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sa2bcity t1_ja8wljh wrote

Reply to comment by TestTubeRagdoll in Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-

Yes, there are flaws with the article I referenced. There are other articles that suggest a more negative clinical course for homozygotes.

Squitieri, F., et al. (2003). Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain, 126(4), 946–955. https://doi.org/10.1093/brain/awg077

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TestTubeRagdoll t1_ja92zob wrote

Yes, this study makes the point better, although it's still small (n=8 homozygotes), and relies on retrospective analysis of clinic records.

Based on that study, it does look like there could be faster progression in homozygotes, although I don't know if there's enough data to argue that the normal allele is specifically conferring an advantage, as opposed to simply a dose effect of having 2 copies of the mutant allele.

It's also worth noting that not all studies show this same trend. For example, a 2019 Neurology study (https://n.neurology.org/content/neurology/92/18/e2101.full.pdf), which was somewhat larger (n=28 homozygotes) and used patients who are part of the EHDN Registry Database (ie using standardized data collection protocols for clinical data) did not see a difference in disease progression between homozygotes and heterozygotes.

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