Psychiatric and neurological manifestations in adults with Smith–Magenis syndrome: A scoping review

Smith–Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a 17p11.2 deletion or a pathogenic variant of the RAI1 gene, which lies within the 17p11.2 region. Various psychiatric and neurological disorders have been reported in SMS, with most literature focusing on children and adolescents. To provide an overview of the current knowledge on this topic in adults with SMS, we performed a comprehensive scoping review of the relevant literature. Our findings suggest that many manifestations that are common in childhood persist into adulthood. Neuropsychiatric manifestations in adults with SMS include intellectual disability, autism spectrum‐ and attention deficit hyperactivity disorder‐related features, self‐injurious and physical aggressive behaviors, sleep–wake disorders, and seizures. Findings of this review may facilitate optimization of management strategies in adults with SMS, and may guide future studies exploring late‐onset psychiatric and neurological comorbidities in SMS.

Although it has been recognized that the manifestations of SMS may change over the lifespan (Siegel & Smith, 2011), research into the phenotype of SMS has focused mainly on children and adolescents.
Insight into the knowledge on psychiatric and neurological manifestations of SMS in adults is important because it facilitates care planning for adolescents and (young) adults with SMS and their families, and improves clinical recognition and initiation of treatment (Gropman et al., 2006;Siegel & Smith, 2011).Also, it is important to identify knowledge gaps throughout the life span, to guide future studies exploring the psychiatric and neurological phenotype in adults with SMS.Therefore, in this review, we aim to provide a comprehensive overview of the literature on psychiatric and neurological manifestations in adults with SMS.

| Literature search and identification of the evidence
A scoping review was performed in accordance with the Preferred Reporting for Systematic Reviews and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR) checklist (Tricco et al., 2018).PubMed (Medline) and Embase were searched on July 1, 2022.Guided by an academic librarian, the search queries included combinations of the following terms: "Smith-Magenis syndrome," "RAI1," "17p11.2"and "neuropsychiatry," "neurology," "psychiatry," "mental disorders," or "intellectual disability." The search had no year or language restrictions.Reference lists of the included studies were searched for cross-references.For details of the search queries, see Supporting Information 1.
All records identified by the searches were imported into Endnote to remove any duplicates (Bramer et al., 2016).Subsequently, all remaining records were imported into the web application Rayyan (https://rayyan.qcri.org)and screened for potential relevance based on title and abstract.After independent screening by two of the authors, discrepancies were discussed until consensus was reached between all authors.If the title and abstract did not provide sufficient information, full-text articles were assessed for eligibility.

| Inclusion criteria
Publications were included when the following criteria were met: (a) the study included one or more adults (aged 18 years or above) with a molecularly confirmed diagnosis of SMS; (b) the paper reported on a trial, cohort study or case study with specific mention of psychiatric and/or neurological manifestations at adult age; (c) the paper was written in English; (d) the study was published in a peer-reviewed journal or conference (abstract) book.Reports with no original data and data without clear distinction between children and adults were excluded from this review.

| Data extraction and synthesis
All relevant articles were screened by one author against inclusion criteria for inclusion in the review based on full text.Subsequently, data were extracted by one of the authors, comprising: general information (e.g., author(s), year of publication, study design, and number of subjects reported to have SMS), demographics (e.g., age and sex), genetic data (e.g., genetic subtype; 17p11.2deletion vs. pathogenic RAI1 variant), and psychiatric and neurological features (e.g., severity of intellectual disability, autism spectrum-and/or attention deficit and hyperactivity disorder [ADHD]-related features, and seizures/epilepsy), any effects of age, and additional genomic variants of potential clinical relevance.Neuroimaging results (e.g., from magnetic resonance imaging or computerized tomography scans), signs of peripheral neuropathy (e.g., decreased pain sensitivity) which may possibly also relate to maladaptive and SIB such as onychotillomania (Smith et al., 2022), and hypotonia were considered to be outside of the realm of this scoping review.A qualitative synthesis of the studies was outlined by one of the authors and further shaped by the collective group of authors.

| RESULTS
The screening of titles and abstracts yielded 75 reports which were further assessed for eligibility (see PRISMA flow diagram; Figure 1).Twenty-three records met the inclusion criteria: 4 cross-sectional studies (Table 1) and 19 case studies (Table 2).All studies were published in peer-reviewed journal articles, with the exception of one conference abstract (Piskorski et al., 2014).The cross-sectional studies reported on at least 25 adults with SMS (10 males, 7 females, sex not reported for the remainder).In the absence of exact numbers of adults included, we were unable to provide percentages of sex, age, and genetic variant.The case studies reported on a total of 28 (46.4% male, 35.7% female, 17.9% sex not reported) adults with SMS, at median age of 28.5 (range 18-65) years.Nineteen (67.9%) cases had a 17p11.2deletion, 8 cases (28.6%) a pathogenic RAI1 variant, and for one individual (3.6%) the genetic subtype was not specified.

| Impaired intellectual functioning
Three of the four cross-sectional studies reported on intellectual functioning in adults with SMS.Os orio et al. (2012) used the Wechsler Adult Intelligence Scale 3rd edition (Wechsler, 1997).They found that their entire cohort scored a full-scale intelligence quotient (FSIQ) that placed them in the mild to moderate intellectual disability range (n = 6, mean = 49.17,SD = 2.40, range = 48-54), with significant impairments in all four indices, that is, perceptual organization, processing speed, verbal comprehension, and working memory.Sloneem et al. (2011) and Nag and Naerland (2021) also reported a high prevalence of intellectual disability in their adult cohort (n = 8, 100% and n = 11, 91%, respectively).
For 25 individuals in the case studies, information about intellectual functioning was provided.All 25 individuals were reported to have intellectual disabilities.For 10 of these individuals, the FSIQscores were reported, ranging from 30 to 70.For most, it was however unclear which instrument was used to establish FSIQ-scores.and adults with SMS, using the Activity Questionnaire (Burbidge & Oliver, 2008).Of the adults, 58.3% had heightened levels of impulsivity and 16.7% had heightened levels of hyperactivity.
In the case studies, 11 (39.3%) of the included individuals were reported to exhibit core ASD-and/or ADHD symptoms, including uneasiness in social contexts, repetitive and stereotypic behaviors, attention deficits, hyperactivity, and impulsivity.Two (7.1%) of these individuals received a formal clinical diagnosis of ASD (Abad et al., 2018;Boudreau et al., 2009).One of these individuals received a formal clinical diagnosis of ADD (Girirajan et al., 2005), and one received a formal clinical diagnosis of ADHD (Maya et al., 2014).Sloneem et al. (2011) noted that at least seven out of the eight (87.5%)adults included exhibited SIBs.The other cross-sectional studies did not provide any information on SIBs.

| Self-injurious behaviors
In the case studies, half of the included cases (14 out of 28; 50.0%) were reported to exhibit some form of SIB.For 10 cases, the specific types of SIBs were detailed.Onychotillomania, that is, a compulsive urge to bite, chew, pick at, or pull off nails, was reported most frequently (nine cases, 31.4%).Other frequently reported SIBs were head banging and/or face slapping and (hand) biting, both reported in seven cases (25.0%).Other SIBs observed in adults with SMS included polyembolokoilamania, inserting foreign items into the vagina or rectum, wound prodding, skin picking, kicking, and grabbing.Sloneem et al. (2011) investigated the prevalence and phenomenology of physical aggressive behavior towards others in eight individuals with SMS.They found that these behaviors were seen in all included adults, in particular hitting.Other common aggressive behaviors were grabbing (n = 7, 87.5%), kicking (n = 6, 75.0%), throwing items at people (n = 5, 62.5%), pinching (n = 4, 50.0%), and biting (n = 4, 50.0%).

| Physical aggressive behaviors
Within the case studies, nine individuals (32.1%) were reported to exhibit some form of aggressive behaviors.

| Self-hugging/arm and/or hand-squeezing behaviors
Across the cross-sectional studies, no information was provided on self-hugging/arm and/or hand-squeezing behaviors.In one of the case T A B L E 1 Cross-sectional studies.studies, Finucane et al. (1994) focused on detailing the arm and handsqueezing behavior of six adults with SMS.They interpreted these behaviors to be tic-like, and noted that they often manifested as a selfhug.One of the six individuals (16.7%) was reported to also demonstrate self-hugging behavior.In addition to the cases described by Finucane et al. (1994), five more cases were reported to exhibit selfhugging behavior (Boudreau et al., 2009;Slager et al., 2003;Yeetong et al., 2016).In total, 11 out of 28 cases (39.3%) were reported to present with either self-hugging and/or arm and hand-squeezing behavior.

| Sleep-wake disorders
The cross-sectional studies did not provide any details on reported sleep-wake disorders in SMS adults.In the 28 case studies, 14 cases (50.0%) were reported to exhibit sleep-wake disorders.

| Seizures/epilepsy
The cross-sectional studies did not provide any details on seizures or epilepsy.In the case studies, five (17.9%) adults with SMS were reported to have a history of recurrent seizures.For three of them, it was specified that they experienced tonic-clonic seizures (Abad et al., 2018;Maya et al., 2014) or absences (Truong et al., 2010).One additional adult was reported to have a history of psychogenic nonepileptic seizures, consisting of hyperventilation with tremors and a rapid pulse (Yeetong et al., 2016).None of the adults were reported to have a formal diagnosis of epilepsy.Also, catamenial seizures, which are reported to be common in SMS (Merideth et al., 2016;Smith & Gropman, 2021), were not reported in any of the cases.

| Other neurological manifestations
One case report noted a spastic leg in a 59-year-old male patient with SMS (de Rijk-van Andel et al., 1991).

| Manifestations and their relationship with genetic subtype
None of the studies reported any comparisons in the prevalence, phenomenology, or severity of psychiatric or neurological manifestations between adults with a 17p11.2deletion and those with a pathogenic RAI1 variant.

| Additional genetic variants of clinical relevance
Two of the included cases were reported to have an additional genetic variant of clinical relevance: a 15q13.3duplication (Acquaviva et al., 2017), and a pathogenic variant in the EHMT1 gene associated with Kleefstra syndrome (Abad et al., 2018), respectively.One case was reported to present with the Joubert syndrome phenotype; however, no causative pathogenic gene variants were known at the time of publication (Natacci et al., 2000).

| DISCUSSION
This study is the first to provide an overview of the psychiatric and neurological manifestations in adults with SMS.The findings of this study suggest that various psychiatric manifestations of SMS that are commonly seen in children and adolescents, and which can have a negative effect on quality of life (Harpin, 2005;Mason et al., 2018;Roth, 2007;Symons et al., 1999), may persist in adulthood (Gropman et al., 2006;Siegel & Smith, 2011).This also suggests that, due to the complex neuropsychiatric profile, lifelong multidisciplinary evaluation, surveillance, and management remain necessary (Smith et al., 2022).
In line with previous research in children (Girirajan et al., 2006;Madduri et al., 2006;Smith et al., 1998), intellectual and developmental disabilities were the most frequently reported neuropsychiatric manifestations in adults with SMS.Although ASD-and ADHD-related features were reported in a substantial proportion of the cases (40% of the case studies), only two individuals received a formal diagnosis of ASD and two of AD(H)D.We propose that systematic studies using standardized diagnostic methods for neurodevelopmental disorders are needed to provide a better insight in the prevalence and expression of these treatable disorders in adults with SMS.Taking into account that "standardized diagnostic methods" have typically not been validated in SMS.
The findings of this review also suggest that SIBs and aggressive behaviors persist in adulthood in a substantial majority of cases.Given that these behaviors are associated with a significant burden for individuals with SMS and their relatives, further studies investigating risk/ contributing factors and strategies to reduce the frequency and severity would be highly valuable.An example of how a specific strategy may be beneficial was provided by Bass and Speak (2005), who described an effective management strategy aimed at reducing SIB in an SMS adult.However, as is typical in genetic neurodevelopmental disorders, systematic studies on treatment efficacy are lacking in adults with SMS.For future research, N-of-1 studies may be considered as a good alternative for large double-blind, randomized placebocontrolled clinical trials that are unfeasible in rare conditions such as SMS (Müller et al., 2021).
Self-hugging/arm and hand-squeezing behavior was reported in a substantial proportion of adults (40% of the case studies).It has previously been proposed that the prevalence may be even higher, because self-hugging/arm and hand-squeezing behavior is perceived as a benign activity that may not be mentioned to clinicians by caregivers (Finucane et al., 1994).Self-hugging/arm and hand-squeezing behavior is generally observed in people with SMS when they are relaxed, happy and/or excited.Whether this behavior may be correlated with other, more harmful behaviors, is unclear from the literature and may warrant further exploration (Finucane et al., 1994).
In about half of the cases included in this review, sleep-wake disorders were reported.Disturbed sleep, characterized in SMS by early sleep onset, frequent awakenings, early sleep offset, and deficits in REM sleep, is usually attributed to an inverted melatonin circadian rhythm (De Leersnyder, 2006;De Leersnyder et al., 2001;Potocki et al., 2000;Vieira et al., 2012).It has been hypothesized that the lifelong sleep-wake disorders that many SMS patients experience also relate to many psychological and behavioral symptoms (Shelley & Robertson, 2005).This idea is strengthened by the observation of a positive correlation between severity of sleep-wake disorders and psychological and behavioral manifestations in children (Garayzábal et al., 2022).Additionally, De Leersnyder et al. (2001) reported that behavioral problems in children with SMS were reduced upon treatment of the sleep-wake disorders (De Leersnyder et al., 2001).The relationships between sleep and behavioral problems reinforce the importance, and possibility, of addressing sleep-wake disorders in the formulation of management strategies for adults with SMS.
In line with previous research in children and adults (Goldman et al., 2006;Greenberg et al., 1996), seizures were reported in approximately 20% of the adults with SMS.Of note, previous research has not found a correlation between the age of individuals with SMS and onset of seizures (Goldman et al., 2006).
Due to the low number of cases with a pathogenic RAI1 variant reported in the adult literature reviewed, no inferences can be drawn about variant-specific manifestations.However, previous research suggests that deletion size and genetic subtype influences cognitive functioning in people with SMS (Madduri et al., 2006).Future research into the potential differences in neuropsychiatric phenotype in individuals with a 17p11.2deletion versus those with a pathogenic RAI1 variant, and the effect of deletion size in those with a 17p11.2deletion, may facilitate personalized management strategies.As three of the reported cases had a second genetic variant of clinical relevance, for those cases, it cannot be ruled out that the psychiatric symptoms were (partly) related to the additional genetic variant (Budisteanu et al., 2021;Bulgheroni et al., 2016;Kleefstra & de Leeuw, 2019).
The main candidate gene for the SMS phenotype, including the psychiatric and neurological manifestations studied in this review, is RAI1, that encodes a protein that acts as transcriptional regulator and is involved in neurodevelopment and neurotransmitter function (Elsea & Williams, 2011).It also plays an important role in circadian rhythm regulation through the transcription of circadian locomotor output cycles kaput (Williams et al., 2012).Longitudinal studies fol- This may be particularly the case for non-intrusive behaviors as these may be perceived as less disruptive than acting-out behaviors.Also, as not all case reports described the same set of manifestations, the overview provided contains missing information.Additionally, as the age of onset of manifestations was not always clear in the literature reviewed, studies reporting on psychiatric and neurological manifestations in adults may have been excluded from this review, and it is possible that manifestations included in the review were no longer present in adulthood.Finally, the limited number and heterogeneity of studies covered by the literature search makes it challenging to compare results, in particular with regard to the frequency of manifestations in SMS.
In summary, this scoping review found that the most commonly reported psychiatric and neurological manifestations in adults with SMS were intellectual disability, features of ASD and ADHD, SIB, aggressive behaviors, self-hugging/arm and/or hand-squeezing behavior, sleep-wake disorders, and seizures.While this comprehensive overview may facilitate clinical recognition and initiation of treatment, there is also a need for systematic studies that: (1) apply deepphenotyping methods to thoroughly explore psychiatric and neurological manifestations in people with SMS across their life span, also including symptoms/disorders that were not studied in this research (e.g., peripheral neuropathy), ( 2) investigate the relevance of the different genetic subtypes on these manifestations, and (3) investigate the efficacy of pharmacological and non-pharmacological management strategies on symptomatology and quality of life for patients and caregivers.

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I G U R E 1 PRISMA 2020 flow diagram.Adapted from: Page et al. (2021).
lowing well-phenotyped individuals with SMS, connecting genetic studies and in vivo measurements such as neuroimaging, electrophysiology, and behavioral and psychiatric assessments might provide insight into pathophysiological mechanisms underlying the expression of psychiatric and neurological manifestations in SMS.Strengths of this review include the systematic search strategy guided by an academic librarian and the involvement of clinical researchers with expertise in SMS and other genetic neurodevelopmental disorders from different backgrounds (JZ; Child and Adolescent, and Adult Psychiatry, EB; Intellectual Disability Medicine).A limitation of this study is the potential influence of publication bias.