To the Editor:
Many important questions remain to be answered about translational research in neurodegenerative diseases1,2,3,4,5,6,7. However, I feel that not enough emphasis has been put on the extent of the knowledge that could be gained from studying genetic forms of these disorders.
Monogenic forms of adult-onset disorders that show autosomal dominant inheritance offer a unique opportunity to investigate the presymptomatic phase of the disease before clinical onset. This can be done in relatives of individuals with disease-causing mutations before the occurrence of signs or symptoms that correspond to the most recent criteria for early clinical diagnosis. Prospective follow-up of individuals who are at risk of a monogenic neurodegenerative disorder with clinical, imaging and biological investigations will allow researchers to identify markers of the presymptomatic phase. In turn, determining the natural history of the presymptomatic phase will lead to the development of markers of early neuronal dysfunction (before overt degeneration and clinical signs). This is crucial for defining when to start disease-modifying treatments as well as for monitoring their effects.
However, there are several limitations to these studies and their clinical application. The first is that knowledge regarding the presymptomatic phase of neurodegenerative disorders will be fully useful only when true disease-modifying (neuroprotective) treatments become available. The second is that, partly because of the absence of such treatments, only a small proportion of at-risk individuals in families with monogenic neurodegenerative disorders request presymptomatic genetic testing. Accordingly, a limited number of asymptomatic gene carriers are available for these studies. Another challenge, therefore, is to design these studies in such a way that at-risk individuals who are unaware of their genetic status (carriers or noncarriers) can participate in these studies without the risk of a breach of confidentiality concerning their genetic status. Nevertheless, several such studies are already ongoing and should generate many more useful preclinical biomarkers. This will also pave the way for trials of potential disease-modifying treatments that could be initiated at the preclinical stage of the disease before the occurrence of irreversible dysfunction or neurodegeneration.
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The author declares no competing financial interests.
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Brice, A. Learning from genetic forms of neurodegeneration. Nat Med 16, 1371 (2010). https://doi.org/10.1038/nm1210-1371a