Hd

neurofilaments in the cell body and proximal axons of motor neurons is a common pathological hallmark of ALS, suggesting a role for neurofilaments in motor neuron pathology. Coding sequences of neurofilaments are polymorphic, and these variants are among putative susceptibility factors in sporadic ALS (78). Excitotoxicity genes and DNA-repair genes are among other candidate risk factors for ALS (18).

In contrast with the other neurodegenerative diseases discussed in this chapter, HD is caused by mutations in a single gene; for this reason other genes are likely to affect the age at onset or the progression of the disease, rather than the risk. The most convincing example is given by the gene encoding the glutamate kainate ionotropic receptor R6 (GluR6), which has been associated with age at onset (79). Different mutations in the same locus (PRNP) can either be causative of familial prion diseases or result in susceptibility variants for the sporadic forms. A common polymorphism at codon 129 of PRNP, leading to a methionine to valine substitution, has been observed to interact with causative mutations in familial CJD, affecting both clinical presentation and progression; moreover this polymorphism has been also associated with the risk of sporadic forms of CJD (60). Susceptibility factors for neurodegeneration are listed in Table 3.

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