SlideShare a Scribd company logo
1 of 35
Metyrosine in Adolescent
Psychosis Associated With
22q11.2 Deletion Syndrome
Carlo G. Carandang, MD, DABPN
Mood Disorders Group
IWK Health Centre
Disclosures
Research Support:
GlaxoSmithKline (USA)
Other Financial Disclosures:
None
Objectives
Learn clinical features of velocardiofacial
syndrome (VCFS)
Learn association of psychosis with VCFS
Learn genetic and biochemical abnormalities
leading to psychosis in VCFS
Discuss case report of metyrosine in psychosis
associated with VCFS
What can we learn from the association between
VCFS and schizophrenia to design candidate gene
studies for polygenic syndromes?
Case Report
Carandang C and Scholten M (in press,
2006). Metyrosine in Psychosis Associated
with 22q11.2 Deletion Syndrome: A Case
Report. Journal of Child and Adolescent
Psychopharmacology.
Velocardiofacial Syndrome
(VCFS)
First described by Robert Shprintzen in 1978
From Latin words
Velum = palate
Cardia = heart
Facies = face
Recent literature uses nomenclature denoting genetic
deletion: 22q11.2 Deletion Syndrome (22q11.2 DS)
VCFS also known as:
Shprintzen Syndrome, DiGeorge Syndrome, Craniofacial
Syndrome, or Conotruncal Anomaly Unusual Face Syndrome
Velocardiofacial Syndrome
(VCFS)
Not uncommon
Prevalence 1 in every 4,000 newborns
8% of all cleft palate patients
VCFS Is a Risk Factor for
Schizophrenia
Prevalence of schizophrenia among patients
with VCFS ranges from 10% to 30%
(Shprintzen et al. 1992, Pulver et al. 1994, Murphy et al. 1999)
Amongst those with schizophrenia,
prevalence of VCFS ranges from 1% to 2%
(Horowitz et al. 2005, Murphy 2002, Karayiorgou et al. 1995)
VCFS Clinical Features
Clinical Features
Cleft palate
Heart defects
Characteristic facies
Hypernasal speech
Learning disabilities
Velocardiofacial Syndrome
(VCFS)
Facial Findings:
• Elongated face
• Almond-shaped eyes
• Wide nose
• Small ears
Pictures From: Shprintzen RJ: Velocardiofacial Syndrome. Otolaryngol Clin North Am 33(6), 2000.
VCFS
Results from hemizygous deletion of the
long arm of chromosome 22, spanning 22
well-characterized genes, including COMT
gene
Only 10% of cases are inherited
For other 90%, cause of deletion unknown
Diagnosis confirmed by fluorescence in situ
hybridization (FISH)
TBX-1 (T-box transcription factor)
CRKL
UFD1L (Ubiquitination degradation)
HIRA(transcription factor)
Centromere
DGCR6
IDD/DGCR2
TSK/DGS-G
ES2/DGS1
GSCL (Goosecoid-like homeobox gene)
CTP (Citrate transporter) CLTCL
TMVCF
CDCrel-1
GP1b (Platelet glycoprotein)
T10
COMT (Catechol-O-methyltransferase)
ARVCF
LZTR-1 (Transcriptionfactor)
ZNF74
CDC45L
RANBP1
Human Ch22q11.2
Heparin cofactor
90% 8%
Psychosis and VCFS
Hypothesized that psychosis associated with
22q11.2 deletion syndrome may be associated
with excess catecholamines from a functional
deficiency of catechol-O-methyltransferase
(COMT)
Deficiency of COMT could result from either or
both:
Half-dose expression (only one copy of allele)
Presence of low-activity COMT variant on the non-
deleted allele
Metyrosine (Demser®)
A key step in the biosynthesis of dopamine
involves the conversion of tyrosine to
dihydroxyphenylalanine (DOPA)
This rate-limiting step is catalyzed by the
enzyme tyrosine hydroxylase
The catalytic conversion is blocked by the
competitive inhibitor, α-methyltyrosine
(metyrosine)
Metyrosine (Demser®)
Metyrosine competitively inhibits the enzyme
tyrosine hydroxylase
Inhibition of tyrosine hydroxylase leads to
decrease of dopamine levels and reduction of
psychotic symptoms
Psychosis associated VCFS are relatively
unresponsive to currently used antipsychotics
(Graf et al. 2001, Gothelf et al. 1999)
Intervention Studies of VCFS
Psychosis
Graf et al. 2001, case series, N=5
Metyrosine was effective in reducing
neuropsychiatric symptoms in 4 patients
Carandang and Scholten, 2006 (in press),
case report
Metyrosine effective in treating psychosis
resistant to antipsychotics
Case Report
15 year-old male presents for 1st
psych
hospitalization
Diagnosed VCFS in early childhood
RFA: Aggression towards mother
Multiple mood symptoms lasting months
Mood lability, tearfulness, hypersomnia, social
withdrawal, apathy, and declining school
performance
Case Report
While in NYC, ran away for 2 days on the
subway
After NYC trip, convinced he will be
miserable if he lives with his parents in the
countryside, and would be happy if he lived
in a big city
Threatened mother with knife, as she was a
barrier to his moving to the big city
Case Report
Early childhood: speech and motor delays
Age 4, problems with attention: a trial of
methylphenidate led to a negative reaction
Elementary school: problems processing
multi-step directions
Recent testing: verbal IQ 85, performance
IQ 83
Case Report
Premorbid functioning otherwise normal
average student, friendly and affectionate person
VCFS confirmed by FISH age 12
Hypernasal speech, typical facies, learning deficits
No other medical problems
2 paternal first cousins and a maternal aunt had
mood disorders
Case Report
Additional Symptoms:
Poor hygiene, poor eye contact, dysarthria,
non-spontaneous/telegraphic speech, affect
blunted, guarded, and exhibited significant
mood lability. Thought processes were
concrete. No loosening of associations were
noted. He perseverated on moving to the big
city
DDx: prodromal schizophrenia vs. mood
disorder
Case Report
Psychosis Clinic: Structured Interview for
Prodromal Syndromes (SIPS)
Scoring of the SIPS was in the psychotic range
with regards to the unusual thought content
While his belief about “moving to the big city to be
happy” was not the bizarre or typical beliefs associated
with psychosis, the patient held this belief with
unwavering conviction and had acted on this belief in
aggressive and risky ways.
His pervasive thoughts also affected his academic,
social, and family functioning.
Patient had minimal insight into the seriousness of his
dangerous behaviors.
Case Report
However, the clinicians and researchers in
the psychosis specialty clinic had difficulty
giving a diagnosis of psychosis (despite the
scoring on the SIPS), as this was an atypical
presentation for psychosis. Nonetheless,
the working diagnosis was Psychotic
Disorder NOS, with the differential
including prodromal psychosis and
Delusional Disorder.
Case Report
In the ensuing months, patient endured
multiple psychiatric hospitalizations
2nd
psych hosp was for suicide attempts
Aripiprazole (Abilify®) was started and
titrated to 10mg daily. The patient initially
responded, as he was less labile, less
withdrawn, and more animated.
Discharged on aripiprazole
Case Report
Readmitted the next month for his third
hospitalization for self-harm behaviors, and
eventually discharged.
1 month later, behaviors again worsened. He had
been making excessive attempts to communicate
with his friend, which prompted a call from the
friend’s parents to the patient’s parents.
Precipitated a rapid decompensation, where the
patient barricaded himself in his room and cut
both his forearms.
Case Report
Police were summoned to escort the patient to the
hospital (4th hospitalization)
When police arrived, the patient attempted to stab
the officer with a knife, who blocked the attempt
and disarmed the patient.
Parents had never seen this level of aggression
with their son, and opined that the treatment with
aripiprazole worsened his symptoms.
Case Report
Inpatient attending consulted with an expert on
VCFS. The expert recommended a trial of
metyrosine (Demser®), as many patients with
VCFS have a COMT deficiency.
Aripiprazole was discontinued and metyrosine
was titrated to 1750mg daily. The patient had
significant response to metyrosine, as he exhibited
less mood lability and was less perseverative on
his belief of moving to the big city to be happy.
He was discharged on a maintenance dose of
metyrosine 1000mg daily, and exhibited
significant functional improvement.
Case Report
While on metyrosine, the patient was able to avoid
hospitalization, attend school, and engage in
relationships with family and friends.
Patient reported improved moods, less irritability,
and denied fixed ideations. In addition, he no
longer believed that it was absolutely necessary
for him to live in the big city to be happy.
Continued to function on metyrosine for over 1
year, at which time he was transferred to another
psychiatrist.
(Carandang and Scholten, in press, 2006)
Innovative
“The treatment of metyrosine for VCFS psychosis
represents a first in psychiatry, where a known
biochemical abnormality in a psychiatric disorder
was corrected by a treatment that targets the
biochemical pathway, leading to reduction of
psychiatric symptoms.”
“Treatment of a specific biochemical consequence
of a genetic variation is important not only for the
treatment of a specific group of patients, but as a
model for elucidating the genetic correlates of
psychiatric disorders.”
Oligogenic Disorders and
Polygenic Syndromes
• Oligogenic diseases (scientifically interesting but not major public
health problems)
• Williams syndrome
• Fragile X
• Tuberous sclerosis
• Velo-cardio-facial syndrome
• Polygenic syndromes (important CNS disorders with more
variable genetic causes and brain/behavioural phenotypes)
• Schizophrenia
• Bipolar Affective Disorder
• Stroke
How Can We Design Candidate Gene
Studies for Polygenic Syndromes?
Study an oligogenic disorder which mimics
the polygenic syndrome
VCFS with psychosis mimics schizophrenia
Study known polymorphisms leading to
biochemical deficits associated with the
oligogenic disorder
COMT gene
Summary
Rule-out VCFS in psychosis evaluations,
especially if the patient has two or more
features of the syndrome and does not
respond to antipsychotic medication.
Definitive diagnosis obtained with FISH.
Consider Metyrosine for VCFS psychosis
not responsive to antipsychotics.
IWK Mood Disorders Group:
Collaborators
Suzanne Zinck, MD
Darcy Santor, PhD
Mark Samuels, PhD (Maritime Medical
Genetics)

More Related Content

What's hot

Schizophrenia Past, Present and Future
Schizophrenia Past, Present and FutureSchizophrenia Past, Present and Future
Schizophrenia Past, Present and Future
Adonis Sfera, MD
 
Ahuja gr young onset dementia
Ahuja gr young onset dementiaAhuja gr young onset dementia
Ahuja gr young onset dementia
applebyb
 
Obsessive compulsive spectrum disoder
Obsessive compulsive spectrum disoderObsessive compulsive spectrum disoder
Obsessive compulsive spectrum disoder
Santanu Ghosh
 
Neuropsychiatric manifestations in neurological disorders
Neuropsychiatric manifestations in neurological disordersNeuropsychiatric manifestations in neurological disorders
Neuropsychiatric manifestations in neurological disorders
webzforu
 

What's hot (20)

Robbins Alzheimers Dementia Toma 2006
Robbins Alzheimers Dementia Toma 2006Robbins Alzheimers Dementia Toma 2006
Robbins Alzheimers Dementia Toma 2006
 
FRONTO TEMPORAL DEMENTIA
FRONTO TEMPORAL DEMENTIAFRONTO TEMPORAL DEMENTIA
FRONTO TEMPORAL DEMENTIA
 
Schizophrenia Past, Present and Future
Schizophrenia Past, Present and FutureSchizophrenia Past, Present and Future
Schizophrenia Past, Present and Future
 
Genetic disease in neurology
Genetic disease in neurologyGenetic disease in neurology
Genetic disease in neurology
 
Delirium in Palliative Care & Hospice
Delirium in Palliative Care & HospiceDelirium in Palliative Care & Hospice
Delirium in Palliative Care & Hospice
 
Ahuja gr young onset dementia
Ahuja gr young onset dementiaAhuja gr young onset dementia
Ahuja gr young onset dementia
 
Dementia overview
Dementia overviewDementia overview
Dementia overview
 
Autoimmune epilepsy
Autoimmune epilepsy Autoimmune epilepsy
Autoimmune epilepsy
 
Geriatric Population. The 3 D’s Geriatric Dementia, Delirium & Depression
Geriatric Population. The 3 D’s Geriatric Dementia, Delirium & DepressionGeriatric Population. The 3 D’s Geriatric Dementia, Delirium & Depression
Geriatric Population. The 3 D’s Geriatric Dementia, Delirium & Depression
 
Genetics in dementia
Genetics in dementiaGenetics in dementia
Genetics in dementia
 
Depression feb2012
Depression feb2012Depression feb2012
Depression feb2012
 
Case presentation
Case presentationCase presentation
Case presentation
 
Genetics of dementia 2017
Genetics of dementia 2017Genetics of dementia 2017
Genetics of dementia 2017
 
Multiple sclerosis
Multiple sclerosisMultiple sclerosis
Multiple sclerosis
 
Obsessive compulsive spectrum disoder
Obsessive compulsive spectrum disoderObsessive compulsive spectrum disoder
Obsessive compulsive spectrum disoder
 
Pathophysiology: Introduction to Neuropsychiatry
Pathophysiology: Introduction to Neuropsychiatry Pathophysiology: Introduction to Neuropsychiatry
Pathophysiology: Introduction to Neuropsychiatry
 
Neuropsychiatric manifestations in neurological disorders
Neuropsychiatric manifestations in neurological disordersNeuropsychiatric manifestations in neurological disorders
Neuropsychiatric manifestations in neurological disorders
 
Clozaril
ClozarilClozaril
Clozaril
 
Delusional Parasitosis
Delusional ParasitosisDelusional Parasitosis
Delusional Parasitosis
 
Research on Young-Onset Dementia and Its Implications for Criminal and Civil ...
Research on Young-Onset Dementia and Its Implications for Criminal and Civil ...Research on Young-Onset Dementia and Its Implications for Criminal and Civil ...
Research on Young-Onset Dementia and Its Implications for Criminal and Civil ...
 

Similar to Metyrosine in Adolescent Psychosis Associated with 22q11.2 Deletion Syndrome

456585540-schizophrenia-clinical-case-study.docx
456585540-schizophrenia-clinical-case-study.docx456585540-schizophrenia-clinical-case-study.docx
456585540-schizophrenia-clinical-case-study.docx
RanushaAnusha2
 
Bipolar disorder mrc psych
Bipolar disorder mrc psychBipolar disorder mrc psych
Bipolar disorder mrc psych
Walk KD
 
Schizophreniaveuegwuwvwvwhwbwhwvwvw .pdf
Schizophreniaveuegwuwvwvwhwbwhwvwvw .pdfSchizophreniaveuegwuwvwvwhwbwhwvwvw .pdf
Schizophreniaveuegwuwvwvwhwbwhwvwvw .pdf
nxrg25985g
 
Schizophrenia - Psychiatry Case Presentation
Schizophrenia - Psychiatry Case PresentationSchizophrenia - Psychiatry Case Presentation
Schizophrenia - Psychiatry Case Presentation
candicelainereyes
 
Discussion 1 Segura Herrera, Rafael EYesterdaySep 2
Discussion 1              Segura Herrera, Rafael EYesterdaySep 2Discussion 1              Segura Herrera, Rafael EYesterdaySep 2
Discussion 1 Segura Herrera, Rafael EYesterdaySep 2
MerrileeDelvalle969
 

Similar to Metyrosine in Adolescent Psychosis Associated with 22q11.2 Deletion Syndrome (20)

psychosis 8.ppt
psychosis   8.pptpsychosis   8.ppt
psychosis 8.ppt
 
Psychiatry 5th year, 2nd & 3rd lectures (Dr. Nazar M. Mohammad Amin)
Psychiatry 5th year, 2nd & 3rd lectures (Dr. Nazar M. Mohammad Amin)Psychiatry 5th year, 2nd & 3rd lectures (Dr. Nazar M. Mohammad Amin)
Psychiatry 5th year, 2nd & 3rd lectures (Dr. Nazar M. Mohammad Amin)
 
Schizophrenia
SchizophreniaSchizophrenia
Schizophrenia
 
456585540-schizophrenia-clinical-case-study.docx
456585540-schizophrenia-clinical-case-study.docx456585540-schizophrenia-clinical-case-study.docx
456585540-schizophrenia-clinical-case-study.docx
 
The recognition of bipolar disorder in primary care
The recognition of bipolar disorder in primary careThe recognition of bipolar disorder in primary care
The recognition of bipolar disorder in primary care
 
Management of schizophrenia [autosaved]
Management of schizophrenia [autosaved]Management of schizophrenia [autosaved]
Management of schizophrenia [autosaved]
 
Bipolar dis copy
Bipolar  dis   copyBipolar  dis   copy
Bipolar dis copy
 
A Clinical Case Report Schizophrenia
A Clinical Case Report  SchizophreniaA Clinical Case Report  Schizophrenia
A Clinical Case Report Schizophrenia
 
Advances in schizophrenia
Advances in schizophreniaAdvances in schizophrenia
Advances in schizophrenia
 
Bipolar disorder mrc psych
Bipolar disorder mrc psychBipolar disorder mrc psych
Bipolar disorder mrc psych
 
Psychiatric comorbidity in child onset lupus
Psychiatric comorbidity in child onset lupus Psychiatric comorbidity in child onset lupus
Psychiatric comorbidity in child onset lupus
 
Case presentation
Case presentationCase presentation
Case presentation
 
Intractable psychosis: a case presentaion
Intractable psychosis: a case presentaion Intractable psychosis: a case presentaion
Intractable psychosis: a case presentaion
 
Schizophreniaveuegwuwvwvwhwbwhwvwvw .pdf
Schizophreniaveuegwuwvwvwhwbwhwvwvw .pdfSchizophreniaveuegwuwvwvwhwbwhwvwvw .pdf
Schizophreniaveuegwuwvwvwhwbwhwvwvw .pdf
 
SCHIZOPHRENIA Epidemiology and Genetics.pptx
SCHIZOPHRENIA Epidemiology and Genetics.pptxSCHIZOPHRENIA Epidemiology and Genetics.pptx
SCHIZOPHRENIA Epidemiology and Genetics.pptx
 
Talking psychiatry...Rett syndrome
Talking psychiatry...Rett syndromeTalking psychiatry...Rett syndrome
Talking psychiatry...Rett syndrome
 
Schizophrenia - Psychiatry Case Presentation
Schizophrenia - Psychiatry Case PresentationSchizophrenia - Psychiatry Case Presentation
Schizophrenia - Psychiatry Case Presentation
 
Personality disorder epidemiology & etiology
Personality disorder  epidemiology & etiologyPersonality disorder  epidemiology & etiology
Personality disorder epidemiology & etiology
 
Schizophrenia
SchizophreniaSchizophrenia
Schizophrenia
 
Discussion 1 Segura Herrera, Rafael EYesterdaySep 2
Discussion 1              Segura Herrera, Rafael EYesterdaySep 2Discussion 1              Segura Herrera, Rafael EYesterdaySep 2
Discussion 1 Segura Herrera, Rafael EYesterdaySep 2
 

More from Carlo Carandang

More from Carlo Carandang (20)

Psychosis in Youth
Psychosis in YouthPsychosis in Youth
Psychosis in Youth
 
Metyrosine and Psychosis
Metyrosine and PsychosisMetyrosine and Psychosis
Metyrosine and Psychosis
 
Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Se...
Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Se...Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Se...
Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Se...
 
Anxiety Disorders
Anxiety DisordersAnxiety Disorders
Anxiety Disorders
 
Clinical Assessment of Children and Adolescents with Depression
Clinical Assessment of Children and Adolescents with DepressionClinical Assessment of Children and Adolescents with Depression
Clinical Assessment of Children and Adolescents with Depression
 
Data Safety Monitoring Boards in Pediatric Clinical Trials
Data Safety Monitoring Boards in Pediatric Clinical TrialsData Safety Monitoring Boards in Pediatric Clinical Trials
Data Safety Monitoring Boards in Pediatric Clinical Trials
 
Teen Depression and Suicide
Teen Depression and SuicideTeen Depression and Suicide
Teen Depression and Suicide
 
Pediatric Bipolar Disorder
Pediatric Bipolar DisorderPediatric Bipolar Disorder
Pediatric Bipolar Disorder
 
SSRIs and Suicidality in Youth
SSRIs and Suicidality in YouthSSRIs and Suicidality in Youth
SSRIs and Suicidality in Youth
 
The Neurobiology of Adolescent Development
The Neurobiology of Adolescent DevelopmentThe Neurobiology of Adolescent Development
The Neurobiology of Adolescent Development
 
Canadian Psychiatry: The Case for Universal Health Care and How Psychiatry Be...
Canadian Psychiatry: The Case for Universal Health Care and How Psychiatry Be...Canadian Psychiatry: The Case for Universal Health Care and How Psychiatry Be...
Canadian Psychiatry: The Case for Universal Health Care and How Psychiatry Be...
 
Clinical assessment of child and adolescent psychiatric emergencies
Clinical assessment of child and adolescent psychiatric emergenciesClinical assessment of child and adolescent psychiatric emergencies
Clinical assessment of child and adolescent psychiatric emergencies
 
Computer Anxiety
Computer AnxietyComputer Anxiety
Computer Anxiety
 
Support Vector Machines- SVM
Support Vector Machines- SVMSupport Vector Machines- SVM
Support Vector Machines- SVM
 
AI and Big Data in Psychiatry: An Introduction and Overview
AI and Big Data in Psychiatry: An Introduction and OverviewAI and Big Data in Psychiatry: An Introduction and Overview
AI and Big Data in Psychiatry: An Introduction and Overview
 
Air Pollution in Nova Scotia: Analysis and Predictions
Air Pollution in Nova Scotia: Analysis and PredictionsAir Pollution in Nova Scotia: Analysis and Predictions
Air Pollution in Nova Scotia: Analysis and Predictions
 
Workplace Disability from Stress, Anxiety, and Depression: Solutions and Prev...
Workplace Disability from Stress, Anxiety, and Depression: Solutions and Prev...Workplace Disability from Stress, Anxiety, and Depression: Solutions and Prev...
Workplace Disability from Stress, Anxiety, and Depression: Solutions and Prev...
 
Analysis of Air Pollution in Nova Scotia Presentation
Analysis of Air Pollution in Nova Scotia PresentationAnalysis of Air Pollution in Nova Scotia Presentation
Analysis of Air Pollution in Nova Scotia Presentation
 
Paxil Study 329 Retracted: A Critical Statistical Analysis
Paxil Study 329 Retracted: A Critical Statistical AnalysisPaxil Study 329 Retracted: A Critical Statistical Analysis
Paxil Study 329 Retracted: A Critical Statistical Analysis
 
How The Neurotransmitter GABA Works For Anxiety
How The Neurotransmitter GABA Works For AnxietyHow The Neurotransmitter GABA Works For Anxiety
How The Neurotransmitter GABA Works For Anxiety
 

Recently uploaded

Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Abortion pills in Kuwait Cytotec pills in Kuwait
 
Sonia Journal club presentation (2).pptx
Sonia Journal club presentation (2).pptxSonia Journal club presentation (2).pptx
Sonia Journal club presentation (2).pptx
palsonia139
 
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose AcademicsHistology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
MedicoseAcademics
 
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose AcademicsConnective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
MedicoseAcademics
 
VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...
VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...
VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...
JRRolfNeuqelet
 

Recently uploaded (20)

Gait deviations in Transtibial prosthesis users
Gait deviations in Transtibial prosthesis usersGait deviations in Transtibial prosthesis users
Gait deviations in Transtibial prosthesis users
 
Quality control tests of suppository ...
Quality control tests  of suppository ...Quality control tests  of suppository ...
Quality control tests of suppository ...
 
ESC HF 2024 Spotlights Day-2.pptx heart failure
ESC HF 2024 Spotlights Day-2.pptx heart failureESC HF 2024 Spotlights Day-2.pptx heart failure
ESC HF 2024 Spotlights Day-2.pptx heart failure
 
Video capsule endoscopy (VCE ) in children
Video capsule endoscopy (VCE ) in childrenVideo capsule endoscopy (VCE ) in children
Video capsule endoscopy (VCE ) in children
 
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
Best medicine 100% Effective&Safe Mifepristion ௵+918133066128௹Abortion pills ...
 
ROSE CASE SPINAL SBRT BY DR KANHU CHARAN PATRO
ROSE  CASE SPINAL SBRT BY DR KANHU CHARAN PATROROSE  CASE SPINAL SBRT BY DR KANHU CHARAN PATRO
ROSE CASE SPINAL SBRT BY DR KANHU CHARAN PATRO
 
Sonia Journal club presentation (2).pptx
Sonia Journal club presentation (2).pptxSonia Journal club presentation (2).pptx
Sonia Journal club presentation (2).pptx
 
How to buy 5cladba precursor raw 5cl-adb-a raw material
How to buy 5cladba precursor raw 5cl-adb-a raw materialHow to buy 5cladba precursor raw 5cl-adb-a raw material
How to buy 5cladba precursor raw 5cl-adb-a raw material
 
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose AcademicsHistology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
 
Sell 5cladba adbb JWH-018 5FADB in stock
Sell 5cladba adbb JWH-018 5FADB in stockSell 5cladba adbb JWH-018 5FADB in stock
Sell 5cladba adbb JWH-018 5FADB in stock
 
Mgr university bsc nursing adult health previous question paper with answers
Mgr university  bsc nursing adult health previous question paper with answersMgr university  bsc nursing adult health previous question paper with answers
Mgr university bsc nursing adult health previous question paper with answers
 
Post-Cycle Therapy (PCT) in bodybuilding docx.pdf
Post-Cycle Therapy (PCT) in bodybuilding  docx.pdfPost-Cycle Therapy (PCT) in bodybuilding  docx.pdf
Post-Cycle Therapy (PCT) in bodybuilding docx.pdf
 
Gallbladder Double-Diverticular: A Case Report المرارة مزدوجة التج: تقرير حالة
Gallbladder Double-Diverticular: A Case Report  المرارة مزدوجة التج: تقرير حالةGallbladder Double-Diverticular: A Case Report  المرارة مزدوجة التج: تقرير حالة
Gallbladder Double-Diverticular: A Case Report المرارة مزدوجة التج: تقرير حالة
 
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose AcademicsConnective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
 
VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...
VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...
VIII.1 Nursing Interventions to Promote Healthy Psychological responses, SELF...
 
Overview on the Automatic pill identifier
Overview on the Automatic pill identifierOverview on the Automatic pill identifier
Overview on the Automatic pill identifier
 
Get the best psychology treatment in Indore at Gokuldas Hospital
Get the best psychology treatment in Indore at Gokuldas HospitalGet the best psychology treatment in Indore at Gokuldas Hospital
Get the best psychology treatment in Indore at Gokuldas Hospital
 
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptxThe Orbit & its contents by Dr. Rabia I. Gandapore.pptx
The Orbit & its contents by Dr. Rabia I. Gandapore.pptx
 
Bangalore whatsapp Number Just VIP Brookefield 100% Genuine at your Door Step
Bangalore whatsapp Number Just VIP Brookefield 100% Genuine at your Door StepBangalore whatsapp Number Just VIP Brookefield 100% Genuine at your Door Step
Bangalore whatsapp Number Just VIP Brookefield 100% Genuine at your Door Step
 
Unveiling Alcohol Withdrawal Syndrome: exploring it's hidden depths
Unveiling Alcohol Withdrawal Syndrome: exploring it's hidden depthsUnveiling Alcohol Withdrawal Syndrome: exploring it's hidden depths
Unveiling Alcohol Withdrawal Syndrome: exploring it's hidden depths
 

Metyrosine in Adolescent Psychosis Associated with 22q11.2 Deletion Syndrome

  • 1. Metyrosine in Adolescent Psychosis Associated With 22q11.2 Deletion Syndrome Carlo G. Carandang, MD, DABPN Mood Disorders Group IWK Health Centre
  • 3. Objectives Learn clinical features of velocardiofacial syndrome (VCFS) Learn association of psychosis with VCFS Learn genetic and biochemical abnormalities leading to psychosis in VCFS Discuss case report of metyrosine in psychosis associated with VCFS What can we learn from the association between VCFS and schizophrenia to design candidate gene studies for polygenic syndromes?
  • 4. Case Report Carandang C and Scholten M (in press, 2006). Metyrosine in Psychosis Associated with 22q11.2 Deletion Syndrome: A Case Report. Journal of Child and Adolescent Psychopharmacology.
  • 5. Velocardiofacial Syndrome (VCFS) First described by Robert Shprintzen in 1978 From Latin words Velum = palate Cardia = heart Facies = face Recent literature uses nomenclature denoting genetic deletion: 22q11.2 Deletion Syndrome (22q11.2 DS) VCFS also known as: Shprintzen Syndrome, DiGeorge Syndrome, Craniofacial Syndrome, or Conotruncal Anomaly Unusual Face Syndrome
  • 6. Velocardiofacial Syndrome (VCFS) Not uncommon Prevalence 1 in every 4,000 newborns 8% of all cleft palate patients
  • 7. VCFS Is a Risk Factor for Schizophrenia Prevalence of schizophrenia among patients with VCFS ranges from 10% to 30% (Shprintzen et al. 1992, Pulver et al. 1994, Murphy et al. 1999) Amongst those with schizophrenia, prevalence of VCFS ranges from 1% to 2% (Horowitz et al. 2005, Murphy 2002, Karayiorgou et al. 1995)
  • 8. VCFS Clinical Features Clinical Features Cleft palate Heart defects Characteristic facies Hypernasal speech Learning disabilities
  • 9. Velocardiofacial Syndrome (VCFS) Facial Findings: • Elongated face • Almond-shaped eyes • Wide nose • Small ears Pictures From: Shprintzen RJ: Velocardiofacial Syndrome. Otolaryngol Clin North Am 33(6), 2000.
  • 10.
  • 11. VCFS Results from hemizygous deletion of the long arm of chromosome 22, spanning 22 well-characterized genes, including COMT gene Only 10% of cases are inherited For other 90%, cause of deletion unknown Diagnosis confirmed by fluorescence in situ hybridization (FISH)
  • 12.
  • 13. TBX-1 (T-box transcription factor) CRKL UFD1L (Ubiquitination degradation) HIRA(transcription factor) Centromere DGCR6 IDD/DGCR2 TSK/DGS-G ES2/DGS1 GSCL (Goosecoid-like homeobox gene) CTP (Citrate transporter) CLTCL TMVCF CDCrel-1 GP1b (Platelet glycoprotein) T10 COMT (Catechol-O-methyltransferase) ARVCF LZTR-1 (Transcriptionfactor) ZNF74 CDC45L RANBP1 Human Ch22q11.2 Heparin cofactor 90% 8%
  • 14. Psychosis and VCFS Hypothesized that psychosis associated with 22q11.2 deletion syndrome may be associated with excess catecholamines from a functional deficiency of catechol-O-methyltransferase (COMT) Deficiency of COMT could result from either or both: Half-dose expression (only one copy of allele) Presence of low-activity COMT variant on the non- deleted allele
  • 15. Metyrosine (Demser®) A key step in the biosynthesis of dopamine involves the conversion of tyrosine to dihydroxyphenylalanine (DOPA) This rate-limiting step is catalyzed by the enzyme tyrosine hydroxylase The catalytic conversion is blocked by the competitive inhibitor, α-methyltyrosine (metyrosine)
  • 16. Metyrosine (Demser®) Metyrosine competitively inhibits the enzyme tyrosine hydroxylase Inhibition of tyrosine hydroxylase leads to decrease of dopamine levels and reduction of psychotic symptoms Psychosis associated VCFS are relatively unresponsive to currently used antipsychotics (Graf et al. 2001, Gothelf et al. 1999)
  • 17.
  • 18. Intervention Studies of VCFS Psychosis Graf et al. 2001, case series, N=5 Metyrosine was effective in reducing neuropsychiatric symptoms in 4 patients Carandang and Scholten, 2006 (in press), case report Metyrosine effective in treating psychosis resistant to antipsychotics
  • 19. Case Report 15 year-old male presents for 1st psych hospitalization Diagnosed VCFS in early childhood RFA: Aggression towards mother Multiple mood symptoms lasting months Mood lability, tearfulness, hypersomnia, social withdrawal, apathy, and declining school performance
  • 20. Case Report While in NYC, ran away for 2 days on the subway After NYC trip, convinced he will be miserable if he lives with his parents in the countryside, and would be happy if he lived in a big city Threatened mother with knife, as she was a barrier to his moving to the big city
  • 21. Case Report Early childhood: speech and motor delays Age 4, problems with attention: a trial of methylphenidate led to a negative reaction Elementary school: problems processing multi-step directions Recent testing: verbal IQ 85, performance IQ 83
  • 22. Case Report Premorbid functioning otherwise normal average student, friendly and affectionate person VCFS confirmed by FISH age 12 Hypernasal speech, typical facies, learning deficits No other medical problems 2 paternal first cousins and a maternal aunt had mood disorders
  • 23. Case Report Additional Symptoms: Poor hygiene, poor eye contact, dysarthria, non-spontaneous/telegraphic speech, affect blunted, guarded, and exhibited significant mood lability. Thought processes were concrete. No loosening of associations were noted. He perseverated on moving to the big city DDx: prodromal schizophrenia vs. mood disorder
  • 24. Case Report Psychosis Clinic: Structured Interview for Prodromal Syndromes (SIPS) Scoring of the SIPS was in the psychotic range with regards to the unusual thought content While his belief about “moving to the big city to be happy” was not the bizarre or typical beliefs associated with psychosis, the patient held this belief with unwavering conviction and had acted on this belief in aggressive and risky ways. His pervasive thoughts also affected his academic, social, and family functioning. Patient had minimal insight into the seriousness of his dangerous behaviors.
  • 25. Case Report However, the clinicians and researchers in the psychosis specialty clinic had difficulty giving a diagnosis of psychosis (despite the scoring on the SIPS), as this was an atypical presentation for psychosis. Nonetheless, the working diagnosis was Psychotic Disorder NOS, with the differential including prodromal psychosis and Delusional Disorder.
  • 26. Case Report In the ensuing months, patient endured multiple psychiatric hospitalizations 2nd psych hosp was for suicide attempts Aripiprazole (Abilify®) was started and titrated to 10mg daily. The patient initially responded, as he was less labile, less withdrawn, and more animated. Discharged on aripiprazole
  • 27. Case Report Readmitted the next month for his third hospitalization for self-harm behaviors, and eventually discharged. 1 month later, behaviors again worsened. He had been making excessive attempts to communicate with his friend, which prompted a call from the friend’s parents to the patient’s parents. Precipitated a rapid decompensation, where the patient barricaded himself in his room and cut both his forearms.
  • 28. Case Report Police were summoned to escort the patient to the hospital (4th hospitalization) When police arrived, the patient attempted to stab the officer with a knife, who blocked the attempt and disarmed the patient. Parents had never seen this level of aggression with their son, and opined that the treatment with aripiprazole worsened his symptoms.
  • 29. Case Report Inpatient attending consulted with an expert on VCFS. The expert recommended a trial of metyrosine (Demser®), as many patients with VCFS have a COMT deficiency. Aripiprazole was discontinued and metyrosine was titrated to 1750mg daily. The patient had significant response to metyrosine, as he exhibited less mood lability and was less perseverative on his belief of moving to the big city to be happy. He was discharged on a maintenance dose of metyrosine 1000mg daily, and exhibited significant functional improvement.
  • 30. Case Report While on metyrosine, the patient was able to avoid hospitalization, attend school, and engage in relationships with family and friends. Patient reported improved moods, less irritability, and denied fixed ideations. In addition, he no longer believed that it was absolutely necessary for him to live in the big city to be happy. Continued to function on metyrosine for over 1 year, at which time he was transferred to another psychiatrist.
  • 31. (Carandang and Scholten, in press, 2006) Innovative “The treatment of metyrosine for VCFS psychosis represents a first in psychiatry, where a known biochemical abnormality in a psychiatric disorder was corrected by a treatment that targets the biochemical pathway, leading to reduction of psychiatric symptoms.” “Treatment of a specific biochemical consequence of a genetic variation is important not only for the treatment of a specific group of patients, but as a model for elucidating the genetic correlates of psychiatric disorders.”
  • 32. Oligogenic Disorders and Polygenic Syndromes • Oligogenic diseases (scientifically interesting but not major public health problems) • Williams syndrome • Fragile X • Tuberous sclerosis • Velo-cardio-facial syndrome • Polygenic syndromes (important CNS disorders with more variable genetic causes and brain/behavioural phenotypes) • Schizophrenia • Bipolar Affective Disorder • Stroke
  • 33. How Can We Design Candidate Gene Studies for Polygenic Syndromes? Study an oligogenic disorder which mimics the polygenic syndrome VCFS with psychosis mimics schizophrenia Study known polymorphisms leading to biochemical deficits associated with the oligogenic disorder COMT gene
  • 34. Summary Rule-out VCFS in psychosis evaluations, especially if the patient has two or more features of the syndrome and does not respond to antipsychotic medication. Definitive diagnosis obtained with FISH. Consider Metyrosine for VCFS psychosis not responsive to antipsychotics.
  • 35. IWK Mood Disorders Group: Collaborators Suzanne Zinck, MD Darcy Santor, PhD Mark Samuels, PhD (Maritime Medical Genetics)