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2020-02-12

Psychiatric illness and regression in individuals with Phelan- McDermid syndrome

Teresa M. Kohlenberg University of Massachusetts Medical School

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Repository Citation Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A. (2020). Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. Open Access Articles. https://doi.org/ 10.1186/s11689-020-9309-6. Retrieved from https://escholarship.umassmed.edu/oapubs/4162

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RESEARCH Open Access Psychiatric illness and regression in individuals with Phelan-McDermid syndrome Teresa M. Kohlenberg1* , M. Pilar Trelles2,3, Brittany McLarney4, Catalina Betancur5, Audrey Thurm6 and Alexander Kolevzon2,3

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

* Correspondence: [email protected] 1Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA Full list of author information is available at the end of the article

© 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. Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 2 of 17

Background PMS and (2) aid in early recognition and treatment Phelan-McDermid syndrome (PMS) is a neurogenetic optimization. syndrome caused by haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal re- Methods gion of the long arm of chromosome 22, ranging from Participants and procedures single-nucleotide variants to large deletions affecting The study was approved by the Institutional Review multiple genes [1]. SHANK3 is a key structural protein Board of the PMS International Registry (PMSIR) in excitatory synapses, with several isoforms with differ- (https://www.pmsf.org/registry/). Informed consent for ent functions in development and in the synapse [2, 3]. participation in the Registry was obtained from the par- Deletions or sequence variants of the SHANK3 gene are ents or legal guardians of participants, who also signed a associated with the neuropsychiatric manifestations of release for inclusion in publication, and for integration the syndrome and required for the diagnosis of PMS [4– of their interview data with their PMSIR data. Families 7]. Individuals with PMS often present with intellectual were recruited by outreach through the PMS Foundation disability (ID), features of autism spectrum disorder community Facebook page, and families were specifically (ASD), hypotonia, and severely delayed or absent speech invited to participate if the individual with PMS had ex- [8–10]. Genotype-phenotype studies in individuals with perienced distinct psychiatric changes, such as mood ep- terminal deletions have found that the severity of speech isodes, psychosis, marked changes in sleep and energy, impairment and intellectual disability increases with in- major loss of skills, sudden new intense obsessive- creasing deletion size [8, 9]. In one recent study examin- compulsive behaviors, or other neuropsychiatric difficul- ing phenotypic manifestations among 17 individuals ties, with or without regression. Families either con- with sequence variants within SHANK3 [7], the majority tacted the researcher (TMK) directly in response to the developed single words, and 44% had phrase speech, in Facebook message or responded after other families contrast to more severe impairment in individuals with relayed the recruitment message on Facebook to parents deletions. with possible clinical concerns as described. In addition Epilepsy is reported in 17% to 70% of individuals with to the 37 English-speaking families, six families were re- PMS [9, 11–14]. As individuals with PMS age, they ap- ferred through the PMS Spanish Association, and two pear to be at increased risk for bipolar disorder [15–20] enrolled and completed the study procedures. and an associated risk of significant cognitive and behav- Thirty-seven caregivers completed interviews on 39 ioral regression [5, 6, 16, 18–20]. Indeed, SHANK3 vari- participants and provided informed consent; one partici- ants have been implicated in the risk for severe pant was excluded from the analysis since criteria were neuropsychiatric disorders, including mood and psych- not met for a distinct psychiatric episode. Three families otic disorders [15, 16, 19, 21, 22]. Gauthier et al. (2010) had responded to the invitation but did not complete in- identified sequence variants in the SHANK3 gene in four terviews or consent after an initial contact established individuals initially diagnosed with atypical, early-onset that they did not meet criteria for a distinct psychiatric schizophrenia, and a history of borderline to mild intel- episode. The final sample included 38 individuals from lectual disability [21]. Catatonia, a unique syndrome of 36 families, ranging in age from 13 to 50 at the time of motor and autonomic dysregulation associated with a contact. The sample includes two sets of monozygotic variety of psychiatric and medical conditions, has also twins with both twins enrolled. Caregivers interviewed been described in PMS [7, 15, 22, 23]. Of note, catatonia were mothers in all but one case, in which the respond- in pediatric populations and in individuals with develop- ent was a sibling who was the legal guardian. Interviews mental disabilities often goes unrecognized [24] and were conducted in English (n = 34) or Spanish (n = 2), poorly treated [25]. and respondents lived in the USA (n = 29), Australia A few previous cross-sectional studies have used sys- (n = 4), Canada (n = 1), England (n = 1), Netherlands tematic methods to characterize the behavioral profile of (n = 1), and Spain (n = 2). individuals with PMS across the lifespan [19, 26–28]. However, the nature and course of psychiatric symptoms Measures in PMS, and in particular their association with regres- A semi-structured interview entitled the Caregiver Inter- sion occurring much later than the early childhood re- view for Psychiatric Illness in Persons with ID (see Add- gressions typical of ASD, have not been extensively itional file 1) was developed by TMK and conducted documented. In this retrospective study, we collected de- with caregivers by child and adolescent psychiatrists velopmental histories, behavioral profiles, and genetic (TMK for English interviews and MPT for Spanish inter- findings of 38 adolescents and adults with PMS and psy- views). The interview includes questions designed to chiatric illness with the aim to (1) better characterize the elicit descriptions of the participant’s developmental his- psychiatric and developmental phenomena reported in tory, major health challenges, the emergence and course Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 3 of 17

of episodes of psychiatric illness or regression, response was 100%, agreement on whether the first mood episode to pharmacologic treatment, and current level of func- was depressive or manic was 88%, and agreement on the tioning. Interviews typically lasted 90 min. All final notes presence of catatonia was 88%. were reviewed and approved by the families before in- The word “regression” is often used to describe a wide clusion in the study. variety of states, including transient loss of skills during Genetic reports were obtained for all participants and psychiatric episodes with and without catatonia. For reviewed by the geneticist (CB) curating results for the clarity, “regression” was defined in this study as a pro- PMSIR. PMSIR data were used to confirm genetic re- longed loss of previously acquired skills that either (a) sults for study participants and for comparisons of began when the individual was psychiatrically well or (b) prevalence of genetic variants, age, and gender. However, began during a psychiatric episode, with loss of skills only 21 of 38 participants in this study had completed persisting for at least 6 months beyond the resolution of the PMSIR clinical and developmental questionnaires, the psychiatric episode. limiting direct comparisons of clinical data between study participants and other Registry members. Nine of Results 38 participants were not enrolled in the Registry prior to Descriptive statistics and comparisons to participants in study participation. the PMSIR are reported in Table 1. Summaries of case Comparisons between functional status and develop- histories and genetic findings are reported in Table 2. mental milestones in study participants vs Registry data There was a strong female predominance in this sample included parent report of whether key developmental (31 females, 7 males) whereas PMS typically affects skills were ever achieved on the Caregiver Interview (for males and females in equal proportion. There were 23 the study sample) and on the Registry’s Developmental individuals with terminal deletions, with a mean size of Questionnaire for a group of respondents of similar age, 1.63 Mb (range 160 kb–6.41 Mb). Five deletions were with Registry data excluding the participants who were secondary to a chromosomal rearrangement: a ring enrolled in the current study. chromosome 22 in three individuals and an unbalanced Assessment of behavioral symptoms and labeling of translocation in two. Twelve individuals with terminal psychiatric diagnoses in the context of neurodevelop- deletions had not had a karyotype, so the possibility of a mental disorders is complicated by cognitive and com- ring chromosome 22 cannot be excluded. Fifteen indi- municative limitations, atypical presenting features, and viduals had pathogenic sequence variants in SHANK3 premorbid characteristics (e.g., echolalia, repetitive be- (12 frameshift variants and 3 nonsense variants). haviors). The Diagnostic and Statistical Manual for Men- As compared with the 509 PMSIR registrants not in tal Disorders, 5th edition [29] does not comprehensively this study who had genetic data available, sequence vari- include modifications of all diagnostic criteria for differ- ants in SHANK3 were present at higher rates in our ential manifestations that may present in the context of sample (39% [15/38] vs 6% [32/509]; Fisher’s exact test, − intellectual disability, and there is a dearth of psycho- p =4×10 8), and conversely, terminal deletions were metrically rigorous instruments validated for psychiatric less frequent (61% [23/38] vs 92% [467/509]; Fisher’s − evaluation in this population. Therefore, we used the exact test, p =8×10 7). Comparisons with 130 PMSIR Diagnostic Manual - Intellectual Disability, Second Edi- registrants of similar age with questionnaire data avail- tion (DM-ID-2) [30] to classify psychiatric episodes. The able are also reported in Table 1. In addition, deletions DM-ID-2 is based on the DSM, adapted to include care- tended to be smaller in the participants of this study giver observations of behavior and to reduce the number than in the PMSIR (mean size 1.634 Mb vs 3.633 Mb; of symptoms required to make diagnoses where persons unpaired two-tailed Student’s t test, p = 0.0019). In par- with intellectual disability may not be able to report ex- ticular, individuals with small deletions, defined as those periences [31]. All cases were reviewed by a child and including at most the four distal genes, ARSA, SHANK3, adolescent psychiatrist (TMK) using a checklist of DM- ACR, and RABL2B, are over-represented among study ID-2 criteria for each of these disorders. The symptoms participants compared to the PMSIR (57% [12/21 dele- reported by caregivers during acute episodes met criteria tions with size information] vs 19% [72 /387]; Fisher’s − for major depressive episode, manic episode, obsessive- exact test, p = 1.6 × 10 4). (Heterozygous loss of ARSA, compulsive disorder, generalized anxiety disorder, brief ACR, and RABL2B does not contribute to the PMS psychotic disorder, schizoaffective disorder, and catato- phenotype, so deletions including these genes are nia associated with another mental disorder (see Add- equivalent to deletions involving only SHANK3.) itional file 2). In addition, two child and adolescent psychiatrists (MPT, AK) randomly reviewed and classi- Developmental history fied eight cases to assure accuracy of diagnostic classifi- Although documentation of the severity of ID was not cation. Agreement on the presence of a mood disorder available, reported levels of adaptive functioning suggest Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 4 of 17

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 defect a 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 aAmong all Registry participants (n = 509, excluding the study participants), there are 467 terminal deletions (92%), 10 interstitial deletions (2%) and 32 sequence variants (6%) b91 participants in this age range (excluding the study participants) completed the Registry Clinical Questionnaire c79 participants in this age range (excluding the study participants) completed the Registry Developmental Questionnaire dPrior to the onset of neuropsychiatric illness, 42% (16/38) of participants had ASD diagnoses that mild to moderate ID was common in this sample Subsequent psychiatric episodes were superimposed and prior to the onset of psychiatric symptoms and regres- caregivers clearly distinguished episodes from baseline sion and that these individuals were less impaired prior states. First episodes ranged from 8 months to 35 years to their psychiatric illness as compared to the PMSIR before study participation. Reported episode length var- reference sample (Table 1). Prior to the onset of psychi- ied from periods of days to months. Most cases (34/38; atric illness, study participants were significantly more 89%) had multiple distinct episodes consistent with a likely than participants in the PMSIR sample to ever mood disorder, including 12 of 38 (32%) with two to have walked independently, achieved toilet training, ver- four distinct episodes, 6 of 38 (16%) with five to nine ep- bal expression with at least phrase speech, and inde- isodes, and 16 of 38 (42%) with more than ten episodes pendence with dressing. (see Table 2 for details). Few cases (4/38; 11%) reported only a single psychiatric episode; all four of these were Psychiatric illness within the 3 years prior to study participation. Psychiatric difficulties began between ages 10 and 18 in Twenty-nine of 38 cases (76%) reported a manic epi- the majority of cases (28/38; 74%). Psychiatric symptoms sode at some point in their illness; 24 of 38 (63%) re- emerged between the ages of 7 and 10 years in 5/38 ported both manic and depressive episodes. Nineteen of cases (13%), while 5/38 cases (13%) developed psychi- 38 cases (50%) were reported to have had psychotic atric symptoms between ages 21 and 32. Using the DM- symptoms during an acute mood episode. One partici- ID-2, first episodes met criteria for a manic episode in pant presented with both depressive and manic episodes 17/38 cases (45%) and for a depressive episode in 14/38 and with psychosis in between mood episodes, suggest- cases (37%). First episodes in the remaining cases in- ing schizoaffective disorder. cluded six (16%) with a mixture of mood and anxiety New anxiety symptoms accompanied mood episodes symptoms, and one case of disorganized, bizarre behav- in the majority of participants (26/38; 68%). Six partici- ior that suggested a brief psychotic episode. pants (16%) met criteria for obsessive-compulsive dis- Most participants (27/38; 71%) had experienced a order at some point in the course of their illness. Four mood episode in the year before the study. The after- participants (11%) met criteria for generalized anxiety math of acute episodes was associated with higher base- disorder. Only two participants (5%) had first episodes line levels of anxiety and irritability and with regression. that were predominantly anxious. Table 2 Case summaries Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study Case 1 Terminal deletion [89 kb] Phrase speech None noted Age 14 Age 14 Mood episode in past year Female arr[hg19] 22q13.33(51, Toilet trained First episode depressed Decreased speech Four years since regression 18 122,483-51,211,392)x1 Dressed self with new tics, fecal smearing Decreased eye contact Minimal recovery years 9 Fed self Then, OCD, new pica, manic New onset incontinence Occasional meaningful months Independent for hygiene episode and catatonia Unable to dress self speech and singing Read sight words Three episodes Lost all academic skills Intermittent feeding self Counted to 100 with utensil Case 2 Mosaic terminal deletion Single words Program Age 27 Age 27 Two years since mood Female and interstitial duplication Toilet trained transition First episode depressed with Decreased speech episode 29 [4.4 Mb] Pretend play with dolls catatonia Incontinent Two years since regression years 6 46,XX; arr[hg19] 22q13.2q13.31 Then new generalized anxiety Decreased independence No recovery months (43,675,642-46,807,366)x3[0.65], disorder (GAD) in ADLs 22q13.31q13.33(46,808, One mood episode Decreased pretend play 071-51,197,838)x1[0.65] Ongoing GAD (2020)12:7 Case 3 Terminal deletion–unbalanced Spoke in full sentences URI Age 12 Age 15 Mood episode in past year Female translocation [207 kb] Toilet trained Beginning new First episode OCD dx PANDAS Decreased speech clarity Three years since 18 46,XX; arr[hg19] 3p26.3 Wrote simple text school Then depressed with new tics, Frequent urinary incontinence regression years 0 (180,509-2,097,153)x3, Used iPad tremors and posturing, Decreased independence Moderate recovery month 22q13.33(50,990,475-51, Then mixed manic and depressed in ADLs Still unpredictably 197,838)x1 symptoms with new aggression, incontinent new anxiety at leaving house Speech improved, still Four episodes (three mood) dysfluent Case 4 Terminal deletion – ring 22 Phrase speech URI Age 16 Age 16 Mood episode in past year Female 46,XX,r [22](p13q13.3).ish Never toilet trained First episode depressive Decreased speech Six years since regression 22 r[22](ARSA-) Dressed self with prompts symptoms5 Decreased response to Skills continue to years 3 Read some sight words Then manic symptoms with environment deteriorate months Did puzzles hand posturing and gait Decreased orientation disturbance Three mood episodes Case 5 Terminal deletion [106 kb] Full sentences Program Age 28 Age 30 No episode in past 3 years Male 46,XY; arr[hg18] 22q13.33 Toilet trained transition First episode depressed Slowly regressed over Six years since regression 36 (49,474,771-49,581,309)x1 Dressed self Then new aggression which several years Moderate recovery years 1 Did all self-care worsened to require two Lost speech Remains largely mute and month Independent with own routines hospitalizations and placement Decreased continence uses single words or Able to return home from in nursing care facility Lost ability to dress and grunts day program unassisted and to Three mood episodes shower Dependent for ADLs be home alone safely Needs help with eating Regained some self-care Moved slowly skills No longer can be left alone Improved mood

Incontinent at night 17 of 5 Page Case 6 Terminal deletion [54 kb] Spoke in full sentences Pneumonia Age 14 Age 26 Mood episode in past year Female arr[hg19] 22q13.33(51, Toilet trained First episode depressed Sporadic incontinence Two years since regression 28 123,491-51,178,264)x1 Dressed self Then mania with complete Confused No recovery years Made snacks insomnia for 12 days, catatonia, Couldn’t read or write Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study 11 Read simple books neuroleptic malignant syndrome Decreased hand skills months Wrote simple text and seizures Poor memory Now ECT dependent 10+ mood episodes Case 7 Terminal deletion – ring 22 Simple repetitive speech None noted Age 30 Age 30 Mood episode in past year Female 46,XX,r [22](q13.3) with Toilet trained First episode depressed Decreased vocalizations Four years since regression 34 deletion of terminal 22q Dressed self with prompts Then both manic and Frequent incontinence Moderate recovery years 6 Some sight words depressed episodes Decreased independence Vocalizes more months Some computer skills 10+ mood episodes with dressing Remains incontinent Feeds self but needs supervision for choking Needs help with dressing Case 8 Terminal deletion [106 kb] Phrase speech None noted Age 11 Age 11 No episode in past year

Female arr[hg18] 22q13.33 Toilet trained First episode manic symptoms Steady developmental 25 years since regression (2020)12:7 36 (49,475,238-49,581,309)×1 Dressed self with supervision Then mixed mood episodes decline from age 11 No recovery years 3 Read simple words 10+ mood episodes Lost almost all language months Played with dolls Incontinent Lost use of utensils No longer dresses self No play interests Case 9 Terminal deletion – ring Spoke in full sentences None noted Age 32 Age 32 Mood episode in past year Female 22 [2.1 Mb] Toilet trained Abrupt onset of stuporous Decreased speech 12 years since regression 43 46,XX,r [22](p13q11.2); Dressed self catatonia with food phobia Incontinent Minimal recovery years 1 arr[hg19] 22q13.32q13.33 Independent for hygiene Then multiple manic and No longer able to dress Decreased speech month (49,056,457-51,179,671)x1 Active in programs depressed episodes self or bathe self Intermittent incontinence 10+ mood episodes Needs supervision for self- care Case Sequence variant – Spoke in full sentences Menses Age 14 No lasting loss of skills Mood episode in past year 10 Frameshift Toilet trained Started at new First had three peri-menstrual No regression Female NM_033517.1:c.3424_3425delCT, Dressed self and did most school manic episodes followed by 17 p.Leu1142Valfs*153 hygiene paranoia years Read sight words Then prolonged severe 11 Wrote name, familiar words, depression with catatonic months copied text features Then acute OCD with tics, posturing and choreiform movements Then mania with first seizure and catatonia, dx seronegative

autoimmune encephalitis 17 of 6 Page Six episodes (five mood episodes) Case Sequence variant – Phrase speech Gastro-enteritis Age 12 Age 12 Mood episode in past year 11 Frameshift Social and interactive First episode manic with agitation, Lost most language Two years since regression Male NM_033517.1:c.3679dupG, Toilet trained new pica, new incontinence, Less social and interactive Minimal recovery Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study 14 p.Ala1227Glyfs*69 Read sight words destructive behavior, mutism, Incontinent Rare speech and years Typed from a model and catatonia Lost all academic skills interaction now 11 Then OCD with agitation and New obsessional and Still incontinent months aggression repetitive behaviors Five+ mood episodes Case Sequence variant – Frameshift Spoke in full sentences Menses Age 11 Age 11 No episode in past year 12 NM_033517.1:c.4906_4921dup16, Toilet trained Viral infections First episode mixed, with Gradual, with each episode 15 years since most severe Female p.Pro1641Leufs*58 dn Dressed and washed agitation, insomnia, cognitive lost skills, twice lost ability regression 43 Read at 3rd grade level dulling, posturing to walk, would regain some No recovery years 8 Math grade level through Then multiple mood skills with therapies, still months 9th grade episodes with catatonia working and verbal to age Worked at supported job in 20+ mood episodes 28; after a severe cold lost library and in town hospital all speech, continence, Balanced own checkbook self-care and many motor skills, cannot use hands (2020)12:7 (dystonic posturing at wrists) Case Terminal deletion [123 kb] Spoke in full sentences Strep infection Age 9 No lasting loss of skills No episode in past year 13 46,XX; arr[hg18] 22q13.33 Toilet trained Menses First episode complex tics No regression Female (49,468,254-49,591,415)x1 Pulled on clothes and choreiform movements 14 Needed help with ADLs w/ high strep titers, dx PANDAS years 1 Read at 1st grade level and resolved with antibiotics month Wrote and typed Then rage outbursts and Used iPad peri-menstrual aggression Then depressive episode with severe anxiety and new generalized anxiety disorder 3+ mood episodes Case Sequence variant – Nonsense No speech, used PECS None noted Age 15 Age 15 No episode in past year 14 NM_033517.1:c.5008A > T, Toilet trained First episode manic Lost toilet training 18 months since regression Male p.Lys1670* (this individual Fed self Then monthly manic episodes Averse to touch Moderate recovery of 16 also has a likely benign Used iPad Then severe aggression requiring Lost computer skills toileting, self-feeding, some years 6 missense variant in SHANK3, Navigated internet hospitalization and residential care Lost social interest computer skills months c.3872C > T, p.Ser1291Leu) Liked music 20+ manic episodes Case Terminal deletion [43 kb] Single words School re-entry Age 9 Age 24 Three years since last 15 arr[hg18] 22q13.33(49,479, Never toilet-trained Possible URIs First episode manic Lost ability to: episode Female 705-49,522,868)x1 Could change own pull-up Then manic spells with Dress self Four years since regression 28 Dress self OCD behaviors Change pull-up No recovery years Drink from cup Then depressed periods Drink from cup 11 with new aggression

months 10+ mood episodes 17 of 7 Page Case Sequence variant – Frameshift Spoke in full sentences Menses Age 13 No lasting loss of skills Mood episode in past year 16 arr[hg19] 22q13.33(51, Toilet trained First episode manic with No regression Female 121,452-51,197,838)x1 Dressed self paranoia 15 Read Then depressive episode Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study years 1 Pretend play with catatonia requiring month Wrote in cursive ICU care and ECT Karate Then recurrent manic episodes Five+ mood episodes Case Terminal deletion [4.3 Mb] Single words or short phrases Menses Age 13 No lasting loss of skills Mood episode in past year 17 arr[hg19] 22q13.31q13.33 Toilet trained First episode depressed No regression Female (46,928,208-51,224,252)x1 dn Dressed self with catatonia 13 Fed self Then mania with urinary years Rode scooter frequency and occasional 10 incontinence, changes in months gait and posture Four mood episodes

Case Terminal deletion [76 kb] Spoke in full sentences Possibly his Age 16 Age 16 Mood episode in past year (2020)12:7 18 arr[hg19] 22q13.33(51,121, Toilet trained increased First episode mixed mood Confused Four years since regression Male 452-51,197,838)x1 Dressed self awareness of disturbance with sleepiness Needs constant supervision No recovery 20 Showered self deficits and irritability Cannot dry self years Read at 3rd grade level Then mania alternating with Puts clothes on while still wet 10 Wrote sentences depression and severe Decreased academic skills months Used calculator aggression Urinary incontinence Used iPhone to call/text Three+ mood episodes Lost interest in usual activities friends Case Sequence variant – Nonsense Spoke in full sentences School Age 17 Age 17 Mood episode in past year 19 NM_033517.1:c.1572C>A, Toilet trained transition First episode manic with Gradual, lost most speech 12 years since regression Male p.Cys524* Independent for ADLs and irritability, confusion, Often incontinent No recovery 26 travel with school groups catatonia and new aggression Lost ability to perform ADLs years 5 Reading at 3rd grade level Then multiple manic and Requires constant 1:1 months Attended community college depressed episodes supervision Competitive tennis Psychotic features occurring Marathoner between mood episodes 20+ mood episodes Case Sequence variant – Frameshift Phrase speech Strep infection Age 14 Age 15 Mood episode in past year 20 NM_033517.1:c.4065_ Asked for needs First episode OCD with enuresis Decreased intelligibility Two years since regression Female 4066delTG, p.Val1357Glyfs*4 Toilet trained at night, aggression and Decreased toileting Moderate recovery of 17 dn Fed self sub-threshold Decreased communication speech clarity and toileting years 1 manic symptoms Decreased feeding self skills month Then similar episodes of OCD with manic symptoms Later diagnosis of autoimmune

encephalitis 17 of 8 Page Three+ mood and OCD episodes Case Sequence variant – Frameshift Phrase speech Strep infection Age 14 Age 14 Mood episode in past year 21 NM_033517.1:c.4065_4066delTG, Toilet trained First episode anxiety/OCD, transient Slow onset Two years since regression Female p.Val1357Glyfs*4 dn Fed self inability to speak, then developed Decreased toileting Moderate recovery of Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study (twin Dressed self mania Decreased communication communication and self- of case Read a few sight words Then diagnosed with PANDAS, Decreased orientation care skills 20) Basic writing Then catatonia Decreased feeding self Less improvement with 17 Five+ mood episodes No longer writes name academics years 1 month Case Terminal deletion [62 kb] Few single words None noted Age 8 No lasting loss of skills Mood episode in past year 22 arr[hg18] 22q13.33(49,406, Not toilet trained First episode manic, No regression Female 251-49,468,408)x1 Needed help for dressing then depressive episodes 15 Fed self with utensils 10+ episodes years 0 month Case Terminal deletion [2.5 Mb] Phrase speech with poor None noted Age 32 No lasting loss of skills Mood episode in past year

23 arr[hg18] 22q13.32q13.33 articulation First episode depressed No regression (2020)12:7 Female (47,003,473-49,515,911)x1 Toilet trained Then recurrent depressed 39 Intact ADLs episodes with severe anxiety, SIB years 5 Read simple books Then mania with catatonia months Memory games 10+ mood episodes Jigsaw puzzles Dot-to-dot coloring Case Terminal deletion [69 kb] Phrase speech Puberty Age 15 Age 18 No episodes in past year 24 arr[hg19] 22q13.33(51, Toilet trained First episode agitation, OCD Decreased urinary continence 18 years since regression Female 128,324-51,197,766)x1 Dressed self Then catatonia and depression Decreased independence No recovery 36 Fed self Then manic episodes for ADLs years 7 Read simple text 10+ mood episodes Lost all academic skills months Wrote at a second grade level Case Terminal deletion – Single words Multiple family Age 21 No loss of skills No episode in 3 years 25 unbalanced translocation Toilet trained health stressors First episode depressed with No regression Female [6.0 Mb] Fed self High strep titers agitation, photophobia, then 24 46,XX,der(22)t(22;acro) Did chores catatonia, diagnosed PANDAS years 1 (q13.33;p12); arr[hg19] One episode month 22q13.31q13.33(45, 156,254-51,197,725)x1 Case Sequence variant–Frameshift Spoke in full Strep infection Age 13 Age 13 Mood episode in past year 26 NM_033517.1:c.4649_ sentences First episode manic with acute Lost language Five years since regression Male 4653dupGCAGC, Toilet trained onset insomnia, tics, anorexia Decreased fine motor skills Minimal recovery 18 p.Pro1552Alafs*14 dn Dressed with assistance diagnosed PANDAS Decreased toileting Slightly improved years 1 (based on the results of his Fed self Then new pica, catatonia Decreased utensil use language and toileting month monozygotic twin brother) Read fluently Then mutism and aggression Decreased interest in people Remains socially 17 of 9 Page Acted out plays associated with recurrence of and hobbies withdrawn Used computer with manic symptoms Destructive Has not regained fine sophistication (e.g., booked 10+ mood episodes Sleep disrupted motor skills travel) Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study Case Sequence variant – Frameshift Phrase speech Strep infection Age 13 Age 13 Mood episode in past year 27 NM_033517.1:c.4649_ Toilet trained First episode manic with acute Lost most language Incontinent Five years since regression Male 4653dupGCAGC, Needed help with dressing onset insomnia, tics, anorexia Decreased feeding self Moderate recovery (twin p.Pro1552Alafs*14 dn Fed self with fingers diagnosed PANDAS Decreased interest in people, Has regained some fine of case Used computer Then depression and catatonia activities motor skills and social 26) Few sight words 10+ manic and depressed episodes interests, but not language 18 and full continence years 1 month Case Terminal deletion [70 kb] Spoke in full sentences Menses Age 16 Age 18 Manic episode in past year 28 arr[hg19] 22q13.33(51, Toilet trained Gradual onset aggression Became confused about daily Six years since regression Female 127,898-51,197,838)×1 Independent with dressing and Then manic episodes with tasks and had trouble with Has recovered all skills 26 care unsafe behaviors self-care years 3 Took own meds 10+ manic episodes Language deteriorated months Black belt in karate Episodes of running away (2020)12:7 Case Sequence variant – Frameshift Spoke in full sentences Menses Age 12 Age 12 Manic episode in past year 29 NM_033517.1:c.3679dupG, Toilet trained Hashimoto’s Gradual onset confusion and Lost all adaptive skills, including Four years since regression Female p.Ala1227Glyfs*69 dn Dressed self encephalopathy choking spells unrelated to continence and speech Minimal recovery of 16 Independent for hygiene food Lost all academic skills relatedness and years 7 Fed self Then episodes of mania and communication months Read at 2nd grade level OCD with catatonia and No recovery of academic disorganized behavior and skills new behavior posing risk of Dependent for ADLs accidental injury Requires constant 10+ mood episodes supervision Appears to understand language but little speech Plays simple computer games Case Terminal deletion with Minimal language Mycoplasma Age 14 Age 15 Mood episode in past year 30 interstitial duplication Toilet trained for urine in pneumonia First episode depressed with Lost daytime continence Three years since Female [6.4 Mb] daytime catatonia Lost interest in play and regression 16 46,XX,del [22](q13.3); Fed self with fork Then OCD and manic symptoms relatedness Moderate recovery years 8 arr[hg18] 22q13.31 Could put on clothes if in Five+ mood episodes Decreased feeding self Has regained energy and months (43,276,438-49,691,432)x1, correct position Decreased vocalization vocalization, not daytime 22q13.31(42,835,935-43, continence 272,271)x3 Case Terminal deletion [5.0 Mb] Spoke a few words None noted Age 14 Age 47 Two years since last mood 31 (5 Mb terminal deletion Toilet trained First episode manic Loss of skills with each psychiatric episode; Female with the breakpoint at Fed self Then repeated mood episodes episode; recovered each time Two years since regression 17 of 10 Page 49 22q13.31) Ambulatory at intervals of five or more years until age 47, then lost all No recovery years 9 Three+ mood episodes language No language months Lost ability to walk Incontinent Lost feeding skills Cannot stand or walk, has Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study difficulty maintaining sitting Cannot feed self Needs total care Case Terminal deletion Spoke in full sentences None noted Age 14 No loss of skills Mood episode in past year 32 [76 kb] Toilet trained First episode anxiety/OCD (resolving) Female 46,XX; arr[hg19] Intact ADLs Then mania No regression 31 22q13.33(51,121,452-51, Planned recipes and cooked Then depression with slow years 197,838)x1 dn Worked with young children recovery over 2 years followed 11 Ran with running group by severe mood cycling months Volunteered at nursing home years later Three+ mood episodes Case Terminal deletion [481 kb] Single words None noted Age 7 Age 16 Mood episode in past year

33 arr[hg18] 22q13.33(49, Never toilet trained First episode bizarre behavior with Lost all meaningful speech; 25 years since regression (2020)12:7 Female 210,245-49,691,432)x1 Fed self agitation, disorientation and insomnia repeats words No recovery 41 Undressed and pulled on pants (possible brief psychotic episode) Unable to feed self, eats by years 0 Read sight words Then OCD and new pica, followed by lowering face to plate month Poured drinks mania Unable to assist with dressing Rode tricycle 10+ mood episodes Lost all play Played with dolls Elopes frequently Case Terminal deletion [53 kb] Spoke in full sentences Multiple social Age 14 Age 14 No episode in past year 34 arr[hg19] 22q13.33(51, Toilet trained stressors First episode depressed with anorexia Decreased speech Four years since regression Female 144,903-51,197,838)x1 Fed self and incontinence Decreased play Moderate recovery of 17 Dressed self Then mania and new pica Decreased dressing language, self-care and years 8 Retrieved and poured cereal Five+ mood episodes Decreased continence play skills month Did puzzles Played with Legos Case Sequence variant – Phrase speech with echolalia Multiple social Age 12 Age 12 Mood episode in past year 35 Frameshift Toilet trained stressors First episode depressed with Steady ongoing regression 11 years since regression Female NM_033517.1:c.4086_ Fed self confusion, new incontinence and Lost all speech No recovery 23 4087delAC, Poured milk catatonia Incontinent Requires constant years 1 p.Arg1363Glnfs*31 Dressed self with assistance Then mania Lost all self-care skills supervision month Needed help with ADLs Three+ mood episodes Only able to walk short Pretend play distances with difficulty Cannot climb stairs Case Sequence variant – Spoke in full sentences Social stressors Age 14 Still recovering from first episode Eight months since onset 36 Frameshift Toilet trained First episode catatonic with urinary with catatonia; cannot yet of psychiatric illness Female NM_033517.1:c.4065_ Dressed self retention, insomnia and pica; did not determine new baseline or Continues to regain

15 4066delTG, Fed self recognize family; paranoid whether lost skills meet language, personality, and 17 of 11 Page years 0 p.Val1357Glyfs*4 dn Read sight words One episode criteria for regression orientation month Used tablet Still not able to open and Math at 1st grade level use hands for ADLs Intermittently incontinent Table 2 Case summaries (Continued) Kohlenberg Case # Genetic defect Level of functioning prior to Reported Age onset psychiatric illness; Age and areas of regression Years since last psychiatric Gender onset psychiatric illness 1 possible psychiatric diagnoses by after onset psychiatric illness 2, 3 episode and regression; Age at triggering DM-ID-2 criteria; associated degree of recovery in that time of stressors features; number of episodes time and skills regained Disorders Neurodevelopmental of Journal al. et study Case Sequence variant – Phrase speech Menses Age 15 Age 15 No episode in past year 37 Nonsense Toilet trained End of school First episode depressed with insomnia, Lost most speech Two years since regression Female NM_033517.1:c.4333C Fed self year severe separation anxiety, apathy, Lost ability to chew food Moderate recovery 17 > T, p.Gln1445* dn Dressed self with assistance decreased speech and interaction, Increased dependence for ADLs Regained some speech years 5 Imaginative play swallowing difficulties, and catatonia Lost all academic skills Eats normally months Wrote name One mood episode Lost imaginary play Mostly continent Copied text Continues to not have Drew pictures academic skills, drawing skills, or imaginary play skills Case Sequence variant – Spoke in full sentences Menses Age 13 Age 15 No episode in past year 38 Frameshift Toilet trained UTI First episode hypomanic Lost all speech One year since regression Female NM_033517.1:c.2763delG, Sociable Then 2 years later manic with Lost ability to feed self Substantial recovery 16 p.Pro922Argfs*34 dn aggression, incontinence; anxiety, Incontinent Recovered language years 9 talking to self, compulsions, then Decreased social interaction Recovered feeding (2020)12:7 months catatonia Improved social interaction Three manic episodes Continues with intermittent incontinence Abbreviations: ADLs activities of daily living, dn de novo, dx diagnosis, ECT electroconvulsive 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 1 All were ambulatory and able to feed themselves with utensils prior to psychiatric illness 2 Cases 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 3 Regression defined as loss of skills that persisted at least 6 months after resolution of acute psychiatric episode 4 Regression occurred years after onset of psychiatric illness 5 “Symptoms” used when sub-threshold for diagnosis of either depressive or manic episode ae1 f17 of 12 Page Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 13 of 17

Symptoms consistent with a diagnosis of catatonia as- to 25 kg accompanying psychiatric episodes. Chronic con- sociated with another mental disorder were reported in stipation, intermittent urinary incontinence, and episodes 20 of 38 cases (53%). Seven of the 20 (35%) were on neu- of acute urinary retention were prevalent in this sample, roleptics at the time of emergence of catatonic symp- particularly as subjects aged. Chronic constipation was toms. Cases with sequence variants in SHANK3 met noted in 32 cases (84%), with episodes of acute urinary re- diagnostic criteria for catatonia significantly more often tention reported in 18 (47%). The discomfort associated (12/15; 80%) than cases with terminal deletions (8/23; with these conditions may lead to non-specific behaviors 35%) (Fisher’s exact test, p = 0.009). such as agitation, aggression, and self-injury in people with ID; these chronic symptoms were not coded as mood epi- Regression sodes. A small subset of subjects (4/38; 11%) had an The interview explored both abilities lost and the degree immune-related disorder. Two participants (5%) were di- of return of skills over time. Caregivers were asked agnosed with Hashimoto’s thyroiditis, one of whom was which skills were lost, at what age, and which, if any, diagnosed with Hashimoto’s encephalopathy, and two par- skills were regained. Seven of the participants (18%) had ticipants (5%) had immunoglobulin deficiency, including experienced regressions in early childhood affecting one with common variable immunodeficiency. communication, social interaction, and/or imaginative play (five by age two, one at age four, one at age seven), Therapeutic interventions but we do not elaborate on those early regressions in the At the time of interview, 32 of 38 participants (84%) current report. Analysis focused on the 25 of 38 cases were receiving one or more psychiatric medications, (66%) who had regressions that began within the 3 years with 14 of 38 (37%) receiving four or more psychi- after the onset of psychiatric episodes. Most of these re- atric medications. More than half (21/38; 55%) took gressions (21/25; 84%) began within a year after the on- anticonvulsants; all of these had mood symptoms, set of psychiatric episodes and involved multiple while 12 also had a history of seizures. Over half domains of function. Descriptions of the areas of skill (55%) were receiving neuroleptics. Benzodiazepines lost and recovery are summarized in Table 2, which in- were used either regularly or on an as-needed basis cludes developmental status in terms of speech, toilet in 16 of 38 cases (42%). Alpha agonists, beta-blockers, training, ability to dress and wash self, academic skills, antihistamines, and trazodone were prescribed for and vocational activities when present. Caregiver reports sleep or aggression. Smaller numbers of participants of recovery of skills ranged from continuing loss of fur- were receiving selective serotonin reuptake inhibitors ther skills to complete return to baseline function before (SSRIs), tricyclic antidepressants, buspirone, lithium, the onset of psychiatric symptoms. Overall, more than cannabinoid oil, or n-acetylcysteine. half of the participants who regressed in the 3 years after Full details of dosages and adjustments to treatment the onset of psychiatric illness reported minimal recov- regimens in response to changing psychiatric status ery (14/25; 56%). were inconsistently available and are therefore not re- Antecedents to the onset of psychiatric illness and re- ported. However, many parents kept extensive notes, gression were explored in the interview. Menstrual cyc- and their reports of responses to medication trials ling was reported to play a triggering role in 11 of 31 suggest two patterns worth noting: (1) participants (35%) of the females. Acute infections were suspected were reported to be sensitive to side effects from neu- triggers in 11 of 38 cases (29%). Psychosocial stressors roleptics, with adverse events including extrapyramidal were suspected triggers in 10 of 38 cases (26%). Several symptoms, worsening aggression and/or onset of cata- participants reported differing antecedent stressors for tonic symptoms reported in 14 of 30 cases (47%), different episodes. while (2) seven of nine participants (78%) treated with SSRIs for depressive symptoms developed agitation, Co-morbid conditions aggression, or other manic-like symptoms within Only a quarter (9/38; 24%) of study participants was weeks of the start of treatment. known to have PMS before the onset of psychiatric symp- Three individuals were treated with electroconvulsive toms and associated regression. Sixteen cases (42%) had therapy (ECT) for catatonia with reported significant diagnoses of ASD before the onset of psychiatric symp- benefit; two continue to require maintenance ECT (dur- toms and regression; five more received an ASD diagnosis ation of treatment 18 months in one, > 8 years in the after the onset of psychiatric illness and regression. other) while the third discontinued after initial response Fifteen of 38 cases (40%) reported one or more due to agitation. One participant with recurrent catato- afebrile seizure. Eight of those 15 cases (53%) re- nia on maintenance ECT was reported to have also ported a seizure in the 2 years preceding the inter- benefited from intravenous immunoglobulin (IVIG) with view. Fifteen of 38 cases (40%) had weight loss of 10 improved cognition and motivation, but developed Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 14 of 17

aseptic meningitis and a rash after the fifth treatment, Several triggers were often reported as temporal ante- leading to discontinuation of IVIG. cedents to the onset of psychiatric changes. Biological Nine participants (26%) were reported to have received triggers included infections and changes in hormonal immunomodulatory treatments for diagnoses of status, while environmental factors included stressful life pediatric autoimmune neuropsychiatric disorders associ- events. Similar patterns have been observed in other, ated with streptococcal infections (PANDAS) syndrome more common neurogenetic syndromes, including Down or of autoimmune encephalopathy. Six were diagnosed syndrome [32], Williams syndrome [33], and 22q11.2 de- with PANDAS syndrome on the basis of clinical symp- letion syndrome [34]. toms and positive strep cultures or elevated titers. One It is critical to emphasize the high incidence of catatonic participant was diagnosed with Hashimoto’s encephalop- symptoms in this subset of individuals with PMS, as cata- athy, and two with seronegative autoimmune encephal- tonia often goes unrecognized or undertreated in individ- itis. Treatments included (1) antibiotics, (2) IVIG, and/ uals with developmental disabilities [25, 35]. Recognition or (3) systemic anti-inflammatories such as nonsteroidal and treatment of both stuporous and hypermotoric cata- anti-inflammatory drugs, steroids, or rituximab. tonia is crucial, as symptoms can lead to life-threatening In four of six cases diagnosed with PANDAS syn- complications. Other genetic conditions involving copy drome, parents reported that antibiotic treatment was number variants, such as 22q11.2 deletions [36], have also effective in reducing or eliminating acute symptoms. been associated with psychiatric symptoms and with cata- Theremainingtwoimprovedslowly;onealsore- tonia. Similar to their use in treating catatonia in other ceived IVIG and the other received lorazepam; these conditions, benzodiazepines and ECT were used in this parents were not confident that antibiotics had played cohort with reported tolerability and effectiveness. a role in recovery. Treatment for PANDAS symptoms Regression has long been recognized in neurodevelop- did not appear to prevent future mood episodes or mental disorders such as ASD [37], but the triggers and regression, as all but one of these cases went on to mechanisms are not well understood, and the literature have further psychiatric episodes and some had later focuses largely on early childhood regression, especially regressions. The one participant diagnosed with as it relates to Rett syndrome [37–40]. Significant cogni- Hashimoto’s encephalopathy continues to receive tive and behavioral regression has been documented in regular infusions of IVIG with steroids, as well as PMS [5, 6, 9, 15, 16, 18, 41]. Verhoeven et al. [20] have rituximab. The two participants with diagnoses of recently published on the course of illness of 24 adoles- seronegative autoimmune encephalopathy receive cents and adults with PMS referred for evaluation and monthly IVIG. treatment of “challenging behaviors and unstable mood.” Eight females were on hormonal therapy to eliminate In that sample, there were five individuals with periodic menstrual cycles and reduce associated mood symptoms. catatonic symptoms, and four other individuals who de- Non-pharmacological treatments varied widely by geo- veloped progressive loss of skills in their third or fourth graphic location and age, with those still in school more decade. likely to be receiving structured behavioral interventions. Two thirds (66%) of our sample described lasting regres- Data on past and current behavioral programs and ther- sions that began within 3 years of the onset of psychiatric apies were not included in the interview. illness. These regressions in communication, self-care, and motor functions left a subset of previously more capable Discussion individuals largely non-verbal, incontinent, and unable to This case series has characterized a subset of individuals dress or feed themselves. Many of these participants con- with PMS who have episodic, severe neuropsychiatric ill- tinue to experience episodic psychiatric illness in addition ness, frequently beginning in adolescence or early adult- to developmental decline. Interestingly, a similar combin- hood, with major impacts on functional status. The ation of rapid onset psychiatric disturbance with marked symptoms and course of illness often closely resembled regression and catatonia has been described in Down syn- bipolar illness, with psychotic features almost exclusively drome [42, 43] and subsequently labeled “Down syndrome present in the context of mood episodes. None of the disintegrative disorder.” A recent case series [44]docu- participants in our sample presented with a primary mented a role for immunotherapy in restoring function psychotic disorder, such as schizophrenia. However, one and stability in these individuals, although it is also recog- participant presented with distinct psychotic and nized that cognitive decline in Down syndrome relates to affective episodes characteristic of schizoaffective dis- amyloid precursor protein gene triplication [45–47]. Re- order. Using the DM-ID-2 criteria [30], all but one of gression in PMS may be more common than in Down the participants had either a mood disorder or an anx- syndrome, and its potentially devastating impact warrants iety disorder, with multiple discrete periods of illness in ongoing study of the natural history, mechanism, and tar- all but four. gets for intervention. Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 15 of 17

Given the methodological limitations and sample se- Finally, our sample underscores the importance of lection bias in this study, we are unable to draw conclu- genetic testing as part of the medical work-up for indi- sions about the prevalence of psychiatric illness and/or viduals with this presentation. Chromosomal microarray regression among people with PMS. This study was also is recommended for the evaluation of all children with limited by the lack of standardized or validated tools to global developmental delay or intellectual disability [49]. measure neuropsychiatric symptoms in severely develop- In the setting of superimposed psychiatric illness or re- mentally disabled children and adults. However, within gression, chromosomal microarray should be considered this self-referred subset of individuals with PMS whose as first tier testing, followed by sequencing of SHANK3 caregivers identified psychiatric illness, we observed a if the microarray is unrevealing. 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 Conclusion the second through fourth decades of life. Of note, a re- This study confirms that individuals with PMS are at cent literature review analyzed prior reports of 56 indi- risk of developing severe neuropsychiatric illness in ado- viduals with PMS with accompanying neuropsychiatric lescence or early adulthood. In most cases, the symp- symptoms, and concluded that “clinicians and caregivers toms appear consistent with the expression of bipolar need to be vigilant for loss of skills and neuropsychiatric disorder in individuals with intellectual disability, with changes in adolescents and adults with PMS, including catatonia noted as a common co-occurring condition. the development of bipolar disorder and catatonia” [48]. Triggers may include infections, changes in hormonal Individuals with PMS who present with new psychiatric status, and stressful life events. Significant cognitive and symptoms require careful monitoring and cautious early behavioral regression beyond a baseline level of disability intervention. Response to traditional psychiatric interven- has been previously reported in PMS and accompanied tions is variable, and the role for immunomodulatory the onset of psychiatric illness in a majority of the cases treatments and ECT in specific subsets of patients should reported here. Our results must be interpreted with cau- be explored in future studies. The pattern of rapid and se- tion given the potential selection bias in recruitment, vere deterioration described in more than half of this but it is clear that people with PMS may show a rapid group calls for further investigation to identify triggers and severe deterioration that requires careful monitoring and the underlying biology and to delineate possible strat- and intervention. Our findings also highlight the rele- egies for prevention and timely intervention. While the vance of genetic testing in the work-up of individuals current study does not allow for specific treatment recom- with intellectual disability and acute psychiatric illness mendations, there is an urgent need for clinical trials to or regression. Future research is needed to clarify the assess the efficacy of existing psychopharmacological prevalence and nature of psychiatric symptoms and re- treatments for psychiatric symptoms in PMS, in addition gression among larger unbiased samples of individuals to developing novel, targeted therapeutics. with PMS and to delineate any shared mechanisms with The preponderance of females in this sample (> 4:1) is other neurodevelopmental disorders presenting with notable and calls for replication. Sequence variants in psychiatric illness and/or regression in adolescence or SHANK3 were also six times more common in this sam- early adulthood. Identification of early clinical and bio- ple than in the PMSIR. These findings raise questions logical markers would contribute to our understanding about whether psychiatric problems and regression dis- of the underlying neurobiology of these disorders and proportionately affect females and/or individuals with potentially aid in monitoring, early intervention, or SHANK3 sequence variants, in contrast to those with de- prevention. letions. In addition, prior to the onset of psychiatric ill- ness, most of the participants described herein were less Additional files severely impaired in their adaptive functioning than is reported in most studies of PMS. This finding is likely Additional file 1. Caregiver Interview for Psychiatric Illness in Persons related to the high proportion of individuals with with ID (CIPIPID) SHANK3 variants and small deletions in this sample. Additional file 2. Adapted Diagnostic Criteria, DM-ID-2 Further studies should attempt to clarify if psychiatric difficulties are actually more common in individuals who Abbreviations are more verbal and social and who have more intact ASD: Autism spectrum disorder; DM-ID-2: Diagnostic Manual - Intellectual adaptive functioning at baseline, or, whether this finding Disability, Second Edition; ECT: Electroconvulsive therapy; ID: Intellectual is the result of selection bias in our sample, as the ma- disability; IVIG: Intravenous immunoglobulin; PANDAS: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; jority of participants (76%) were only diagnosed with PMS: Phelan-McDermid syndrome; PMSIR: Phelan-McDermid Syndrome PMS after the onset of psychiatric symptoms. International Registry Kohlenberg et al. Journal of Neurodevelopmental Disorders (2020) 12:7 Page 16 of 17

Acknowledgements 6. Bonaglia MC, Giorda R, Beri S, de Agostini C, Novara F, Fichera M, et al. We thank the families for their many contributions and the Phelan- Molecular mechanisms generating and stabilizing terminal 22q13 deletions McDermid Syndrome Foundation for its support. in 44 subjects with phelan/mcdermid syndrome. PLoS Genet. 2011;7(7): e1002173. Funding 7. De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, et al. MPT receives research support from the National Institute of Health National Delineation of the genetic and clinical spectrum of Phelan-McDermid Research Service Award Institutional Training Program (T32) and the Beatrice syndrome caused by SHANK3 point mutations. Mol Autism. 2018;9(1):1–20. and Samuel A. Seaver Foundation. AT receives support from the Intramural 8. Sarasua SM, Boccuto L, Sharp JL, Dwivedi A, Chen CF, Rollins JD, et al. Research Program of the National Institute of Mental Health (ZICMH002961). Clinical and genomic evaluation of 201 patients with Phelan-McDermid AK receives support from the National Institute of Neurological Disorders syndrome. Hum Genet. 2014;133(7):847–59. [cited 2015 Jan 12]; Available and Stroke (R01NS105845-01 and U54 NS092090-01) and from the Beatrice from: http://www.ncbi.nlm.nih.gov/pubmed/24481935 and Samuel A. Seaver Foundation. 9. Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype-phenotype correlations in Availability of data and materials 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013;4(1):18. The datasets analyzed in the current study are available at the PMS [cited 2015 Jan 12]; Available from: http://www.pubmedcentral.nih.gov/ International Registry to authorized users (https://www.pmsf.org/registry/). articlerender.fcgi?artid=3707861&tool=pmcentrez&rendertype=abstract 10. Kolevzon A, Angarita B, Bush L, Wang AT, Frank Y, Yang A, et al. Phelan- ’ McDermid syndrome : a review of the literature and practice parameters for Authors contributions medical assessment and monitoring. J Neurodev Disord. 2014;6:39. TK and MPT collected the data. BL and CB performed the analyses of the PMS 11. Khan O, Zhou X, Leon J, Kessler R, Gaughan T, D’Souza P, et al. Prospective International Registry data. CB reviewed all genetic reports and performed longitudinal overnight video-EEG evaluation in Phelan-McDermid analyses of the relationship between genetic results and clinical findings. All Syndrome. Epilepsy Behav. 2018;80:312–20. authors were involved in drafting or revising the manuscript, have read and 12. Jeffries AR, Curran S, Elmslie F, Sharma A, Wenger S, Hummel M, et al. agreed to its content, and are accountable for all aspects of the accuracy and Molecular and phenotypic characterization of ring chromosome 22. Am J integrity of the manuscript, in accordance with ICMJE criteria. Med Genet A. 2005;137(2):139–47. [cited 2015 Jan 12]; Available from: http:// www.ncbi.nlm.nih.gov/pubmed/16059935 Ethics approval and consent to participate 13. Dhar SU, Del Gaudio D, German JR, Peters SU, Ou Z, Bader PI, et al. 22q13.3 Informed consent was obtained for participants, who were enrolled in the Phelan- Deletion syndrome: clinical and molecular analysis using array CGH. Am J McDermid Syndrome International Registry (https://www.pmsf.org/registry/). Med Genet Part A. 2010;152(3):573–81. [cited 2015 Jan 12]; Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3119894&tool= Consent for publication pmcentrez&rendertype=abstract All participants signed a release for publication of results. 14. Holder JL, Quach MM. The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss of function Competing interests mutations. Epilepsia. 2016;57(10):1651–9. AK receives research support from AMO Pharma and consults to Ovid 15. Serret S, Thümmler S, Dor E, Vesperini S, Santos A, Askenazy F. Lithium as a Therapeutics, Takeda, 5 AM Ventures, sema4, and LabCorp. The other authors rescue therapy for regression and catatonia features in two SHANK3 declare that they have no competing interests. patients with autism spectrum disorder: case reports. BMC Psychiatry. 2015; 15(1):107. Available from: http://www.biomedcentral.com/1471-244X/15/ Author details 107%5Cnhttp://www.ncbi.nlm.nih.gov/pubmed/25947967%5Cnhttp://www. 1Department of Psychiatry, University of Massachusetts Medical School, pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4428105 Worcester, MA, USA. 2Seaver Autism Center for Research and Treatment, 16. Denayer A, Van Esch H, De Ravel T, Frijns JP, Van Buggenhout G, Vogels A, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3Department et al. Neuropsychopathology in 7 patients with the 22q13 deletion of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. syndrome: Presence of bipolar disorder and progressive loss of skills. Mol 4Phelan-McDermid Syndrome Foundation, Osprey, FL, USA. 5Sorbonne Syndromol. 2012;3(1):14–20. [cited 2015 Jan 12]. https://doi.org/10.1159/ Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris 000339119. Seine, Paris, France. 6Neurodevelopmental and Behavioral Phenotyping 17. Verhoeven WMA, Egger JIM, Cohen-Snuijf R, Kant SG, de Leeuw N. Phelan- Service, Intramural Research Program, National Institute of Mental Health, McDermid syndrome: clinical report of a 70-year-old woman. Am J Med National Institutes of Health, Bethesda, MD, USA. Genet A. 2013;161A(1):158–61. [cited 2015 Jan 12]; Available from: http:// www.ncbi.nlm.nih.gov/pubmed/23166010 Received: 31 May 2019 Accepted: 23 January 2020 18. 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