*Limitations*

There are several limitations with this review article that have mostly been discussed in the course of this review. First, the search strategy used to capture relevant articles vastly over-included studies and returned a huge number of results that were irrelevant. The difficulty with this search centred on the labelling words used to describe this condition, and that there is not a unified term. Our compromise, after trialling many search strategies, was to include the word "regression" without additional restrictions. While this returned the best results in so far as the few relevant articles, there were also a plethora of studies referencing only statistical regression that needed to be manually eliminated. It is recognised that it is not good practice to have such a large difference between the number of articles sourced and those retained, it was deemed necessary based on the confusion seen in the terminology used for this condition. Although the methodology was time consuming and over-inclusive, using the particular search criteria selected we are confident that the correct papers have been identified and included.

The articles included in this paper were all observational studies, both case and cohort studies. The positive aspects of observational data are that records are usually qualitative and highly descriptive, allowing for cross-referencing between symptoms to be explored and person-by-person outcomes evaluated based on interventions. The negatives are that the quality of evidence is low. Cochrane's levels of evidence quality [31] describe randomised controlled trials as giving the highest quality of evidence and observational studies amongst the lowest. As such any conclusions drawn from the studies must be very cautiously considered. It is our hope that further insight and raising awareness will lead to a greater interest in research of this condition and promote controlled trials in the future.

Despite these limitations this review has provided insight into an under-researched condition with significant impacts on people with DS and their families. This review intends to bring to light a serious condition affecting a minority of young adults and adolescents, many of whom never recover their baseline functioning. It is important that we now seek to focus on prevention and treatment of this condition.

**Author Contributions:** Conceptualisation M.W., A.H. and S.Z.; methodology, M.W., software M.W.; validation M.W., A.H. and S.Z., formal analysis, M.W., investigation, M.W., resources, M.W., writing—original draft, M.W., A.H. and S.Z. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the UK Down Syndrome Association.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors would like to recognize the support from the UK Down Syndrome Association.

**Conflicts of Interest:** The authors declare no conflict of interest.
