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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.