"Metyrosine in Adolescent Psychosis Associated with 22q11.2 Deletion Syndrome," Halifax, Nova Scotia, Canada; June 7, 2006 Dalhousie University, Department of Psychiatry, Clinical Conference *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?

1. Metyrosine in Adolescent
Psychosis Associated With
22q11.2 Deletion Syndrome
Carlo G. Carandang, MD, DABPN
Mood Disorders Group
IWK Health Centre

2. Disclosures
Research Support:
GlaxoSmithKline (USA)
Other Financial Disclosures:
None

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.

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)

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)

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)