Master Slide

PMS Across the Lifetime

Alexander Kolevzon, MD

Seaver Autism Center for Research and Treatment

Icahn School of Medicine at Mount Sinai

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

*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

sema4 X

Labcorp X

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.

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

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.

Natural History

Natural History

Mount Sinai, Rush, NIH, Boston

Timelines

Baseline

1-Year

follow-up

2-Year

follow-up

Year 1 36

Year 2 54 36

Year 3 54 36

Year 4 54

Developmental

Synaptopathies

Associated with TSC,

PTEN and SHANK3

Mutations

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 1 30 25

Year 2 30 30 25 25

Year 3 30 30 30 25 25

Year 4 30 30 25 25

Year 5 30 25

Physical and neurological exam Renal ultrasound

Clinical Genetics Evaluation Electroencephalography

Medical and Psychiatric History Laboratory bloodwork

Echocardiography Height and weight measurement

Electrocardiography Head circumference

Phenotyping

Phenotyping Domain Measure

Global Cognitive Ability Mullen Scales for Early Learning or

Stanford Binet-5

Psychoeducational Profile-III

Adaptive Behavior Vineland Adaptive Behavior Scales II

Language Mullen and Vineland Subscales

Macarthur Bates Communication Developmental Inventory

Peabody Picture Vocabulary Test-4

Expressive Vocabulary Test-2

Communication Complexity Scale

Motor Functioning Mullen and Vineland Subscales

Developmental Coordination Disorder Questionnaire

Autism Symptoms 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

Other Symptoms Aberrant Behavior Checklist

Sleep Questionnaire

Regression Interview

San Martin Quality of Life

Early Detection Screen for Dementia

Wisconsin Activities of Daily Living Form

N %

Nonverbal IQ classification (n=30)

Average (IQ 100-110) 1 3.3

Mild intellectual disability (IQ 50-55 to 70) 3 10

Moderate intellectual disability (IQ 35-40 to 50-55) 3 10

Severe intellectual disability (IQ 20-25 to 35-40) 7 23.3

Profound intellectual disability (IQ < 20-25 16 53.3

75%

9.40%

15.60%

Autism

ASD

non-ASD

Autism Spectrum Disorder (ASD)

and IQ diagnostic classifications

Soorya et al., 2013

*Phelan & McDermid, 2012

*

Jimmy Holder, MD

Developmental Trajectories

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

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

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

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

Developmental Trajectories

Serret, BMC Psychiatry (2015)

• 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.

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.

Challenges

• Measures

• Design (ages; cross-sectional; prospective)

• Time points

• Feasibility (costs; 5-year grant cycles)

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?

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

PSYCHOPATHOLOGICAL PHENOTYPE AND

POSSIBLE TREATMENT STRATEGIES IN PATIENTS

WITH PHELAN-McDERMID SYNDROME

International European Conference on Phelan-McDermid Syndrome

Madrid, 21-23 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)

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

•

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

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

Characteristics of 24 patients with Phelan-McDermid syndrome - 1

Age range: 16-52 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

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

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)

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

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.

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 (500-1200 mg daily; dose adjustment according to

clinical response and/or plasma level)

-ECT: none

Antipsychotics

Quetiapine: n=6 (500-1200 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

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.

Example of male patient aged 38 with regression (published as patient 2 in Neuropsychiatr Dis Treat 8: 175-179, 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?).

Development of generalized cerebral atrophy

between 2011 en 2018 seen on T2* images

MRI brain of male patient aged 38 with progressive regression

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).

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.

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.