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ENROLL-HD for MND?

European Journal of Human Genetics volume 31, pages 493–494 (2023)Cite this article

Motor Neuron Disease (MND) is an incurable neurodegenerative disorder. In around 20% of cases there is an identifiable monogenic cause, with autosomal dominant inheritance in the majority of families [1]. The most commonly identified monogenic causes are missense variants in SOD1 and an expansion in c9orf72. Many contemporary treatment trials for MND utilise novel therapeutics which target specific molecular genetic causes of MND. For example, Tofersen for SOD1-MND in the ATLAS trial [2]. Given the rarity of monogenic MND, a major challenge for such trials is recruiting a sufficient number of participants. Based on the experience of the VALOR study for Tofersen - which demonstrated better secondary trial outcomes in those who received Tofersen earlier - it is likely that future trials may seek to recruit participants who carry causal genetic variants but who do not have overt clinical features of MND. This poses an additional challenge - since predictive genetic testing for MND in clinical practice is relatively uncommon leading to even smaller eligible cohorts [3]. What then can be done to address these barriers to clinical trials?

The ENROLL-HD study is a prospective, international, multi-centre study which recruits people with expansions in the Htt gene causing Huntington’s Disease (HD) [4]. Participants have yearly phenotyping visits where multiple assessments of cognition and motor function are made. This provides a trial ready cohort of participants, with clinical characteristics that represent the whole spectrum of HD. While MND and HD are genetically and clinically distinct, they share some common features that might indicate that a project based on ENROLL-HD could be of value in MND. For example, it is now recognised that, like in HD, genetic MND has a defined prodromal period with subtle cognitive and motor abnormalities [5]. An ENROLL-MND/ALS project could be initiated by recruiting participants who have a causal MND gene variant identified through clinical genetic testing; as is the process in the UK for identifying ENROLL-HD participants.

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Funding

Motor Neuron Disease Association Healthcare Project Grant (McNeill/Oct21/967-794). University of Sheffield Knowledge Exchange funding.

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  1. These authors contributed equally: Eva Pears, Louis Stokes.

Authors and Affiliations

  1. Department of Neuroscience, the University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK

    Eva Pears, Louis Stokes & Alisdair McNeill

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  1. Eva Pears
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  2. Louis Stokes
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  3. Alisdair McNeill
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Contributions

AM conceived and supervised the study, wrote the first draft of the manuscript. EP analysed data and edited the manuscript. LS analysed data and edited the manuscript.

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Correspondence to Alisdair McNeill.

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The authors declare no competing interests.

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University of Sheffield (045890).

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Pears, E., Stokes, L. & McNeill, A. ENROLL-HD for MND?. Eur J Hum Genet 31, 493–494 (2023). https://doi.org/10.1038/s41431-023-01309-9

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