Canavan Disease
!!! not finished !!!! more some kind of working copy !!!
Contents
Summary
Canavan Disease is an autosomal recessive disorder, in which a dysfunctional enzyme causes severe brain damage. There is no cure and almost all patients die within the first decade of their life. The juvenile / mild type is less severe. The treatment is based on the symptoms and supportive.
Reihenfolge!!!
Names
Canavan Disease is also known under a variety of other names describing the the chemical basis or phenotype of the disease. Examples are "Spongy Degeneration Of Central Nervous System", "Aspartoacylase (ASPA) Deficiency", or "Aminoacylase 2 (ACY2) Deficiency". [which will be descibed in section xxx] The trivial name, Canavan Disease, stems from the name of Myrtelle Canavan (1879 – 1953), an american physician that first described the disease in 1931.
Inheritance
Canavan disease is an autosomal recessive genetic defect of the ASPA (Aspartocyclase) gene on chromosome 17. 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. !!! prevalence !!!
Diagnosis
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 beforehand is if both parents carry one copy of the disease causing gene. This can be done by simple DNA testing.
Prenatal
There are several types of prenatal testing possibilities depending 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 parent’s 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. (screening) 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.
Postnatal
Postnatal testing for Canavan Disease can as well 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 not known). 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
Diagnosing a patient with Canavan Disease if he is suffering from a mild or juvenile form, is a bit more challenging, as the postnatal diagnosis methods, except testing the gene itself, won't 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 go unrecognized.
Treatment
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 you are 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 also affects the metabolism there is need to control the nutrition and hydration. This includes specialized food to make up for 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 antiepileptic drugs against seizures and spastic behaviour.
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. Right now there seems to be only one, which have a positive effect. Since N-Acetyl aspartate (NAA) is one important factor in the biochemical background of Canavan Disease. NAA level is too high - Lithium Citrate may be able to manage... === Animal Models?! === (zu viel?)
Phenotype
Canavan Disease has a variety of different phenotypes all over the body. The head itsself shows signs of macrocephaly, which is an increased head circumference. Over time, people which have the disease, loose mental skills (mental retardation) and abilities to move the head. Another typical phenotype is problem with the eyes. Persons with Canavan Disease may become blind or have a nystagmus (greek: nystazoo - nicken, schlafen, german: Augenzittern). Also typical are problems with swallowing, which brings several problems with feeding the children. Also that they cannot talk or loose hearing brings communicational problems. But also complete paralysis, seizures and problems moving the muscles are common. Children suffering from Canavan Disease usually die within the first dacade. In the mild/juvenile form of Canavan Disease, the children usually have some developmental delay and some speech problems.
Biochemical disease mechanism
The example protein is involved in the example pathway...
Canavan Disease belongs to the group of leukodystrophies. This comes from (greek: leukos white dys bad 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. Therefore it may have an effect on the nerves itsself. The concrete biochemical background is the following: The enzyme aspartoacylase (ASPA) depends on the gene product of the ASPA gene. The enzyme decomposes N acetyl aspartate (NAA). Components of NAA are needed for the formation of the myelin sheath around the nerve fibers. Another sideeffect is that the degenerated white matter leaves several soft tissue or even complete spaces behind.
graphical pathway representation:
Gene, Mutations
The ASPA gene sits on chromosome 17 on the p-arm (upper part, short arm) band 1 subband 3 subsubband 2. siehe pic! Disease causing mutations: Glu285Ala, Tyr231X, and Ala305Glu -nucleic changes: see table
DNA Nucleotide Change Protein Amino Acid Change c.433-2A>G -- c.693C>A p.Tyr231X c.854A>C p.Glu285Ala 98 3 c.863A>G p.Tyr288Cys c.914C>A p.Ala305Glu 1 30-60
Reference sequence
DEFINITION Homo sapiens aspartoacylase (ASPA), transcript variant 1, mRNA. TITLE Expression of aspartoacylase (ASPA) and Canavan disease NCBI Reference Sequence: NM_000049.2
>sp|P45381|ACY2_HUMAN Aspartoacylase OS=Homo sapiens GN=ASPA PE=1 SV=1 MTSCHIAEEHIQKVAIFGGTHGNELTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKK CTRYIDCDLNRIFDLENLGKKMSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTS NMGCTLILEDSRNNFLIQMFHYIKTSLAPLPCYVYLIEHPSLKYATTRSIAKYPVGIEVG PQPQGVLRADILDQMRKMIKHALDFIHHFNEGKEFPPCAIEVYKIIEKVDYPRDENGEIA AIIHPNLQDQDWKPLHPGDPMFLTLDGKTIPLGGDCTVYPVFVNEAAYYEKKEAFAKTTK LTLNAKSIRCCLH
http://www.rcsb.org/pdb/explore/explore.do?structureId=2I3C
>2I3C:A|PDBID|CHAIN|SEQUENCE AIATSCHIAEEHIQKVAIFGGTHGNELTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKKCTRYIDCDLNRIFDLENL GKKMSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTSNMGCTLILEDSRNNFLIQMFHYIKTSLAPLPCYVYLIE HPSLKYATTRSIAKYPVGIEVGPQPQGVLRADILDQMRKMIKHALDFIHHFNEGKEFPPCAIEVYKIIEKVDYPRDENGE IAAIIHPNLQDQDWKPLHPGDPMFLTLDGKTIPLGGDCTVYPVFVNEAAYYEKKEAFAKTTKLTLNAKSIRCCLH >2I3C:B|PDBID|CHAIN|SEQUENCE AIATSCHIAEEHIQKVAIFGGTHGNELTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKKCTRYIDCDLNRIFDLENL GKKMSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTSNMGCTLILEDSRNNFLIQMFHYIKTSLAPLPCYVYLIE HPSLKYATTRSIAKYPVGIEVGPQPQGVLRADILDQMRKMIKHALDFIHHFNEGKEFPPCAIEVYKIIEKVDYPRDENGE IAAIIHPNLQDQDWKPLHPGDPMFLTLDGKTIPLGGDCTVYPVFVNEAAYYEKKEAFAKTTKLTLNAKSIRCCLH
References
http://en.wikipedia.org/wiki/Myrtelle_Canavan http://ghr.nlm.nih.gov/condition/canavan-disease https://www.counsyl.com/diseases/canavan-disease/ http://omim.org/entry/608034 http://omim.org/entry/271900 http://www.uniprot.org/uniprot/P45381
pic: aspa gene : http://www.genecards.org/cgi-bin/carddisp.pl?gene=ASPA
