40% of cases have unknown aetiology. Can be divided into neurodegenerative, syndromic and non-syndromic. Many chromosomal (Downs syndrome) and genetic (phenylketonuria) abnormalities cause learning disability. Note the example of phenylketonuria showing the way in which genes and environment (phenylalanine in the diet) can interact.
The mutation responsible for the fragile X syndrome has been identified and the gene in which it occurs has been named FMR1 (Fragile-X Mental Retardation). Its transmission is complex, since although the mutation can act as an X-linked recessive it "gets worse" as it passed on through different generations - a trinucleotide repeat sequence (CGGn) enlarges.
There is strong evidence for a genetic basis for this condition, and it is thought that abnormalities of a variety of different genes may combine to cause disease. Mapping studies are underway. Rarely cases are due to mutations affecting the neuroligin or neurexin 1 genes. The autism phenotype can also occur with fragile X syndrome and mutations of MECP2 which more usually cause Rett syndrome. 1% of subjects with autism have a deletion at 16p11.2. Recent studies implicate the cell adhesion molecules cadherin 9 and 10 in the risk of autism itself and in the susceptibiilty to produce stereotyped conversation in normal subjects.
Prader-Willi and Angelman syndromes are caused by deletion of the same region of 15q11-13. Which occurs depends on whether deletion affects the paternal or maternal chromosome. This is because different genes are normally inactivated through methylation on the paternal and maternal chromosomes - a phenomenon known as imprinting. Prader-Willi syndrome, with mild LD and hyperphagia, is caused by deletion on paternal chromosome leading to loss of function of SNORD116. Angelman syndrome, with severe LD and happy demeanour, is due to deletion on maternal chromosome leading to loss of function of UBE3A.
This is a form of autosomal dominant presenile dementia characterised by choreiform movements. Linkage and association studies led eventually to the identification of the responsible mutation, which consists of an CAG repeat expansion in the gene coding for a protein now named huntingtin. This has allowed animal models of disease to be constructed, and new treatment approaches to be tested. The CAG repeat expansion leads to the accumulation of polyglutamine residues.
These are sometimes inherited in an autosomal dominant fashion and then may be due to mutations in the genes coding for microtubule associated protein tau (MAPT), granulin gene (GRN) or chromatin modifying protein 2B (CHMP2B).
Senile-onset Alzheimer's disease is a common cause of dementia with a similar prevalence to multi-infarct dementia. Presenile Alzheimer's disease is a rare presenile dementia which is inherited as an autosomal dominant disease and causes similar changes in the brain, notably neurofibrillary tangles (rich in tau protein) and amyloid plaques. Identical lesions also occur in patients with Downs syndrome (trisomy 21) in middle-age. The gene which codes for the protein forming this amyloid is on chromosome 21q, and following linkage studies it was shown that mutations in this gene (for APP - amyloid precursor protein) account for a small minority of cases of presenile Alzheimer's disease. Other presenile cases are due to mutations in genes on chromosomes 14 and 1, named presenilin 1 (PS1) and presenilin 2 (PS2). The presenilins are thought to involved in the normal processing of APP.
Association studies show that the risk of senile onset Alzheimer's disease is strongly influenced by the genotype of apolipoprotein E. Three alleles are commonly found: e2, e3 and e4. Inheriting one copy of the ApoE-e4 allele trebles the risk of Alzheimer's, while inheriting a second copy trebles the risk again. Apolipoprotein E does bind to the amyloid precursor protein and to neurofibrillary tangles, and this may provide some clue to the aetiology of senile onset Alzheimer's disease.
Association studies suggest that the neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. SORL1 directs recycling of APP. Preliminary studies suggest that GAB2 may influence risk in subjects who are APOE4 carriers.
It is assumed that other loci may also influence susceptibility to late onset Alzheimer's disease, and linkage studies suggest that such loci may be present on chromosomes 10 and/or 12. Recent association studies have implicated CLU, PICALM, CR1 and BIN1.
Molecular genetic insights have allowed the construction of mouse models of Alzheimer's disease, so that new treatment approaches can be tested.
These are degenerative brain diseases with spongiform changes in which variable degrees of amyloid deposition occur as a result of the accumulation of prion protein derviatives. Some forms of these diseases occur as autosomal dominant disorders within families: Gerstman-Straussler syndrome, fatal familial insomnia, familial Creutzfeld-Jacob disease (CJD). In these cases there are mutations in the prion protein gene which cause an abnormal form of the protein to be produced.
Other prion diseases, for example kuru (and in animals BSE), are transmitted horizontally and occur in subjects with the genetically normal form of prion protein. The abnormal prion protein acts as the "infective agent" and stimulates a conformational change in the host protein, thus setting off a "chain reaction". In Britain a small number of atypical cases of CJD have recently occurred in young subjects, leading to suspicions that they are related to BSE. These cases show pronounced amyloid depositon, a longer time course, lack of characteristic EEG changes and are seen in unusually young subjects. This is now termed "variant CJD". Following partial digestion the abnormal protein from these cases has a similar electrophoretic pattern to that found in BSE.
An equivalent transmissible spongiform encephalopathy occurs in deer and elk, where it is termed "chronic wasting disease". This is spreading through North America and there have been reports of hunters and venison eaters developing CJD.
Most cases of CJD occur sporadically, with no known risk factors.
The diagram shows a simplified graphical representation of possible mechanisms leading to the deposition of amyloid in these diseases.
| Normal amyloid precursor protein (APP) is soluble |
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| Mutations in the APP gene can lead to abnormal forms of the protein which can go on to form amyloid |
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| ApoE e2 may reduce the probability of amyloid formation from APP |
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| ApoE e4 may increase the probability of amyloid formation from APP |
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| Normal prion protein is soluble |
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| Mutations in the prion protein gene (PRIP) may lead to abnormal products which can form amyloid |
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| In transmitted prion disease, prion protein in an abnormal conformation can induce a conformational change in the normal protein |
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January 2012
http://www.mds.qmw.ac.uk/statgen/dcurtis/lectures/pgenorg.htm
Dave Curtis (david.curtis@qmul.ac.uk)
