation of these products in the brain's nerve cells and usually to death of the patient.

Phenotype

Infantile TSD

TSD can be further classified into the three forms, infantile, juvenile and adult TSD. The most common and classical form of TSD is the infantile variant. A phenotypic feature common to all variants is the "cherry red" macula. Since HexA deficiency leads to GM2 accumulation in nerve cells, this also applies to the retinal ganglion cells. In the vertebrate eye, these are positioned between the light source and the rod and cone cells that actually register the light. However, since the macula is the point of highest acuity, it is usually depleted of ganglion cells to improve the achieved resolution [Suvarna2008]. This allows a view onto the outer retinal layers, where the red color simply stems from the blood flow. For the rest of the retina the accumulated GM2 in ganglion nerve cells leads to a decreased transparency and altered color. Therefore the red spot seen in the macula is in fact the only portion of the retina that has the normal color. This phenotypic trait however is not exclusive to TSD. Other storage diseases like Gaucher's disease or Adult Niemann Pick disease also cause a red macula [Suvarna2008].

Other common phenotypes are blindness, closely related with the above mentioned effects that cause the red spot, as well as a disturbance of gait, general detoriations of motor functions and seizures [Jeyakumar2002]. A startled response to sound has been reported as an early detection method as well [Schneck1964].

Other forms of TSD

Juvenile and adult TSD are rare. Effects like a deterioration of motor functions and general weakness are present, albeit less strong as in the infantile form. In the adult other prominent features like blindness and seizures are not exhibited anymore [Jeyakumar2002]. While patients with juvenile TSD, showing symptoms as early as one year of age usually die at an age of around 15 years [Maegawa2006], the adult variant of TSD is often non-fatal [ref! book? TODO].

Nonetheless there is no cure for any TSD variant [Desnick2001]. Although the adult variant might not lead to death, current treatment can only slow the disease's progress [Maegawa2007].

Prevalence

In the general population TSD is rare with 1 case in 201000 live births and a carrier frequency of 1 in 300 people [Maegawa2006]. However, in Ashkenazi Jews (1 in 30) and eastern Quebec French Canadians (1 in 14) the carrier frequency is much higher. Carrier screenings have been set up successfully over 30 years ago to reduce births of infants with TSD in the Jewish community [Charrow2004,Schneider2009].

Genetic basis

TSD is caused by mutations in HEXA on chromosome 15. HEXA codes for the alpha subunit of the alpha/beta heterodimer beta-Hexosaminidase A. The beta subunit is coded for by HEXB. HEXA is a recessive gene, therefore TSD only occurs in patients that carry a defective copy of HEXA on both autosomal chromosomes.

Biochemical Basis

GM2

GM2 is a ganglioside and therefore composed of a glycosphingolipid with at least one sialic acid attached to the sugar chain. A more specific name of GM2 is β-D-GalNAc-(1→4)-[α-Neu5Ac-(2→3)]-β-D-Gal-(1→4)-β-D-Glc-(1↔1)-N-octadecanoylsphingosine. From this one can derive, that the sialic acid in this case is α-Neu5Ac. <xr id=fig:tsd_gm2/> shows GM2 with annotated subunits.

<figure id="fig:tsd_gm2">

Shown is the sceletal formula of the ganglioside GM2. Names of sugars are highlighted in green, the single sialic acid in orange and the components of the sphingolipid in blue. Red numbers denote the numbering of C atoms. The purple lightning symbol highlights the glycosidic bond broken by Hex A. The figure was adapted from Wikipedia

</figure>


Hexosaminidase

Beta-Hexosaminidase A (Hex A) is an essential enzyme for the degradation of GM2. In presence of the cofactor GM2-activator protein (GM2AP) the alpha subunit of Hex A catalyzes the removal of β-D-GalNAc from GM2, resulting in GM3 that is then further processed until sphingosine remains (cf. KEGG pathway [hsa00604]).

The details of the catalytic process have been proposed in [Lemieux2006] and are outlined in <xr id="fig:tsd_hexa_catalysis">. As can be seen, no residues of GM2AP are directly involved in the process. The task of GM2AP is the delivery of GM2 to Hex A. The residues of Hexosaminidase that stabilize the complex and carry out the nucleophilic attack might be interesting targets for a later analysis. <figure id="fig:tsd_hexa_catalysis">

File:TSD TODO
asdasd

</figure>

From the same publication two high resolution structures are available in the PDB entries [2GK1] and [2GJX].

While Hex A is the only relevant structure for TSD, homodimeric isozymes of two beta subunits (Hex B) and two alpha subunits (Hex S) also exist [ref TODO].


hier das bild vom diseasepathway eigenes oder das aus der publication, die stukturen, etc. siehe artikel TODO (or above same section)

Nomenclature

Since there is contradicting nomenclature used in the literature in the following HEXA and HEXB always refer to the genes and their respective sequences. Hexosaminidase A and B denote the respective isozymes, i.e. the alpha/beta and beta/beta heterodimers. This might be abbreviated to Hex A and Hex B. If no further description is given, the text is referring to Hex A. Lastly, the subunits are always explicitly referred to as such.

Distinction to other sphingolipidoses

While TSD was the first reported [Tay1881,Sachs1887], it is strongly related with two other gangliosidoses: Sandhoff disease and the AB variant are also both autosomal recessive diseases, affect the degradation of GM2, lead to comparable phenotypes and usually have a fatal outcome [Jeyakumar2002]. <xr id="tbl:tsd_types_overview"/> gives an overview of the three types of GM2 gangliosidosis.

<figtable id="tbl:tsd_types_overview">

The three major types of GM2 gangliosidosis. The column Alt. Name denotes the name based on the scheme introduced by Sandhoff et al. [Sandhoff1971]. It describes the types of hexosaminidase isozymes that remain functional. Further names used in the literature are noted as well. The gene column shows the defective gene and the chromosome it is found on.
Name Alt. Names Gene OMIM
TSD Variant B, Type I GM2-gangliosidosis 15:HEXA 272800
Sandhoff disease Variant 0, Type II GM2-gangliosidosis 5:HEXB 268800
AB variant Variant AB 5:GM2A 272750

</figtable>

Template:Quote

    • Gaucher
    • Fabry


Mutations

<figtable id="tbl:tsd_hexa_mutations">

List of known HEXA mutations. It was adapted from the curated UniProtKB:Swissprot article[REF]. [MORe DBS + refs] were checked as well but did not contain additional information... add the terminating ones! and then really make a short googling
Mutation Effect Reference dbSNP Comment
P25S TSD (late infantile)
L39R TSD (infantile)
L127F TSD
L127R TSD (infantile)
R166G TSD (late infantile)
R170Q TSD (infantile) ;; inactive or unstable protein
R170W TSD (infantile)
R178C TSD (infantile) ;; inactive protein
R178H TSD (infantile) ;; inactive protein
R178L TSD (infantile) rs28941770
Y180H TSD rs28941771
V192L TSD (infantile)
N196S TSD
K197T TSD
V200M TSD rs1800429
H204R TSD (infantile)
S210F TSD (infantile)
F211S TSD (infantile)
S226F TSD
R247W TSD in HEXA pseudodeficiency
R249W TSD in HEXA pseudodeficiency
G250D TSD (juvenile)
G250S TSD
R252H TSD
R252L TSD
D258H TSD (infantile)
G269D TSD
G269S TSD ; late onset; inhibited subunit dissociation
S279P TSD (late infantile)
S293I TSD rs1054374 in
N295S TSD
M301R TSD (infantile)
D314V TSD
I335F TSD
V391M TSD ; mild; associated with spinal muscular atrophy
N399D TSD rs1800430 in
W420C TSD (infantile) ;; inactive protein
I436V TSD rs1800431 in
G454S TSD (infantile)
G455R TSD (late infantile)
C458Y TSD (infantile)
W474C TSD ; subacute
E482K TSD (infantile)
L484Q TSD (infantile)
W485R TSD (infantile)
R499C TSD (infantile)
R499H TSD (juvenile)
R504C TSD (infantile) rs28942071
R504H TSD (juvenile) ;; inhibited subunit dissociation

</figtable>

no mapping done, since that is task 5!


Tasks

Templates

Ref books etc

Or, better,: <ref>Template:Cite book </ref>

Ref images

Multiple work but might need some manual tweaking, see commented out code. Using only a single images works. See <xr id=fig:singleimg/>. blabla bal <figure id="fig:singleimg">

File:Ts.jpg
Standard Agent's Life-Cycle

</figure>

References

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