*Systematic Review* **A Systematic Review of Unexplained Early Regression in Adolescents and Adults with Down Syndrome**

**Madeleine Walpert, Shahid Zaman and Anthony Holland \***

Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge CB2 8AH, UK; CIDDRG@medschl.cam.ac.uk (M.W.); shz10@medschl.cam.ac.uk (S.Z.) **\*** Correspondence: ajh1008@medschl.cam.ac.uk

**Abstract:** A proportion of young people with Down syndrome (DS) experience unexplained regression that severely impacts on their daily lives. While this condition has been recognised by clinicians, there is a limited understanding of causation and an inconsistent approach to diagnosis and treatment. Varied symptomology and little knowledge of the cause of this regression have impacted on clinician's ability to prevent or manage this condition. The purpose of this review was to examine the current evidence surrounding unexplained regression in adolescents and young adults, and to establish patterns that may be of use to clinicians, as well as raising awareness of this condition. Four areas were specifically reviewed, (1) terminology used to refer to this condition, (2) the symptoms reported, (3) potential trigger events and, (4) treatments and prognosis. A variety of terminology is used for this condition, which has constrained past attempts to identify patterns. An extensive number of symptoms were reported, however sleep impairment, loss of language and distinct changes in personality and behaviour, such as disinterest and withdrawal, were among the most frequently seen. Life events that were tentatively associated with the onset of a regressive period included a significant change in environmental circumstances or a transition, such as moving home or leaving school. Prognosis for this condition is relatively positive with the majority of individuals making at least a partial recovery. However, few patients were found to make a full recovery to their previous level of functioning and serious adverse effects could persist in those who have made a partial recovery. This is an under-researched condition with significant impacts on people with DS and their families. There are no established treatments for this condition and there is relatively little recognition in the research community. Further studies that focus on the prevention and treatment of this condition with controlled treatment trials are needed.

**Keywords:** Down syndrome; early regression; idiopathic regression

**1. Introduction**

Down syndrome (DS) is the most common syndrome associated with the presence of an intellectual disability, affecting approximately 3.3–6.7 per 10,000 individuals worldwide [1]. Family members and clinicians have noted the occurrence of cognitive deterioration and skills loss specifically in a small portion of adolescents and young adults, often without a distinct cause. This unexplained regression is profound and has a serious impact on both the individual and their families. A great number of different terms have been used in the diagnosis of this regression. Recently, "Down syndrome disintegrative disorder" (DSDD) and idiopathic regression in DS (IRDS) have been used more frequently. The latter term, IRDS, will be used in this review.

Despite the occurrence of IRDS being well-recognised by clinicians as affecting a minority of young people with DS, research in this area is sparse [2–4]. Characteristically, the symptoms and signs of this condition include significant impacts on the person's cognitive and language functioning, their ability to perform daily tasks, a considerable loss of previously acquired daily skills, mild to severe alterations in personality and behaviour

**Citation:** Walpert, M.; Zaman, S.; Holland, A. A Systematic Review of Unexplained Early Regression in Adolescents and Adults with Down Syndrome. *Brain Sci.* **2021**, *11*, 1197. https://doi.org/10.3390/ brainsci11091197

Academic Editor: Margaret B. Pulsifer

Received: 12 July 2021 Accepted: 8 September 2021 Published: 10 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

and the onset of social withdrawal. IRDS is described by families as having a profound effect on the abilities of the person with DS to live as they have previously been able to. This has a knock-on effect on members of their family and other carers, and often results in the need for major changes in their living situation and care needs.

This condition typically occurs in early adolescence to young adulthood and there are currently no confirmed causes or triggers and no consistent treatment pathways. In IRDS, presenting symptoms sometimes overlap with features of autism and dementia, however the age profiles for these other conditions are different. Autism spectrum disorder (ASD) presents in early childhood and a diagnosis of Alzheimer's disease (AD), based on the onset of clinical symptoms, is most commonly made in the fifth decade. With dementia in people with DS, the neuropathological hallmarks are often seen earlier, (around the 40s) [5,6], but a clinical diagnosis of dementia is not usually made until the patient is in their 50s. This high risk of AD for people with DS is customarily theorised to be linked to the triplication of chromosome 21 and therefore the presence of three copies of the amyloid precursor protein gene, and the resultant lifelong overproduction of the beta-amyloid (Aβ) protein [7]. Despite the high risk of AD specific to people with DS, there is minimal evidence to suggest that AD presentation occurs at the age when individuals are most likely to be affected by IRDS. Furthermore, with IRDS there is often stabilisation and/or recovery of symptoms, as opposed to when it is dementia where progression with no recovery is what is to be expected. It is generally accepted that IRDS symptoms are not a consequence of either the above conditions and should be considered as separate.

A recent paper by Santoro et al. [4] reported the findings from a retrospective chart review of 35 people with DS and regression. Using a checklist of symptoms were classified into five core "features" including: (a) adaptive functions, (b) functional and procedural memory deficits (c) motor control impairment; (d) catatonia and; (e) disturbances associated with mental ill-health. The strengths of this study included the analysis of symptomatology in a group of people with DS, who experts had agreed had unexplained regression, and the use of an agreed checklist of symptoms. Most importantly, and uniquely in this field, this study compared symptomatology and test scores of patients with an agedmatched group of people with DS with no evidence of IRDS, thus helping to validate the recorded clinical observations. The authors do not report the temporal sequence of specific clinical symptoms. However, the majority of symptoms identified in those with IRDS were not experienced in the healthy controls, the exceptions to this being the mental health categorisations and externalising behaviours (hyperactive, irritable, disruptive, agitated) where there were no significant differences between IRDS and DS groups.

During the preparation of this systematic review another review paper was published summarising reported studies of regression in people with DS [8]. This paper identified language regression, mood disturbance and new onset insomnia as being particularly common features. They proposed that there were two potential causative mechanisms, one relating to immune dysfunction, and the other being stress related. Clinically, it was argued that an extensive work-up is still required to identify possible rare causes of regression, including the co-occurrence of other genetic disorders, such as Lesch Nyhan syndrome, in which a similar regression occurs but much earlier in life. Our systematic review complements this paper, drawing in greater depth on case studies as well as reports on case series of IRDS in adolescents and young adults with DS, and examining how symptoms cluster and co-present. Our primary objective, by extending the work undertaken by Rosso et al. [8], was to help improve diagnosis by heightening awareness of this condition among clinicians and providing further details of the main characteristics and their relationships to each other. We also reflect on terminology, clinical practice and possible causation.

Our review has focussed on observations from case studies and research on IRDS in adolescents and young adults with DS. The specific aims were to identify patterns of (a) symptomology, (b) potential trigger events and, (c) prognosis, treatments and outcomes. Possible causation will be considered to highlight the need for treatment trials for this

condition based on the understanding of causal mechanisms. In addition to raising awareness of the condition we highlight the importance and necessity of further research of this condition.
