HD Lighthouse Contributing Editor's Comment: Additional evidence for the role of excitotoxicity in HD pathology is provided by this study. The idea behind this theory is that the overstimulation of N-methyl-d-aspartate (NMDA)-type glutamate receptors causes a variety of problems including excessive calcium in the associated ion channels and eventually leads to cell death. Researchers know that this is a problem in stroke and brain injury, and have reason to believe that it also occurs in chronic neurological diseases.

Two genes involving the NMDA receptors were found to explain some of the variation in the age of onset. We know from the studies with the Venezuela HD patients that the number of CAG repeats, environmental factors and other genes all have an influence on the age of onset. This study has added to our knowledge about the other influential genes. The primary reason for doing this kind of research is to get ideas about effective intervention; the study supports the need for more research on ways to prevent overstimulation of the NMDA receptors as a therapeutic strategy. Research on memantine would fall into this category.
--Marsha L. Miller
Posted to the HDL: 14 Mar 2005

NR2A and NR2B receptor gene variations modify age at onset in Huntington disease.

N -Methyl- D: -aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N -methyl- D: -aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

Tracked on the Lighthouse:
NMDA receptors
excitotoxicity

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Source: Neurogenetics. 2005 Feb;6(1):25-8

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