Master Slide. PMS Across the Lifetime. Alexander Kolevzon, MD Seaver Autism Center for Research and Treatment Icahn School of Medicine at Mount Sinai

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1 Master Slide PMS Across the Lifetime Alexander Kolevzon, MD Seaver Autism Center for Research and Treatment Icahn School of Medicine at Mount Sinai

2 Disclosures of Potential Conflicts Source Research funding Advisor/ consultant Employee Speakers Bureau Books, Intellectual Property In-Kind Services Stock of Equity Honorarium Seaver Foundation X NIH/NINDS X New York Community Trust X Simons Foundation X American Psychiatric Publishing X Amo Pharma X Coronis X Ovid X 5AM Ventures X sema4 X Labcorp X *Mount Sinai and Joseph Buxbaum hold a shared patent for IGF-1 in Phelan-McDermid syndrome The following presentation contains information concerning a use that has not been approved by the U.S. Food and Drug Administration

3 Aims 1. To comprehensively characterize PMS using standard medical, cognitive, and behavioral measures. 2. Track the natural history using repeated longitudinal assessments. 3.To identify biomarkers using neuroimaging and electrophysiology. 4.To identify genetic factors which contribute to diverse phenotypes. 5. Test novel treatments.

4 Consortium 6 sites: Mount Sinai (Kolevzon); Rush University (Soorya; Berry-Kravis); Boston Children s (Sahin); National Institute of Health (Thurm); UT Southwestern (Powell); Stanford (Bernstein) 100+ patients

5 Natural History Understanding the natural history of PMS will: 1) Clarify the phenotype; 2) Identify targets for therapeutic interventions; 3) Build the foundation for future clinical trials; 4) Identify demographic, genetic, environmental, and other variables that correlate with disease outcomes; 5) Develop best clinical practices.

6 Natural History Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations Mount Sinai, Rush, NIH, Boston Timelines 1-Year follow-up 2-Year follow-up Baseline Year 1 36 Year Year Year 4 54

7 Natural History RESUBMISSION Adds 90 participants Expands age range down to 18 months and up to 45 years-old Adds 3- and 4-year time points Timelines Baseline 1-Year 2-Year 3-Year 4-Year Year Year Year Year Year

8 Phenotyping Physical and neurological exam Clinical Genetics Evaluation Medical and Psychiatric History Echocardiography Electrocardiography Renal ultrasound Electroencephalography Laboratory bloodwork Height and weight measurement Head circumference

9 Phenotyping Domain Global Cognitive Ability Measure Mullen Scales for Early Learning or Stanford Binet-5 Psychoeducational Profile-III Adaptive Behavior Vineland Adaptive Behavior Scales II Language Motor Functioning Autism Symptoms Other Symptoms Mullen and Vineland Subscales Macarthur Bates Communication Developmental Inventory Peabody Picture Vocabulary Test-4 Expressive Vocabulary Test-2 Communication Complexity Scale Mullen and Vineland Subscales Developmental Coordination Disorder Questionnaire Autism Diagnostic Observation Schedule Autism Diagnostic Interview-Revised (ADI-R) Pervasive Developmental Disorders Behavior Inventory Repetitive Behavior Scales-Revised Sensory Profile Questionnaire Short Form Sensory Assessment for Neurodevelopmental Disorders Aberrant Behavior Checklist Sleep Questionnaire Regression Interview San Martin Quality of Life Early Detection Screen for Dementia Wisconsin Activities of Daily Living Form

10 Autism Spectrum Disorder (ASD) and IQ diagnostic classifications 15.60% 9.40% 75% Autism ASD non-asd N % Nonverbal IQ classification (n=30) Average (IQ ) Mild intellectual disability (IQ to 70) 3 10 Moderate intellectual disability (IQ to 50-55) 3 10 Severe intellectual disability (IQ to 35-40) Profound intellectual disability (IQ < Soorya et al., 2013

11 *Phelan & McDermid, 2012 *

12 Jimmy Holder, MD

13 Developmental Trajectories

14 Regression - Definition Developmental regression refers to a condition in which children reach their developmental milestones at the expected times but at some point they start to lose the skills they developed and the developmental milestones they have met. It may also be used to refer cases in which the child was developing at a normal pace but then his or her development seems to have stopped. Genetic and Rare Diseases Information Center (GARD) NIH

15 Regression in Idiopathic Autism Occurrence of reported regression is higher in autism spectrum disorder (ASD) than other idiopathic developmental conditions; Mainly affecting language and social skills; Meta-analytic review (Barger et al., 2013) included: 85 studies (n = 29,035) Overall prevalence of regression in ASD is 32.1% Mean age of onset of regression as 1.78 years

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18 Regression in PMS Among 32 cases described in the literature with regression or some fundamental change in the phenotype: 17 males:15 females 14 terminal deletions; 11 ring chromosome 22; 4 SHANK3 mutations; 3 unspecified Average age of regression: 23 years, 9 months 13 cases with bipolar disorder or mood cycling; 3 with catatonia; 2 with psychosis; 1 with unipolar depression; 13 with some combination of cognitive, behavioral, or physical regression Betancur, C

19 Case Reports Two patients with mutations in exon 21 premature stop. Significant regression in early adolescence in the context of a shift in their care from an autism day care center to a new autism unit. Partly verbal with words and short sentences at baseline. Severe intellectual disability but no motor skill deficits at baseline. Change began with loss of language and self-help skills, sleep disturbance, increased impulsivity and aggression, apathy, and eventually catatonic features. EEG and MRI were within normal limits. Multiple medication trials failed. Atypical bipolar disorder was diagnosed. Lithium led to the return of baseline functioning. Serret et al., 2015

20 Developmental Trajectories Serret, BMC Psychiatry (2015)

21 Regression present in 18/42 (43%) of cases according to the ADI-R; Average age of onset was around 6 years-old; Affecting motor (10%), self-help (9%), and language (6%) skills; 39% regained the skills; Seizures or abnormal EEG was not associated with regression; Deletion size was not associated with regression.

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24 Preliminary Data: Results from the RDCRN Data was collected using a Regression Interview in 72 participants. 38% of caregivers indicated at least one skill had been lost at some point; 36% indicated that at least one skill in the social-communication domain was lost; 14% indicated that at least one motor skill was lost; The most frequent skill reported to be lost was babbling occurred in 22% of participants.

25 Challenges Measures Design (ages; cross-sectional; prospective) Time points Feasibility (costs; 5-year grant cycles)

26 Open Questions Is regression in childhood related to regression in adolescence or adulthood? What are potential causes of regression? Worsening seizures Structural brain abnormalities Acute illness Psychiatric disorders Immunologic changes How should treatment be guided by age of presentation, symptoms and potential mechanisms?

27 Acknowledgments Seaver Center Team Joseph Buxbaum Paige Siper Pilar Trelles Danielle Halpern Ting Wang Michelle Gorenstein Jennifer Foss-Feig Yitzchak Frank Reymundo Lozano Hala Harony-Nicolas Silvia De Rubeis Elodie Drapeau Michael Breen Sven Sandin PMS Consortium Latha Soorya Elizabeth Berry-Kravis Audrey Thurm Jon Bernstein Craig Powell Matt Mosconi Lauren Ethridge Neuropsych Group Deborah Pearson Thomas Frazier Catalina Betancur Boston Children s Team Mustafa Sahin April Levin Chuck Nelson

28 PSYCHOPATHOLOGICAL PHENOTYPE AND POSSIBLE TREATMENT STRATEGIES IN PATIENTS WITH PHELAN-McDERMID SYNDROME International European Conference on Phelan-McDermid Syndrome Madrid, September 2018 Prof. Dr. Willem M.A. Verhoeven 1. Former Head at the Centre of Excellence for Neuropsychiatry and Director Residency Training, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands 2. Emeritus Professor of Psychopharmacotherapy, Department of Psychiatry, Erasmus University Rotterdam, The Netherlands 3. Present function: consultant neuropsychiatrist for institutes for people with intellectual disabilities and psychiatric hospitals (diagnostic, pharmacological and genetic issues)

29 Main clinical characteristics of Phelan-McDermid syndrome - neonatal hypotonia - recurrent upper airway infections - absence of major dysmorphisms - developmental delay / highly variable intellectual disability - impaired to absent speech and expressive language - increased sensitivity to sensory stimuli - sleep disturbances - symptoms from the autism spectrum - decreased perspiration / high pain treshold - hypothyroidism / lymphoedema - epileptic manifestations - congenital cardiac and urogenital anomalies - structural cerebral abnormalities (e.g. cerebellar vermis hypoplasia) - regression (loss of acquired skills), permanently or for extended period and often triggered by seizures or infections - atypical bipolar disorder ± catatonic features

30 Overview of 24 adult patients with Phelan-McDermid syndrome (cumulative prospective study) Etiology de novo deletion: 18 patients (f=11; m=7); in two caused by unbalanced translocation and in two brothers by germline mosaicism in the mother [could not be proven] de novo mutation: 6 patients (f=4; m=2); in two sisters caused by mosaicism in the mother

31 Overview of the deletion size in 18 patients with Phelan-McDermid syndrome * *Figure composed by Dr. Nicole de Leeuw, Department of Human Genetics, Radboudumc, Nijmegen

32 Characteristics of 24 patients with Phelan-McDermid syndrome - 1 Age range: years (+ one 76-year-old female) Level of intellectual disability mild/moderate: n=5 moderate: n=5 moderate/severe: n=4 severe: n=6 profound: n=4 Language development limited reciprocal conversation: n=3 sentences or 2-3 word phrases: n=11 single or no functional words: n=10

33 Characteristics of 24 patients with Phelan-McDermid syndrome 2 Pre-existent behavioural concerns* Mood lability / depression n=19 Psychotic symptoms n=4 Catatonic symptoms n=5 ADHD-like symptoms n=16 OCD-like symptoms n=5 Regression n=4 *several patients with more than one behavioural concern

34 Characteristics of 24 patients with Phelan-McDermid syndrome - 3 -History of challenging behaviours: nearly all -Sleep disturbances: n=8 -Genuine epileptic seizures: n=2 -Secondary epileptic seizures: n=2 (meningeoma / malignant hypertension with ischaemic infarct in infancy) -Lymphoedema: n=3 -Hypothyriodism: n=1 -Congenital renal anomalies: n=2 -MRI brain adulthood (only in 12): cerebellar vermis hypoplasia and/or enlarged ventricles/cerebral atrophy: n=6; other 9 without abnormalities -Regression: n=4 (age start: ± 40 years; so far only in deletion patients)

35 Characteristics of 24 patients with Phelan-McDermid syndrome - 4 Previous psychiatric diagnoses* Autism spectrum disorder: n=19 Attention Deficit Hyperactivity Disorder: n=1 Depression: n=10 Psychosis: n=7 (with catatonic features: n=4) Bipolar disorder: n=3 *in some patients more than one psychiatric diagnosis Previous pharmacological treatment** Variety of antipsychotics and antidepressants or combination: nearly all Mood stabilizing agents: n=11 Psychostimulants: n=1 Clonidine: n=1 **duration of treatment mostly to short and dose adjustment not based on plasmaconcentration

36 Actual psychiatric diagnoses in 24 patients with Phelan-McDermid syndrome* Atypical bipolar disorder: n=17 (71%) Autism spectrum disorder: n=7 Schizoaffective disorder: n=1 Recurrent catatonic features: n=4 Obsessive compulsive disorder: n=1 No psychiatric diagnosis: n=2 P.M. In some patients more than one psychiatric diagnosis *Diagnoses actualized in interdisciplinary consultation meetings and, in the presence of the parents or primary caregivers, followed by treatment advices.

37 Treatment advice in 24 patients with Phelan-McDermid syndrome Mood stabilizing agents -Valproic acid: n=11 (600 up to 2100 mg daily; dose adjustment according to clinical response and/or plasma concentration) -Carbamazepine: n=1 (600 mg) -Lithium carbonate: n=6 ( mg daily; dose adjustment according to clinical response and/or plasma level) -ECT: none Antipsychotics Quetiapine: n=6 ( mg daily) Olanzapine: n=4 (2,5-15 mg daily) Contextual measures only n= 6 P.M. In almost all patients combination of psychotropics and contextual measures

38 Treatment effects in 24 patients with Phelan-McDermid syndrome In 60% of patients with a diagnosis of atypical bipolar disorder gradual stabilization of mood and behaviour after start of treatment with mood stabilizing agent (mostly valproic acid) in combination with atypical antipsychotic (10 patients). In case of comorbid catatonic features (n=5), remission in all patients either spontaneously or after treatment with lorazepam ± low dose olanzapine. Contextual measures (avoiding overestimation and excessive environmental stimuli) crucial in maintaining remission of psychiatric symptoms. Course of disease, treatment efficacy and general functioning interdisciplinary monitored (interval 3, 6 or 12 months) for a period varying from 1 to 5 years. In case of slowly progressive regression (n=4), no effect of psychopharmacological interventions. In those patients, adjusting contextual factors at the level of performance in terms of daily activities and cognitive functions.

39 Example of male patient aged 38 with regression (published as patient 2 in Neuropsychiatr Dis Treat 8: , 2012) Since about 3 years gradual decline of daily activities and cognitive as well as motor functioning despite adequate treatment with valproic acid and quetiapine together with adjustment of contextual parameters. At present, dementia-like syndrome and apathy symptoms (lack of motivation, interest and initative). Advise: discontinuation of all psychotropics and renewed referral to clinical geneticist (additional disorder?).

40 MRI brain of male patient aged 38 with progressive regression Development of generalized cerebral atrophy between 2011 en 2018 seen on T2* images

41 Conclusions about psychopathological phenotype and treatment approaches in 24 patients with genetically proven Phelan-McDermid syndrome -A 1. The psychopathological phenotype is characterized by atypical bipolar disorder. 2. Catatonic symptoms (n=5) resolve either spontaneously or after introduction of olanzapine ± temporarily lorazepam. 3. The preferred pharmacological treatment strategy comprises a mood stabilizing agent (valproic acid or, if possible, lithium carbonate), combined with an atypical antipsychotic (quetiapine or olanzapine).

42 Conclusions about psychopathological phenotype and treatment approaches in 24 patients with genetically proven Phelan-McDermid syndrome -B 4. In general, any psychopharmacological intervention should be accompanied by adaptation of contextual parameters. 5. Start psychotropics always slowly and in low dose, preferably after pharmacogenetic analysis (CYP2D6 and CYP2C19) and under regular control of plasma concentration and metabolic parameters. 6. The efficacy of treatment interventions of any kind should be monitored periodically in multidisciplinary consensus meetings.

43 Concluding Remarks 1. Phelan-McDermid syndrome may be underrecognized because of the absence of major dysmorphic features and unfamiliarity with genetic disorders in general psychiatric practice. 2. In case of normal array analysis, exome sequencing is warranted to detect SHANK3 mutation. 3. It can be expected that with regular use of exome sequencing a diagnosis of Phelan-McDermid syndrome will be established more frequently. 4. If technically possible, MRI brain scanning should always be performed and repeated in case of suspected regression.