Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

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Teresa Kohlenberg, M. Pilar Trelles, Brittany Mclarney, Catalina Betancur,

Audrey Thurm, Alexander Kolevzon

To cite this version:

Teresa Kohlenberg, M. Pilar Trelles, Brittany Mclarney, Catalina Betancur, Audrey Thurm, et al..

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. Journal of

Neu-rodevelopmental Disorders, BioMed Central, 2020, 12 (1), pp.7. �10.1186/s11689-020-9309-6�.

�inserm-02479574�

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R E S E A R C H

Open Access

Psychiatric illness and regression in

individuals with Phelan-McDermid

syndrome

Teresa M. Kohlenberg

1*

, M. Pilar Trelles

2,3

, Brittany McLarney

4

, Catalina Betancur

5

, Audrey Thurm

6

and

Alexander Kolevzon

2,3

Abstract

Background: Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood.

Methods: Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison.

Results: The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events.

Conclusions: This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS.

Keywords: Phelan-McDermid syndrome, SHANK3, Mania, Depression, Bipolar disorder, Psychosis, Catatonia, Regression

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence:tesik@rcn.com

1_{Department of Psychiatry, University of Massachusetts Medical School,}

Worcester, MA, USA

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Background

Phelan-McDermid syndrome (PMS) is a neurogenetic

syndrome caused by haploinsufficiency of the SHANK3

gene due to a spectrum of anomalies in the terminal re-gion of the long arm of chromosome 22, ranging from single-nucleotide variants to large deletions affecting multiple genes [1]. SHANK3 is a key structural protein in excitatory synapses, with several isoforms with differ-ent functions in developmdiffer-ent and in the synapse [2,3].

Deletions or sequence variants of the SHANK3 gene are

associated with the neuropsychiatric manifestations of the syndrome and required for the diagnosis of PMS [4– 7]. Individuals with PMS often present with intellectual disability (ID), features of autism spectrum disorder (ASD), hypotonia, and severely delayed or absent speech [8–10]. Genotype-phenotype studies in individuals with terminal deletions have found that the severity of speech impairment and intellectual disability increases with in-creasing deletion size [8,9]. In one recent study examin-ing phenotypic manifestations among 17 individuals with sequence variants within SHANK3 [7], the majority developed single words, and 44% had phrase speech, in contrast to more severe impairment in individuals with deletions.

Epilepsy is reported in 17% to 70% of individuals with PMS [9, 11–14]. As individuals with PMS age, they ap-pear to be at increased risk for bipolar disorder [15–20] and an associated risk of significant cognitive and behav-ioral regression [5, 6, 16, 18–20]. Indeed, SHANK3 vari-ants have been implicated in the risk for severe neuropsychiatric disorders, including mood and psych-otic disorders [15, 16,19, 21,22]. Gauthier et al. (2010) identified sequence variants in theSHANK3 gene in four individuals initially diagnosed with atypical, early-onset schizophrenia, and a history of borderline to mild intel-lectual disability [21]. Catatonia, a unique syndrome of motor and autonomic dysregulation associated with a variety of psychiatric and medical conditions, has also been described in PMS [7,15,22,23]. Of note, catatonia in pediatric populations and in individuals with develop-mental disabilities often goes unrecognized [24] and poorly treated [25].

A few previous cross-sectional studies have used sys-tematic methods to characterize the behavioral profile of individuals with PMS across the lifespan [19, 26–28]. However, the nature and course of psychiatric symptoms in PMS, and in particular their association with regres-sion occurring much later than the early childhood re-gressions typical of ASD, have not been extensively documented. In this retrospective study, we collected de-velopmental histories, behavioral profiles, and genetic findings of 38 adolescents and adults with PMS and psy-chiatric illness with the aim to (1) better characterize the psychiatric and developmental phenomena reported in

PMS and (2) aid in early recognition and treatment optimization.

Methods

Participants and procedures

The study was approved by the Institutional Review Board of the PMS International Registry (PMSIR) (https://www.pmsf.org/registry/). Informed consent for participation in the Registry was obtained from the par-ents or legal guardians of participants, who also signed a release for inclusion in publication, and for integration of their interview data with their PMSIR data. Families were recruited by outreach through the PMS Foundation community Facebook page, and families were specifically invited to participate if the individual with PMS had ex-perienced distinct psychiatric changes, such as mood ep-isodes, psychosis, marked changes in sleep and energy, major loss of skills, sudden new intense obsessive-compulsive behaviors, or other neuropsychiatric difficul-ties, with or without regression. Families either con-tacted the researcher (TMK) directly in response to the Facebook message or responded after other families relayed the recruitment message on Facebook to parents with possible clinical concerns as described. In addition to the 37 English-speaking families, six families were re-ferred through the PMS Spanish Association, and two enrolled and completed the study procedures.

Thirty-seven caregivers completed interviews on 39 participants and provided informed consent; one partici-pant was excluded from the analysis since criteria were not met for a distinct psychiatric episode. Three families had responded to the invitation but did not complete in-terviews or consent after an initial contact established that they did not meet criteria for a distinct psychiatric episode. The final sample included 38 individuals from 36 families, ranging in age from 13 to 50 at the time of contact. The sample includes two sets of monozygotic twins with both twins enrolled. Caregivers interviewed were mothers in all but one case, in which the respond-ent was a sibling who was the legal guardian. Interviews were conducted in English (n = 34) or Spanish (n = 2), and respondents lived in the USA (n = 29), Australia (n = 4), Canada (n = 1), England (n = 1), Netherlands (n = 1), and Spain (n = 2).

Measures

A semi-structured interview entitled the Caregiver Inter-view for Psychiatric Illness in Persons with ID (see

Add-itional file 1) was developed by TMK and conducted

with caregivers by child and adolescent psychiatrists (TMK for English interviews and MPT for Spanish inter-views). The interview includes questions designed to elicit descriptions of the participant’s developmental his-tory, major health challenges, the emergence and course

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of episodes of psychiatric illness or regression, response to pharmacologic treatment, and current level of func-tioning. Interviews typically lasted 90 min. All final notes were reviewed and approved by the families before in-clusion in the study.

Genetic reports were obtained for all participants and reviewed by the geneticist (CB) curating results for the PMSIR. PMSIR data were used to confirm genetic re-sults for study participants and for comparisons of prevalence of genetic variants, age, and gender. However, only 21 of 38 participants in this study had completed the PMSIR clinical and developmental questionnaires, limiting direct comparisons of clinical data between study participants and other Registry members. Nine of 38 participants were not enrolled in the Registry prior to study participation.

Comparisons between functional status and develop-mental milestones in study participants vs Registry data included parent report of whether key developmental skills were ever achieved on the Caregiver Interview (for the study sample) and on the Registry’s Developmental Questionnaire for a group of respondents of similar age, with Registry data excluding the participants who were enrolled in the current study.

Assessment of behavioral symptoms and labeling of psychiatric diagnoses in the context of neurodevelop-mental disorders is complicated by cognitive and com-municative limitations, atypical presenting features, and premorbid characteristics (e.g., echolalia, repetitive be-haviors). The Diagnostic and Statistical Manual for Men-tal Disorders, 5th edition [29] does not comprehensively include modifications of all diagnostic criteria for differ-ential manifestations that may present in the context of intellectual disability, and there is a dearth of psycho-metrically rigorous instruments validated for psychiatric evaluation in this population. Therefore, we used the Diagnostic Manual - Intellectual Disability, Second Edi-tion (DM-ID-2) [30] to classify psychiatric episodes. The DM-ID-2 is based on the DSM, adapted to include care-giver observations of behavior and to reduce the number of symptoms required to make diagnoses where persons with intellectual disability may not be able to report ex-periences [31]. All cases were reviewed by a child and adolescent psychiatrist (TMK) using a checklist of DM-ID-2 criteria for each of these disorders. The symptoms reported by caregivers during acute episodes met criteria for major depressive episode, manic episode, obsessive-compulsive disorder, generalized anxiety disorder, brief psychotic disorder, schizoaffective disorder, and catato-nia associated with another mental disorder (see Add-itional file 2). In addition, two child and adolescent psychiatrists (MPT, AK) randomly reviewed and classi-fied eight cases to assure accuracy of diagnostic classifi-cation. Agreement on the presence of a mood disorder

was 100%, agreement on whether the first mood episode was depressive or manic was 88%, and agreement on the presence of catatonia was 88%.

The word“regression” is often used to describe a wide variety of states, including transient loss of skills during psychiatric episodes with and without catatonia. For clarity, “regression” was defined in this study as a pro-longed loss of previously acquired skills that either (a) began when the individual was psychiatrically well or (b) began during a psychiatric episode, with loss of skills persisting for at least 6 months beyond the resolution of the psychiatric episode.

Results

Descriptive statistics and comparisons to participants in

the PMSIR are reported in Table 1. Summaries of case

histories and genetic findings are reported in Table 2. There was a strong female predominance in this sample (31 females, 7 males) whereas PMS typically affects males and females in equal proportion. There were 23 individuals with terminal deletions, with a mean size of 1.63 Mb (range 160 kb–6.41 Mb). Five deletions were secondary to a chromosomal rearrangement: a ring chromosome 22 in three individuals and an unbalanced translocation in two. Twelve individuals with terminal deletions had not had a karyotype, so the possibility of a ring chromosome 22 cannot be excluded. Fifteen

indi-viduals had pathogenic sequence variants in SHANK3

(12 frameshift variants and 3 nonsense variants).

As compared with the 509 PMSIR registrants not in this study who had genetic data available, sequence

vari-ants in SHANK3 were present at higher rates in our

sample (39% [15/38] vs 6% [32/509]; Fisher’s exact test, p = 4 × 10− 8_{), and conversely, terminal deletions were}

less frequent (61% [23/38] vs 92% [467/509]; Fisher’s exact test, p = 8 × 10− 7). Comparisons with 130 PMSIR registrants of similar age with questionnaire data avail-able are also reported in Tavail-able 1. In addition, deletions tended to be smaller in the participants of this study than in the PMSIR (mean size 1.634 Mb vs 3.633 Mb; unpaired two-tailed Student’s t test, p = 0.0019). In par-ticular, individuals with small deletions, defined as those including at most the four distal genes,ARSA, SHANK3, ACR, and RABL2B, are over-represented among study participants compared to the PMSIR (57% [12/21 dele-tions with size information] vs 19% [72 /387]; Fisher’s exact test, p = 1.6 × 10− 4). (Heterozygous loss of ARSA, ACR, and RABL2B does not contribute to the PMS phenotype, so deletions including these genes are equivalent to deletions involving onlySHANK3.)

Developmental history

Although documentation of the severity of ID was not available, reported levels of adaptive functioning suggest

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that mild to moderate ID was common in this sample prior to the onset of psychiatric symptoms and regres-sion and that these individuals were less impaired prior to their psychiatric illness as compared to the PMSIR reference sample (Table1). Prior to the onset of psychi-atric illness, study participants were significantly more likely than participants in the PMSIR sample to ever have walked independently, achieved toilet training, ver-bal expression with at least phrase speech, and inde-pendence with dressing.

Psychiatric illness

Psychiatric difficulties began between ages 10 and 18 in the majority of cases (28/38; 74%). Psychiatric symptoms emerged between the ages of 7 and 10 years in 5/38 cases (13%), while 5/38 cases (13%) developed psychi-atric symptoms between ages 21 and 32. Using the DM-ID-2, first episodes met criteria for a manic episode in 17/38 cases (45%) and for a depressive episode in 14/38 cases (37%). First episodes in the remaining cases in-cluded six (16%) with a mixture of mood and anxiety symptoms, and one case of disorganized, bizarre behav-ior that suggested a brief psychotic episode.

Most participants (27/38; 71%) had experienced a mood episode in the year before the study. The after-math of acute episodes was associated with higher base-line levels of anxiety and irritability and with regression.

Subsequent psychiatric episodes were superimposed and caregivers clearly distinguished episodes from baseline states. First episodes ranged from 8 months to 35 years before study participation. Reported episode length var-ied from periods of days to months. Most cases (34/38; 89%) had multiple distinct episodes consistent with a mood disorder, including 12 of 38 (32%) with two to four distinct episodes, 6 of 38 (16%) with five to nine ep-isodes, and 16 of 38 (42%) with more than ten episodes (see Table 2for details). Few cases (4/38; 11%) reported only a single psychiatric episode; all four of these were within the 3 years prior to study participation.

Twenty-nine of 38 cases (76%) reported a manic epi-sode at some point in their illness; 24 of 38 (63%) re-ported both manic and depressive episodes. Nineteen of 38 cases (50%) were reported to have had psychotic symptoms during an acute mood episode. One partici-pant presented with both depressive and manic episodes and with psychosis in between mood episodes, suggest-ing schizoaffective disorder.

New anxiety symptoms accompanied mood episodes in the majority of participants (26/38; 68%). Six partici-pants (16%) met criteria for obsessive-compulsive dis-order at some point in the course of their illness. Four participants (11%) met criteria for generalized anxiety disorder. Only two participants (5%) had first episodes that were predominantly anxious.

Table 1 Demographic and clinical variables in the study sample as compared to the Phelan-McDermid Syndrome International Registry (PMSIR) participants 13 or older

This study (n = 38) PMSIR (n = 130) Comparison

Mean age at data collection 24.7 years ± 9.92 20.8 years ± 7.65 t(166) = 2.56, p = .011

χ2 (1) = 10.21, p = .001 Gender Male 18% (7/38) 47% (61/130) χ2(1) = 10.20, p = .001 Female 82% (31/38) 53% (69/130) Genetic defecta Terminal deletion 61% (23/38) 91% (118/130) χ2(1) = 19.79, p < .001 Interstitial deletion – 2% (3/130)

SHANK3 sequence variant 39% (15/38) 7% (9/130)

ASD diagnosis (ever)d 55% (21/38) 41% (37/91b) χ2(1) = 2.105, p = .147

History afebrile seizure(s) 39% (15/38) 41% (37/91) χ2(1) = .044, p = .834

Walked independently (ever) 100% (38/38) 81% (64/79c) χ2(1) = 8.212, p = .004

Spoke in phrases or sentences (ever) 79% (30/38) 51% (40/79) χ2(1) = 8.317, p = .004

Toileted independently“always” or “sometimes” (ever) 89% (34/38) 48% (38/79) χ2(1) = 18.029, p < .001

Dressed self independently (ever) 78% (30/38) 42% (33/79) χ2(1) = 13.26, p < .001

Chronic constipation 84% (32/38) 15% (14/91) χ2(1) = 55.428, p = <.001

Acute urinary retention 47% (18/38) 3% (3/87) χ2(1) = 37.091, p < .001

a

Among all Registry participants (n = 509, excluding the study participants), there are 467 terminal deletions (92%), 10 interstitial deletions (2%) and 32 sequence variants (6%)

b

91 participants in this age range (excluding the study participants) completed the Registry Clinical Questionnaire

c

79 participants in this age range (excluding the study participants) completed the Registry Developmental Questionnaire

d

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Table 2 Case summaries Case # Gende r Age at time of study Genetic de fect Level of functioni ng prior to onset psychiat ric ill ness 1

Reported possible triggeri

ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained Case 1 Fema le 18 years 9 mont hs Term inal dele tion [89 kb] arr[hg1 9] 22 q13.33( 51, 122,483 -51,21 1,392)x1 Phrase speech Toilet trained Dressed self Fed se lf Indepen dent for hygie ne Read sig ht words Counte d to 100 None note d Age 14 First episod e depre ssed with new tics , fecal smearing Then, OCD, new pica, manic episod e and cataton ia Three ep isodes Age 14 Decre ased spee ch Decre ased eye cont act New onset inco ntinenc e Un able to dress se lf Lo st all aca demi c skills Mood ep isode in pas t year Four years since regressi on Minim al recove ry Occas ional mean ingful speech and singing Intermit tent feed ing self with utens il Case 2 Fema le 29 years 6 mont hs Mosaic term inal de letion and interstiti al dupli cation [4.4 Mb] 46,XX; arr[ hg19] 22q1 3.2q13.3 1 (43,6 75,642-4 6,807,3 66)x3[0 .65], 22q13. 31q13.3 3(46, 808, 071-51,197, 838)x1[ 0.65] Single words Toilet trained Pretend play wit h do lls Program transition Age 27 First episod e depre ssed with catato nia Then new general ized anxiet y disorde r (GAD) One mood ep isode Ongoing GAD Age 27 Decre ased spee ch Inc ontinen t Decre ased indepe ndence in ADLs Decre ased preten d pla y Two years sinc e mood episod e Two years sinc e regres sion No reco very Case 3 Fema le 18 years 0 mont h Term inal dele tion –unba lanced transloc ation [207 kb ] 46,XX; arr[ hg19] 3p26 .3 (180, 509-2,09 7,153)x3 , 22q13. 33(50,990 ,475-5 1, 197,838 )x1 Spoke in full senten ces Toilet trained Wrote sim ple text Used iPad URI Beginni ng new schoo l Age 12 First episod e OCD dx PAN DAS Then de pressed wit h new tics, trem ors an d posturing, Then mi xed manic an d de pressed symp toms with new aggres sion, new an xiety at leaving hou se Four episod es (thre e mood ) Age 15 Decre ased spee ch clarity Frequ ent urin ary incon tinence Decre ased indepe ndence in ADLs Mood ep isode in pas t year Three years since regressi on Moderate recove ry Still unpredictably incon tinent Speec h improve d, still dysfluent Case 4 Fema le 22 years 3 mont hs Term inal dele tion – ring 22 46,XX,r [ 22 ](p13 q13.3).ish r[ 22 ](ARS A-) Phrase speech Neve r toile t train ed Dressed self with prom pts Read som e sig ht words Did puzzles URI Age 16 First episod e depre ssive symp toms 5 Then mani c symp toms with hand posturing an d gai t disturbance Three moo d ep isodes Age 16 Decre ased spee ch Decre ased response to envi ronme nt Decre ased orien tation Mood ep isode in pas t year Six years since reg ression Skills cont inue to deteriorate Case 5 Male 36 years 1 mont h Term inal dele tion [106 kb ] 46,XY; arr[ hg18] 22q13. 33 (49,4 74,771-4 9,581,3 09)x1 Full sen tences Toilet trained Dressed self Did all self-c are Indepen dent with own routine s Able to return home from day program unas sisted an d to be home alon e safely Program transition Age 28 First episod e depre ssed Then new aggression which worsen ed to requi re tw o hospi talization s and placement in nurs ing care faci lity Three moo d ep isodes Age 30 Slo wly reg ressed over se veral ye ars Lo st spe ech Decre ased contine nce Lo st abi lity to dre ss and showe r Need s help with eating Move d slow ly No longer can be left alon e No ep isode in pas t 3 years Six years since reg ression Moderate recove ry Rema ins larg ely mute and uses sing le words or grunts Depend ent for ADLs Regain ed som e self-c are skills Improve d mood Incon tinent at night Case 6 Fema le 28 years Term inal dele tion [54 kb] arr[hg1 9] 22 q13.33( 51, 123,491 -51,17 8,264)x1 Spoke in full senten ces Toilet trained Dressed self Made snac ks Pneum onia Age 14 First episod e depre ssed Then mani a wit h complet e insomn ia for 12 days, catato nia, Age 26 Sp oradic inc ontinen ce Con fused Coul dn ’t read or write Mood ep isode in pas t year Two years sinc e regres sion No reco very

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Table 2 Case summaries (Continued) Case # Gende r Age at time of study Genetic de fect Level of functioni ng prior to onset psychiat ric ill ness 1

ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained 11 mont hs Read sim ple boo ks Wrote sim ple text neuro leptic mal ignant syndrom e and seizures Now EC T depe ndent 10+ mood episod es Decre ased hand skills Poor memor y Case 7 Fema le 34 years 6 mont hs Term inal dele tion – ring 22 46,XX,r [ 22 ](q13 .3) with deleti on of term inal 22 q Simple rep etitive spee ch Toilet trained Dressed self with prom pts Some sig ht words Some com pute r skil ls None note d Age 30 First episod e depre ssed Then bot h manic an d depre ssed ep isodes 10+ mood episod es Age 30 Decre ased voca lizations Frequ ent inco ntinenc e Decre ased indepe ndence with dre ssing Mood ep isode in pas t year Four years since regressi on Moderate recove ry Vocalizes more Rema ins inco ntinent Feeds self but nee ds super vision for chok ing Needs help with dress ing Case 8 Fema le 36 years 3 mont hs Term inal dele tion [106 kb ] arr[hg1 8] 22 q13.33 (49,4 75,238-4 9,581,3 09)×1 Phrase speech Toilet trained Dressed self with super vision Read sim ple words Played with dolls None note d Age 11 First episod e mani c symp toms Then mi xed mood ep isodes 10+ mood episod es Age 11 Stea dy devel opment al de cline from age 11 Lo st alm ost all language Inc ontinen t Lo st use of ut ensils No longer dress es self No play intere sts No ep isode in pas t year 25 years sinc e regres sion No reco very Case 9 Fema le 43 years 1 mont h Term inal dele tion – ring 22 [2.1 Mb] 46,XX,r [ 22 ](p13 q11.2); arr[hg1 9] 22 q13.32q1 3.33 (49,0 56,457-5 1,179,6 71)x1 Spoke in full senten ces Toilet trained Dressed self Indepen dent for hygie ne Active in progr ams None note d Age 32 Abrupt ons et of stuporous catato nia with food phobia Then mu ltiple mani c and depre ssed ep isodes 10+ mood episod es Age 32 Decre ased spee ch Inc ontinen t No longer abl e to dre ss se lf or bat he self Mood ep isode in pas t year 12 years sinc e regres sion Minim al recove ry Decre ased spee ch Intermit tent inc ontinen ce Needs super vision for self -care Case 10 Fema le 17 years 11 mont hs Sequenc e variant – Frame shift NM _03 3517 .1: c.3 424 _342 5delCT , p.Leu1142Valfs*153 Spoke in full senten ces Toilet trained Dressed self and did most hygie ne Read sig ht words Wrote na me, familiar words , copie d text Menses Started at new schoo l Age 14 First had three pe ri-mens trual manic episod es fol lowed by paranoia Then prolong ed se vere depre ssion with catato nic feature s Then acut e OCD with tics, posturing an d chore iform movem ents Then mani a wit h first se izure and cataton ia, dx seron egative autoim mune enceph alitis Six episod es (five mood episod es) No lasting loss of skills Mood ep isode in pas t year No reg ression Case 11 Male Sequenc e variant – Frame shift NM_03 3517.1: c.367 9dupG, Phrase speech Social and interact ive Toilet trained Gastro-enter itis Age 12 First episod e mani c with agitation , new pica, new inco ntinenc e, Age 12 Lo st mos t languag e Les s social an d interac tive Mood ep isode in pas t year Two years sinc e regres sion Minim al recove ry

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ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained 14 years 11 mont hs p.Ala1227Gly fs*69 Read sig ht words Typed from a mod el destruc tive beh avior, muti sm, and cataton ia Then OCD with agi tation and aggres sion Five+ mood episodes Inc ontinen t Lo st all aca demi c skills New obsess ional an d rep etitive beh aviors Rare speech and interact ion now Still inconti nent Case 12 Fema le 43 years 8 mont hs Sequenc e variant – Frameshift NM_03 3517.1: c.490 6_492 1dup16 , p.Pro1 641Leu fs*58 dn Spoke in full senten ces Toilet trained Dressed and washed Read at 3rd grade level Math grade level throu gh 9th grade Worke d at sup ported job in library and in tow n hospi tal Balanced own chec kbook Menses Viral inf ections Age 11 First episod e mixed , with agitation , insomn ia, cognit ive dulling, posturing Then mu ltiple moo d episod es with cataton ia 20+ mood episod es Age 11 Gra dual, with each ep isode lost skil ls, tw ice lost ability to walk, would regain som e skil ls with therapies, still work ing and verbal to age 28; after a se vere cold lost all spee ch, contine nce, se lf-care an d many mot or skil ls, canno t use hands (dys tonic po sturing at wrists) No ep isode in pas t year 15 years sinc e mos t severe regressi on No reco very Case 13 Fema le 14 years 1 mont h Term inal dele tion [123 kb ] 46,XX; arr[ hg18] 22q1 3.33 (49,4 68,254-4 9,591,4 15)x1 Spoke in full senten ces Toilet trained Pulled on clothe s Needed help wit h AD Ls Read at 1st grad e level Wrote an d type d Used iPad Strep infect ion Menses Age 9 First episod e com plex tics and choreiform movem ents w/ high strep titers, dx PANDAS and resolved with antibiotics Then rage out bursts and peri-m enstrual aggres sion Then de pressive ep isode wit h severe anxiet y and new general ized anxiet y disorde r 3+ mood ep isodes No lasting loss of skills No ep isode in pas t year No reg ression

Case 14 Male 16 years

6 mont hs Sequenc e variant – Nonsense NM_03 3517.1: c.500 8A > T, p.Lys16 70* (this indi vidual also has a like ly benign missen se variant in SHANK 3 , c.387 2C > T, p.Ser1291L eu) No spee ch, used PE CS Toilet trained Fed se lf Used iPad Navigated intern et Liked music None note d Age 15 First episod e mani c Then mont hly mani c episod es Then severe agg ressi on requi ring hospi talization and residential car e 20+ mani c episod es Age 15 Lo st toil et trai ning Ave rse to tou ch Lo st com puter skil ls Lo st soc ial intere st No ep isode in pas t year 18 mont hs sinc e regres sion Moderate recove ry of toileti ng, self-fee ding, som e compu ter sk ills Case 15 Fema le 28 years 11 mont hs Term inal dele tion [43 kb] arr[hg1 8] 22 q13.33( 49,479, 705-49,522, 868)x1 Single words Neve r toile t-trai ned Could chang e own pull-u p Dress self Drink from cup School re-ent ry Possib le U RIs Age 9 First episod e mani c Then mani c spells with OCD behaviors Then de pressed pe riods with new agg ressi on 10+ mood episod es Age 24 Lo st abi lity to: Dres s self Chan ge pull-up Drink from cu p Three years since las t episod e Four years since regressi on No reco very Case 16 Fema le 15 Sequenc e variant – Frameshift arr[hg1 9] 22 q13.33( 51, 121,452 -51,19 7,838)x1 Spoke in full senten ces Toilet trained Dressed self Read Menses Age 13 First episod e mani c with paranoia Then de pressive ep isode No lasting loss of skills Mood ep isode in pas t year No reg ression

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ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained years 1 mont h Pretend play Wrote in cursi ve Karate with catato nia req uiring ICU car e and ECT Then recurrent mani c episod es Five+ mood episodes Case 17 Fema le 13 years 10 mont hs Term inal dele tion [4.3 Mb ] arr[hg1 9] 22 q13.31q1 3.33 (46,9 28,208-5 1,224,2 52)x1 dn Single words or short phrases Toilet trained Dressed self Fed se lf Rode scoote r Menses Age 13 First episod e depre ssed with catato nia Then mani a wit h urinary frequency and occasion al inco ntinenc e, chang es in gait an d post ure Four mood episod es No lasting loss of skills Mood ep isode in pas t year No reg ression

Case 18 Male 20 years 10 mont

hs Term inal dele tion [76 kb] arr[hg1 9] 22 q13.33( 51,121, 452-51,197, 838)x1 Spoke in full senten ces Toilet trained Dressed self Show ered se lf Read at 3rd grade level Wrote se ntences Used calculator Used iPhone to cal l/text friends Possib ly his increased awareness of deficits Age 16 First episod e mixed moo d disturbance with slee piness and irritability Then mani a alt ernating wit h depre ssion and severe aggres sion Three + mood episod es Age 16 Con fused Need s cons tant super vision Cann ot dry self Pu ts clothes on while still wet Decre ased acade mic skil ls Urinary inc ontinen ce Lo st intere st in usual activ ities Mood ep isode in pas t year Four years since regressi on No reco very

5 mont hs Sequenc e variant – Nonsense NM_03 3517.1: c.157 2C>A , p.Cys524* Spoke in full senten ces Toilet trained Indepen dent for ADLs an d travel with sch ool groups Readin g at 3rd grad e le vel Atten ded com mun ity colle ge Compe titive tennis Marathon er School transition Age 17 First episod e mani c with irritability, confus ion, catato nia and new agg ressi on Then mu ltiple mani c and depre ssed ep isodes Psycho tic feature s occurring betw een mood ep isodes 20+ mood episod es Age 17 Gra dual, lost mos t spee ch Ofte n inco ntinent Lo st abi lity to pe rform ADLs Re quires constant 1: 1 super vision Mood ep isode in pas t year 12 years sinc e regres sion No reco very Case 20 Fema le 17 years 1 mont h Sequenc e variant – Frameshift NM_03 3517.1: c.406 5_ 4066de lTG, p.Val13 57Glyfs *4 dn Phrase speech Asked for nee ds Toilet trained Fed se lf Strep infect ion Age 14 First episod e OCD with enu resis at night , aggres sion an d sub-t hresho ld manic symptom s Then simil ar ep isodes of O CD with mani c symptom s Later diagnosis o f autoimmu ne encep halitis Three + mood and O CD ep isodes Age 15 Decre ased intel ligibility Decre ased toile ting Decre ased comm unicat ion Decre ased feeding self Mood ep isode in pas t year Two years sinc e regres sion Moderate recove ry of speech clarity an d toile ting skills Case 21 Fema le Sequenc e variant – Frameshift NM_03 3517.1: c.406 5_406 6del TG, p.Val 1357Gly fs*4 dn Phrase speech Toilet trained Fed se lf Strep infect ion Age 14 First episod e anxie ty/OCD, transien t inability to speak, the n develo ped Age 14 Slo w ons et Decre ased toile ting Mood ep isode in pas t year Two years sinc e regres sion Moderate recove ry of

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ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained (twin of case 20) 17 years 1 mont h Dressed self Read a few sight words Basic writing mania Then dia gnosed with PANDAS , Then catat onia Five+ mood episodes Decre ased comm unicat ion Decre ased orien tation Decre ased feeding self No longer write s name comm unicat ion an d self -care sk ills Less im provement with acade mics Case 22 Fema le 15 years 0 mont h Term inal dele tion [62 kb] arr[hg1 8] 22 q13.33( 49,406, 251-49,468, 408)x1 Few sing le words Not toile t trained Needed help for dress ing Fed se lf with ut ensils None note d Age 8 First episod e mani c, then de pressive ep isodes 10+ ep isodes No lasting loss of skills Mood ep isode in pas t year No reg ression Case 23 Fema le 39 years 5 mont hs Term inal dele tion [2.5 Mb ] arr[hg1 8] 22 q13.32q1 3.33 (47,0 03,473-4 9,515,9 11)x1 Phrase speech with poor articulation Toilet trained Intact ADLs Read sim ple boo ks Mem ory games Jigsaw puzzles Dot-to-dot coloring None note d Age 32 First episod e depre ssed Then recurrent depre ssed episod es with severe anxiet y, SIB Then mani a wit h cataton ia 10+ mood episod es No lasting loss of skills Mood ep isode in pas t year No reg ression Case 24 Fema le 36 years 7 mont hs Term inal dele tion [69 kb] arr[hg1 9] 22 q13.33( 51, 128,324 -51,19 7,766)x1 Phrase speech Toilet trained Dressed self Fed se lf Read sim ple text Wrote at a se cond grad e level Puberty Age 15 First episod e agi tation, OCD Then catat onia and de pression Then mani c episod es 10+ mood episod es Age 18 Decre ased urinary contine nce Decre ased indepe ndence for ADLs Lo st all aca demi c skills No ep isodes in past ye ar 18 years sinc e regres sion No reco very Case 25 Fema le 24 years 1 mont h Term inal dele tion – unba lanced trans location [6.0 Mb] 46,XX,der(22 )t(22;acro) (q13.33 ;p12); arr[h g19] 22q13. 31q13.3 3(45, 156,254 -51,19 7,725)x1 Single words Toilet trained Fed se lf Did chore s Multiple family health stressors High strep ti ters Age 21 First episod e depre ssed with agitation , photop hobia, then catato nia, diagno sed PAN DAS One episode No loss of skil ls No ep isode in 3 years No reg ression

1 mont h Sequenc e variant –Fra meshi ft NM_03 3517.1: c.464 9_ 4653du pGCAGC, p.Pro1 552Alafs* 14 dn (based on the resul ts of his monoz ygotic twin brother) Spoke in full senten ces Toilet trained Dressed with assistan ce Fed se lf Read fl uently Acted out plays Used compu ter with sophist ication (e.g ., boo ked travel) Strep infect ion Age 13 First episod e mani c with acut e onset insom nia, tics, an orexia diagno sed PAN DAS Then new pica, catato nia Then mu tism and aggres sion asso ciated with recurrence of manic symptom s 10+ mood episod es Age 13 Lo st languag e Decre ased fine mot or skills Decre ased toile ting Decre ased utens il use Decre ased interest in peo ple an d hobbi es Des tructive Slee p disrup ted Mood ep isode in pas t year Five years since regres sion Minim al recove ry Slightly improve d language an d toile ting Rema ins social ly withdrawn Has not regaine d fin e motor skil ls

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ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained

Case 27 Male (twin of

case 26) 18 years 1 mont h Sequenc e variant – Frameshift NM_03 3517.1: c.464 9_ 4653du pGCAGC, p.Pro1 552Alafs* 14 dn Phrase speech Toilet trained Needed help wit h dre ssing Fed se lf with fin gers Used compu ter Few sig ht words Strep infect ion Age 13 First episod e mani c with acut e onset insom nia, tics, an orexia diagno sed PAN DAS Then de pression an d catato nia 10+ mani c and depressed episod es Age 13 Lo st mos t languag e Inco ntinent Decre ased feeding self Decre ased interest in peo ple, activ ities Mood ep isode in pas t year Five years since regres sion Moderate recove ry Has reg ained some fine motor skil ls and soc ial interest s, but not language and fu ll contine nce Case 28 Fema le 26 years 3 mont hs Term inal dele tion [70 kb] arr[hg1 9] 22 q13.33( 51, 127,898 -51,19 7,838)× 1 Spoke in full senten ces Toilet trained Indepen dent with dressing and care Took own meds Black belt in ka rate Menses Age 16 Gradual onset agg ressi on Then mani c episod es with unsa fe be haviors 10+ mani c episod es Age 18 Be came confus ed abou t daily task s and had trouble with se lf-care Lan guage de teriorated Ep isodes of runn ing away Manic ep isode in pas t year Six years since reg ression Has recove red all skil ls Case 29 Fema le 16 years 7 mont hs Sequenc e variant – Frameshift NM_03 3517.1: c.367 9dupG, p.Ala1227Gly fs*69 dn Spoke in full senten ces Toilet trained Dressed self Indepen dent for hygie ne Fed se lf Read at 2nd grad e level Menses Hashimot o’ s enceph alopathy Age 12 Gradual onset conf usion and choking spells unrelated to food Then ep isodes of mani a and OCD with catato nia and disorganized be havior and new be havior posing risk of accidental injury 10+ mood episod es Age 12 Lo st all adap tive skills, including cont inence an d spee ch Lo st all aca demi c skills Manic ep isode in pas t year Four years since regressi on Minim al recove ry of relatedness and comm unicat ion No reco very of academic skills Depend ent for ADLs Requ ires cons tant super vision Appears to understand language but little spee ch Plays simpl e compu ter games Case 30 Fema le 16 years 8 mont hs Term inal dele tion with inters titial dup lication [6.4 Mb] 46,XX,del [ 22 ](q13 .3); arr[hg1 8] 22 q13.31 (43,2 76,438-4 9,691,4 32)x1, 22q13. 31(42,835 ,935-4 3, 272,271 )x3 Minim al language Toilet trained for uri ne in daytime Fed se lf with fork Could put on clothes if in correct positio n Mycoplasma pneum onia Age 14 First episod e depre ssed with catato nia Then OCD and manic symptom s Five+ mood episodes Age 15 Lo st day time contine nce Lo st intere st in play and rel atedness Decre ased feeding self Decre ased voca lization Mood ep isode in pas t year Three years since regressi on Moderate recove ry Has reg ained energy and vocalizat ion, not daytime contine nce Case 31 Fema le 49 years 9 mont hs Term inal dele tion [5.0 Mb ] (5 Mb term inal dele tion with the break point at 22q13. 31) Spoke a few words Toilet trained Fed se lf Ambul atory None note d Age 14 First episod e mani c Then rep eated mood ep isodes at intervals of five or more years Three + mood episod es Age 47 Lo ss of skills wit h each psychiatric ep isode; recove red each time unt il age 47, the n lost all languag e Lo st abi lity to wal k Lo st feed ing skil ls Two years sinc e last moo d episod e; Two years sinc e regres sion No reco very No languag e Incon tinent Cannot stand or wal k, has

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ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained difficul ty mai ntaining sitting Cannot feed self Needs total car e Case 32 Fema le 31 years 11 mont hs Term inal dele tion [76 kb] 46,XX; arr[ hg19] 22q13. 33(51,121 ,452-5 1, 197,838 )x1 dn Spoke in full senten ces Toilet trained Intact ADLs Plann ed recipes and cooke d Worke d with you ng chi ldren Ran with runn ing group Volunt eere d at nurs ing hom e None note d Age 14 First episod e anxie ty/OCD Then mani a Then de pression with slow recove ry over 2 years followed by severe mood cycling years later Three + mood episod es No loss of skil ls Mood ep isode in pas t year (resolving) No reg ression Case 33 Fema le 41 years 0 mont h Term inal dele tion [481 kb ] arr[hg1 8] 22 q13.33( 49, 210,245 -49,69 1,432)x1 Single words Neve r toile t train ed Fed se lf Undress ed and pulled on pants Read sig ht words Poured drink s Rode tricycle Played with dolls None note d Age 7 First episod e bizarre be havior with agitation , disorie ntation and insom nia (possible brief psyc hotic episode) Then OCD and new pica, fol lowed by mania 10+ mood episod es Age 16 Lo st all me aningful spee ch; rep eats words Un able to feed self, eat s by lowe ring face to plate Un able to assist with dress ing Lo st all pla y Elo pes frequently Mood ep isode in pas t year 25 years sinc e regres sion No reco very Case 34 Fema le 17 years 8 mont h Term inal dele tion [53 kb] arr[hg1 9] 22 q13.33( 51, 144,903 -51,19 7,838)x1 Spoke in full senten ces Toilet trained Fed se lf Dressed self Retriev ed and poured cere al Did puzzles Played with Legos Multiple social stressors Age 14 First episod e depre ssed with an orexia and incon tinence Then mani a an d new pica Five+ mood episodes Age 14 Decre ased spee ch Decre ased play Decre ased dress ing Decre ased contine nce No ep isode in pas t year Four years since regressi on Moderate recove ry of language, self-c are and play skil ls Case 35 Fema le 23 years 1 mont h Sequenc e variant – Frame shift NM_03 3517.1: c.408 6_ 4087de lAC, p.Arg1363Gl nfs*31 Phrase speech with echolal ia Toilet trained Fed se lf Poured mi lk Dressed self with assistan ce Needed help wit h AD Ls Pretend play Multiple social stressors Age 12 First episod e depre ssed with confus ion, new incon tinence and catato nia Then mani a Three + mood episod es Age 12 Stea dy ongoing regres sion Lo st all spe ech Inc ontinen t Lo st all se lf-care skills Mood ep isode in pas t year 11 years sinc e regres sion No reco very Requ ires cons tant super vision Only abl e to wal k short distances with diffic ulty Cannot climb stairs Case 36 Fema le 15 years 0 mont h Sequenc e variant – Frame shift NM_03 3517.1: c.406 5_ 4066de lTG, p.Val 1357Gly fs*4 dn Spoke in full senten ces Toilet trained Dressed self Fed se lf Read sig ht words Used tablet Math at 1st grad e le vel Social stressors Age 14 First episod e catat onic with urin ary rete ntion, insomn ia and pica; did not recogni ze fam ily; paranoi d One episode Stil l recove ring from first ep isode with catat onia; cannot yet de termine new bas eline or whe ther lost skills me et criteria for regres sion Eight mont hs since onset of psych iatric illness Contin ues to regain language, personality, and orien tation Still not abl e to op en and use ha nds for AD Ls Intermit tently inc ontinen t

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ng stressors Age onset psych iatric illness; psych iatric diagnose s by DM-ID-2 criteria; associ ated feature s; numbe r of episod es Age an d area s o f reg ression afte r ons et psyc hiatric illnes s 2, 3 Years since last psyc hiatric episod e and regressi on; degre e of recove ry in that time and skills reg ained Case 37 Fema le 17 years 5 mont hs Sequenc e variant – Nons ense NM_03 3517.1: c.433 3C > T, p.Gl n1445 * dn Phrase speech Toilet trained Fed se lf Dressed self with assistan ce Imaginative pla y Wrote na me Copied te xt Drew picture s Menses End of sch ool year Age 15 First episod e depre ssed with insom nia, severe separation an xiety, apath y, decreased spee ch and interact ion, swallowing diff iculties, and cataton ia One mood ep isode Age 15 Lo st mos t spee ch Lo st abi lity to che w food Inc reased depe nde nce for ADLs Lo st all aca demi c skills Lo st im aginary play No ep isode in pas t year Two years sinc e regres sion Moderate recove ry Regain ed som e spee ch Eats nor mally Mostly contine nt Contin ues to not ha ve acade mic skil ls, draw ing skills, or imaginary pla y skills Case 38 Fema le 16 years 9 mont hs Sequenc e variant – Frame shift NM_03 3517.1: c.276 3delG, p.Pro9 22Arg fs*34 dn Spoke in full senten ces Toilet trained Sociable Menses UTI Age 13 First episod e hyp omani c Then 2 years lat er manic with aggres sion, inco ntinenc e; an xiety, talking to se lf, compu lsion s, the n catato nia Three mani c ep isodes Age 15 Lo st all spe ech Lo st abi lity to feed se lf Inc ontinen t Decre ased social interac tion No ep isode in pas t year One ye ar since regressi on Substantial recove ry Recov ered languag e Recov ered feed ing Improve d soc ial interact ion Contin ues with intermit tent inc ontinen ce Abbreviations :ADLs activities of daily living, dn de novo, dx diagnosis, ECT electroconvulsiv e therapy, ICU intensive care unit, OCD obsessive-compulsive disorder, PANDAS pediatric autoimmune neuropsychiatric disorder associated with streptococcus, PECS Picture Exchange Communication System, UTI urinary tract infection, URI upper respiratory tract infection 1All were ambulatory and able to feed themselves with utensils prior to psychiatric illness 2Cases 11, 14, 17, 22, 30, 33, and 35 had regression in speech, play, and social interaction before age 8, as well as subsequent regressions accompanying psychiatric illness at an older age 3Regression defined as loss of skills that persisted at least 6 months after resolution of acute psychiatric episode 4Regression occurred years after onset of psychiatric illness 5“Symptoms ” used when sub-threshold for diagnosis of either depressive or manic episode

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Symptoms consistent with a diagnosis of catatonia as-sociated with another mental disorder were reported in 20 of 38 cases (53%). Seven of the 20 (35%) were on neu-roleptics at the time of emergence of catatonic

symp-toms. Cases with sequence variants in SHANK3 met

diagnostic criteria for catatonia significantly more often (12/15; 80%) than cases with terminal deletions (8/23; 35%) (Fisher’s exact test, p = 0.009).

Regression

The interview explored both abilities lost and the degree of return of skills over time. Caregivers were asked which skills were lost, at what age, and which, if any, skills were regained. Seven of the participants (18%) had experienced regressions in early childhood affecting communication, social interaction, and/or imaginative play (five by age two, one at age four, one at age seven), but we do not elaborate on those early regressions in the current report. Analysis focused on the 25 of 38 cases (66%) who had regressions that began within the 3 years after the onset of psychiatric episodes. Most of these re-gressions (21/25; 84%) began within a year after the on-set of psychiatric episodes and involved multiple domains of function. Descriptions of the areas of skill lost and recovery are summarized in Table2, which in-cludes developmental status in terms of speech, toilet training, ability to dress and wash self, academic skills, and vocational activities when present. Caregiver reports of recovery of skills ranged from continuing loss of fur-ther skills to complete return to baseline function before the onset of psychiatric symptoms. Overall, more than half of the participants who regressed in the 3 years after the onset of psychiatric illness reported minimal recov-ery (14/25; 56%).

Antecedents to the onset of psychiatric illness and re-gression were explored in the interview. Menstrual cyc-ling was reported to play a triggering role in 11 of 31 (35%) of the females. Acute infections were suspected triggers in 11 of 38 cases (29%). Psychosocial stressors were suspected triggers in 10 of 38 cases (26%). Several participants reported differing antecedent stressors for different episodes.

Co-morbid conditions

Only a quarter (9/38; 24%) of study participants was known to have PMS before the onset of psychiatric symp-toms and associated regression. Sixteen cases (42%) had diagnoses of ASD before the onset of psychiatric symp-toms and regression; five more received an ASD diagnosis after the onset of psychiatric illness and regression.

Fifteen of 38 cases (40%) reported one or more afebrile seizure. Eight of those 15 cases (53%) re-ported a seizure in the 2 years preceding the inter-view. Fifteen of 38 cases (40%) had weight loss of 10

to 25 kg accompanying psychiatric episodes. Chronic con-stipation, intermittent urinary incontinence, and episodes of acute urinary retention were prevalent in this sample, particularly as subjects aged. Chronic constipation was noted in 32 cases (84%), with episodes of acute urinary re-tention reported in 18 (47%). The discomfort associated with these conditions may lead to non-specific behaviors such as agitation, aggression, and self-injury in people with ID; these chronic symptoms were not coded as mood epi-sodes. A small subset of subjects (4/38; 11%) had an immune-related disorder. Two participants (5%) were di-agnosed with Hashimoto’s thyroiditis, one of whom was diagnosed with Hashimoto’s encephalopathy, and two par-ticipants (5%) had immunoglobulin deficiency, including one with common variable immunodeficiency.

Therapeutic interventions

At the time of interview, 32 of 38 participants (84%) were receiving one or more psychiatric medications, with 14 of 38 (37%) receiving four or more psychi-atric medications. More than half (21/38; 55%) took anticonvulsants; all of these had mood symptoms, while 12 also had a history of seizures. Over half (55%) were receiving neuroleptics. Benzodiazepines were used either regularly or on an as-needed basis in 16 of 38 cases (42%). Alpha agonists, beta-blockers, antihistamines, and trazodone were prescribed for sleep or aggression. Smaller numbers of participants were receiving selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, buspirone, lithium, cannabinoid oil, or n-acetylcysteine.

Full details of dosages and adjustments to treatment regimens in response to changing psychiatric status were inconsistently available and are therefore not re-ported. However, many parents kept extensive notes, and their reports of responses to medication trials suggest two patterns worth noting: (1) participants were reported to be sensitive to side effects from neu-roleptics, with adverse events including extrapyramidal symptoms, worsening aggression and/or onset of cata-tonic symptoms reported in 14 of 30 cases (47%), while (2) seven of nine participants (78%) treated with SSRIs for depressive symptoms developed agitation, aggression, or other manic-like symptoms within weeks of the start of treatment.

Three individuals were treated with electroconvulsive therapy (ECT) for catatonia with reported significant benefit; two continue to require maintenance ECT (dur-ation of treatment 18 months in one, > 8 years in the other) while the third discontinued after initial response due to agitation. One participant with recurrent catato-nia on maintenance ECT was reported to have also benefited from intravenous immunoglobulin (IVIG) with improved cognition and motivation, but developed

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aseptic meningitis and a rash after the fifth treatment, leading to discontinuation of IVIG.

Nine participants (26%) were reported to have received

immunomodulatory treatments for diagnoses of

pediatric autoimmune neuropsychiatric disorders associ-ated with streptococcal infections (PANDAS) syndrome or of autoimmune encephalopathy. Six were diagnosed with PANDAS syndrome on the basis of clinical symp-toms and positive strep cultures or elevated titers. One participant was diagnosed with Hashimoto’s encephalop-athy, and two with seronegative autoimmune encephal-itis. Treatments included (1) antibiotics, (2) IVIG, and/ or (3) systemic anti-inflammatories such as nonsteroidal anti-inflammatory drugs, steroids, or rituximab.

In four of six cases diagnosed with PANDAS syn-drome, parents reported that antibiotic treatment was effective in reducing or eliminating acute symptoms. The remaining two improved slowly; one also re-ceived IVIG and the other rere-ceived lorazepam; these parents were not confident that antibiotics had played a role in recovery. Treatment for PANDAS symptoms did not appear to prevent future mood episodes or regression, as all but one of these cases went on to have further psychiatric episodes and some had later

regressions. The one participant diagnosed with

Hashimoto’s encephalopathy continues to receive regular infusions of IVIG with steroids, as well as rituximab. The two participants with diagnoses of

seronegative autoimmune encephalopathy receive

monthly IVIG.

Eight females were on hormonal therapy to eliminate menstrual cycles and reduce associated mood symptoms. Non-pharmacological treatments varied widely by geo-graphic location and age, with those still in school more likely to be receiving structured behavioral interventions. Data on past and current behavioral programs and ther-apies were not included in the interview.

Discussion

This case series has characterized a subset of individuals with PMS who have episodic, severe neuropsychiatric ill-ness, frequently beginning in adolescence or early adult-hood, with major impacts on functional status. The symptoms and course of illness often closely resembled bipolar illness, with psychotic features almost exclusively present in the context of mood episodes. None of the participants in our sample presented with a primary psychotic disorder, such as schizophrenia. However, one

participant presented with distinct psychotic and

affective episodes characteristic of schizoaffective dis-order. Using the DM-ID-2 criteria [30], all but one of the participants had either a mood disorder or an anx-iety disorder, with multiple discrete periods of illness in all but four.

Several triggers were often reported as temporal ante-cedents to the onset of psychiatric changes. Biological triggers included infections and changes in hormonal status, while environmental factors included stressful life events. Similar patterns have been observed in other, more common neurogenetic syndromes, including Down syndrome [32], Williams syndrome [33], and 22q11.2 de-letion syndrome [34].

It is critical to emphasize the high incidence of catatonic symptoms in this subset of individuals with PMS, as cata-tonia often goes unrecognized or undertreated in individ-uals with developmental disabilities [25, 35]. Recognition and treatment of both stuporous and hypermotoric cata-tonia is crucial, as symptoms can lead to life-threatening complications. Other genetic conditions involving copy number variants, such as 22q11.2 deletions [36], have also been associated with psychiatric symptoms and with cata-tonia. Similar to their use in treating catatonia in other conditions, benzodiazepines and ECT were used in this cohort with reported tolerability and effectiveness.

Regression has long been recognized in neurodevelop-mental disorders such as ASD [37], but the triggers and mechanisms are not well understood, and the literature focuses largely on early childhood regression, especially as it relates to Rett syndrome [37–40]. Significant cogni-tive and behavioral regression has been documented in PMS [5, 6, 9, 15, 16, 18, 41]. Verhoeven et al. [20] have recently published on the course of illness of 24 adoles-cents and adults with PMS referred for evaluation and treatment of“challenging behaviors and unstable mood.” In that sample, there were five individuals with periodic catatonic symptoms, and four other individuals who de-veloped progressive loss of skills in their third or fourth decade.

Two thirds (66%) of our sample described lasting regres-sions that began within 3 years of the onset of psychiatric illness. These regressions in communication, self-care, and motor functions left a subset of previously more capable individuals largely non-verbal, incontinent, and unable to dress or feed themselves. Many of these participants con-tinue to experience episodic psychiatric illness in addition to developmental decline. Interestingly, a similar combin-ation of rapid onset psychiatric disturbance with marked regression and catatonia has been described in Down syn-drome [42,43] and subsequently labeled“Down syndrome disintegrative disorder.” A recent case series [44] docu-mented a role for immunotherapy in restoring function and stability in these individuals, although it is also recog-nized that cognitive decline in Down syndrome relates to amyloid precursor protein gene triplication [45–47]. Re-gression in PMS may be more common than in Down syndrome, and its potentially devastating impact warrants ongoing study of the natural history, mechanism, and tar-gets for intervention.

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Given the methodological limitations and sample se-lection bias in this study, we are unable to draw conclu-sions about the prevalence of psychiatric illness and/or regression among people with PMS. This study was also limited by the lack of standardized or validated tools to measure neuropsychiatric symptoms in severely develop-mentally disabled children and adults. However, within this self-referred subset of individuals with PMS whose caregivers identified psychiatric illness, we observed a distinct pattern of affective episodes, with onset typically in puberty, a strikingly high incidence of catatonic symp-toms, and an association with substantial regression in the second through fourth decades of life. Of note, a re-cent literature review analyzed prior reports of 56 indi-viduals with PMS with accompanying neuropsychiatric symptoms, and concluded that“clinicians and caregivers need to be vigilant for loss of skills and neuropsychiatric changes in adolescents and adults with PMS, including the development of bipolar disorder and catatonia” [48].

Individuals with PMS who present with new psychiatric symptoms require careful monitoring and cautious early intervention. Response to traditional psychiatric interven-tions is variable, and the role for immunomodulatory treatments and ECT in specific subsets of patients should be explored in future studies. The pattern of rapid and se-vere deterioration described in more than half of this group calls for further investigation to identify triggers and the underlying biology and to delineate possible strat-egies for prevention and timely intervention. While the current study does not allow for specific treatment recom-mendations, there is an urgent need for clinical trials to assess the efficacy of existing psychopharmacological treatments for psychiatric symptoms in PMS, in addition to developing novel, targeted therapeutics.

The preponderance of females in this sample (> 4:1) is notable and calls for replication. Sequence variants in SHANK3 were also six times more common in this sam-ple than in the PMSIR. These findings raise questions about whether psychiatric problems and regression dis-proportionately affect females and/or individuals with SHANK3 sequence variants, in contrast to those with de-letions. In addition, prior to the onset of psychiatric ill-ness, most of the participants described herein were less severely impaired in their adaptive functioning than is reported in most studies of PMS. This finding is likely related to the high proportion of individuals with SHANK3 variants and small deletions in this sample.

Further studies should attempt to clarify if psychiatric difficulties are actually more common in individuals who are more verbal and social and who have more intact adaptive functioning at baseline, or, whether this finding is the result of selection bias in our sample, as the ma-jority of participants (76%) were only diagnosed with PMS after the onset of psychiatric symptoms.

Finally, our sample underscores the importance of genetic testing as part of the medical work-up for indi-viduals with this presentation. Chromosomal microarray is recommended for the evaluation of all children with global developmental delay or intellectual disability [49]. In the setting of superimposed psychiatric illness or re-gression, chromosomal microarray should be considered as first tier testing, followed by sequencing of SHANK3 if the microarray is unrevealing.

Conclusion

This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in ado-lescence or early adulthood. In most cases, the symp-toms appear consistent with the expression of bipolar disorder in individuals with intellectual disability, with catatonia noted as a common co-occurring condition. Triggers may include infections, changes in hormonal status, and stressful life events. Significant cognitive and behavioral regression beyond a baseline level of disability has been previously reported in PMS and accompanied the onset of psychiatric illness in a majority of the cases reported here. Our results must be interpreted with cau-tion given the potential seleccau-tion bias in recruitment, but it is clear that people with PMS may show a rapid and severe deterioration that requires careful monitoring and intervention. Our findings also highlight the rele-vance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric symptoms and re-gression among larger unbiased samples of individuals with PMS and to delineate any shared mechanisms with other neurodevelopmental disorders presenting with psychiatric illness and/or regression in adolescence or early adulthood. Identification of early clinical and bio-logical markers would contribute to our understanding of the underlying neurobiology of these disorders and potentially aid in monitoring, early intervention, or prevention.

Additional files

Additional file 1. Caregiver Interview for Psychiatric Illness in Persons with ID (CIPIPID)

Additional file 2. Adapted Diagnostic Criteria, DM-ID-2

Abbreviations

ASD:Autism spectrum disorder; DM-ID-2: Diagnostic Manual - Intellectual Disability, Second Edition; ECT: Electroconvulsive therapy; ID: Intellectual disability; IVIG: Intravenous immunoglobulin; PANDAS: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; PMS: Phelan-McDermid syndrome; PMSIR: Phelan-McDermid Syndrome International Registry

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Acknowledgements

We thank the families for their many contributions and the Phelan-McDermid Syndrome Foundation for its support.

Funding

MPT receives research support from the National Institute of Health National Research Service Award Institutional Training Program (T32) and the Beatrice and Samuel A. Seaver Foundation. AT receives support from the Intramural Research Program of the National Institute of Mental Health (ZICMH002961). AK receives support from the National Institute of Neurological Disorders and Stroke (R01NS105845-01 and U54 NS092090-01) and from the Beatrice and Samuel A. Seaver Foundation.

Availability of data and materials

The datasets analyzed in the current study are available at the PMS International Registry to authorized users (https://www.pmsf.org/registry/). Authors’ contributions

TK and MPT collected the data. BL and CB performed the analyses of the PMS International Registry data. CB reviewed all genetic reports and performed analyses of the relationship between genetic results and clinical findings. All authors were involved in drafting or revising the manuscript, have read and agreed to its content, and are accountable for all aspects of the accuracy and integrity of the manuscript, in accordance with ICMJE criteria.

Ethics approval and consent to participate

Informed consent was obtained for participants, who were enrolled in the Phelan-McDermid Syndrome International Registry (https://www.pmsf.org/registry/). Consent for publication

All participants signed a release for publication of results. Competing interests

AK receives research support from AMO Pharma and consults to Ovid Therapeutics, Takeda, 5 AM Ventures, sema4, and LabCorp. The other authors declare that they have no competing interests.

Author details

1_{Department of Psychiatry, University of Massachusetts Medical School,}

Worcester, MA, USA.2Seaver Autism Center for Research and Treatment,

Icahn School of Medicine at Mount Sinai, New York, NY, USA.3_Department

of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

4_{Phelan-McDermid Syndrome Foundation, Osprey, FL, USA.}5_Sorbonne

Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris

Seine, Paris, France.6_{Neurodevelopmental and Behavioral Phenotyping}

Service, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

Received: 31 May 2019 Accepted: 23 January 2020

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