pku neuro psych webinar

1

Understanding and Managing the Neurocognitive and Psychiatric

Issues Associated with PKU

2

Key Points

• Awareness– Even patients following dietary restrictions can experience

PKU-related neurocognitive and psychiatric issues

• Assessment– Patient assessment is the first step in the management

process

• Treatment– Strategies for improving patient functioning exist – Control blood phe levels– Address comorbid conditions

3

Learning Objectives

• Understand the susceptibility of patients with PKU to neurocognitive and psychiatric complications.

• Be aware of the neurocognitive testing used to gauge neurocognitive function in patients with PKU.

• Recognize patients with neurocognitive impairment and participate in referral to a psychologist.

• Determine if a patient’s history or clinical presentation is consistent with a comorbid psychiatric condition.

• Recognize patients with psychiatric comorbidity and participate in referral to a psychologist or psychiatrist.

4

Lecture Overview

• Review of PKU

• Neurocognitive complications

• Psychiatric issues

• Management of neurocognitive and psychiatric issues

5

Review of PKU• Rare, chronic, metabolic disorder• Approximately 1 of every 15,000 infants in US is born

with PKU• Deficiency of liver enzyme phenylalanine hydroxylase

(PAH); therefore, phenylalanine (phe) accumulates in blood and body tissues

• Autosomal recessive disease caused by mutations in the PAH gene

• Wide genetic variability → wide clinical variability

NIH Consensus Development Panel. Pediatrics. 2001;108(4):972-82. Blau, et al. Mol Genet Metabol. 2009;96(4):158-63.NIH Consensus Development Panel. Pediatrics. 2001;108(4):972-82. Blau, et al. Mol Genet Metabol. 2009;96(4):158-63.

PhenylalaninePhenylalanine TyrosineTyrosinePAHPAH

6

Dietary Compliance and Blood Phe Levels in Patients with PKU Over Time

28 27

50

79

0

10

20

30

40

50

60

70

80

0 - 4 y.o. 5 - 9 y.o. 10 - 14 y.o. 15 - 19 y.o.

% P

atie

nts

Ab

ove

R

eco

mm

end

ed

Blo

od

Ph

e L

evel

% P

atie

nts

Ab

ove

R

eco

mm

end

ed

Blo

od

Ph

e L

evel

Walter, et al. Lancet. 2002;360:55-7.Walter, et al. Lancet. 2002;360:55-7.

N = 178N = 178 N = 137N = 137 N = 98N = 98 N = 77N = 77

7

Lecture Overview

• Review of PKU


– Pathophysiology

– Intelligence / IQ

– Executive function

– Academic performance

– Maternal PKU

– Neurocognitive testing



8

Possible Mechanisms of Neurotoxicity

• Dopamine depletion– Dopamine

• Precursor to norepinephrine, epinephrine• Neurotransmitter essential to executive function

• White matter pathology and disruptions in the interconnectivity between brain regions– White matter

• Myelin insulates nerve fibers found in white matter which increases speed of transmission of nerve signals (mental processing speed)

• Excess phe is believed to damage myelin

Anderson, et al. Mol Genet Metabol. 2010;99(S1):3-9. Christ, et al. Mol Genet Metabol. 2010;99(S1):22-32.De Groot, et al. Mol Genet Metabol. 2010;99(S1):86-9.Anderson, et al. Mol Genet Metabol. 2010;99(S1):3-9. Christ, et al. Mol Genet Metabol. 2010;99(S1):22-32.De Groot, et al. Mol Genet Metabol. 2010;99(S1):86-9.

9

Prefrontal Cortex

• Area of the brain that supports various neurocognitive activities, including executive function

• PKU-associated dopamine dysregulation →• Disruption of prefrontal cortex (PFC) function• Poor performance on measures of executive

function

De Sonneville, et al. Mol Genet Metabol. 2010;99(S1):10-17.Christ, et al. Mol Genet Metabol. 2010;99(S1):33-40.De Sonneville, et al. Mol Genet Metabol. 2010;99(S1):10-17.Christ, et al. Mol Genet Metabol. 2010;99(S1):33-40.

10

Vulnerable Neurocognitive Domains

Moyle, et al. Neuropsychol Rev. 2007;17(2):91-101.Moyle, et al. Neuropsychol Rev. 2007;17(2):91-101.

MotorSkills

InformationProcessing

Speed

InhibitoryControl

WorkingMemory

Attention

IQ

PKU

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Intelligence / IQ

• Robust relationship between blood phe levels and IQ

• Early-treated children experience loss of IQ if diet is discontinued

• Those who continue diet are more likely to achieve greater IQ / academic success

Brumm, et al. Mol Genet Metabol. 2010;99(S1):18-21.Brumm, et al. Mol Genet Metabol. 2010;99(S1):18-21.

12

IQ in Patients with PKU

102

112

70

80

90

100

110

120

130

Peer Group PKU

100

107

70

80

90

100

110

120

130

Siblings PKU

Comparison to Peer Group1Comparison to Peer Group1 Comparison to Siblings2Comparison to Siblings2

P < 0.0001P < 0.0001 P < 0.001P < 0.001

N = 21N = 21 N = 55N = 55N = 55N = 55N = 26N = 26

IQ (

Wec

hsle

r In

telli

genc

e S

cale

)IQ

(W

echs

ler

Inte

llige

nce

Sca

le)

1) Gassio, et al. Pediatr Neurol. 2005;33(4):267-71. 2) Koch, et al. J Inherit Metab Dis. 1984;7(2):86-90.1) Gassio, et al. Pediatr Neurol. 2005;33(4):267-71. 2) Koch, et al. J Inherit Metab Dis. 1984;7(2):86-90.

13

Impact of Blood Phe Levels on IQ

Observation PeriodBlood Phe Levels

(μmol/L)Lifetime IQ Loss for Each 100

μmol/L ↑ in Blood Phe

0 - 12 years old 423 - 750 1.3 - 3.1 points

Lifetime 394 - 666 1.9 - 4.1 points

N = 3361N = 3361

Waisbren, et al. Mol Genet Metabol. 2007;92:63-70.Waisbren, et al. Mol Genet Metabol. 2007;92:63-70.

14

Impact of Blood Phe Variability on IQ

• Study design– Retrospective review– N = 46 children under dietary control

• Study results– Inverse relationship between FSIQ and blood phe levels – FSIQ ↓ 4.3 points for every 1 point ↑ in standard deviation of blood

phe levels– Patient (7 y.o. female) with low blood phe variability → IQ = 116– Patient (6 y.o. male) with high blood phe variability → IQ = 92– Stability of blood phe levels may have a greater impact on cognitive

functioning than total exposure to phe in well-treated children.

Anastasoaie, et al. Mol Genet Metab. 2008;95:17-20.

15

Executive Function

Higher-order cognitive abilities• Working memory• Inhibitory control• Cognitive flexibility• Decision making• Problem solving• Abstract reasoning• Planning / organization• Strategic planning

De Sonneville, et al. Mol Genet Metabol. 2010;99(S1):10-17. Christ, et al. Mol Genet Metabol. 2010;99(S1):22-32. Christ, et al. Mol Genet Metabol. 2010;99(S1):33-40.De Sonneville, et al. Mol Genet Metabol. 2010;99(S1):10-17. Christ, et al. Mol Genet Metabol. 2010;99(S1):22-32. Christ, et al. Mol Genet Metabol. 2010;99(S1):33-40.

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Role of Executive Function inSelf-Management

Executive Task

Plan diet

Maintain supplies of formula and supplements

Record phe intake

Resist restricted foods (inhibitory control)

Take blood phe levels

Adjust diet based on blood phe levels

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PKU Adult Collaborative StudyPreliminary Review

• Study design– Neurocognitive testing in early-treated adults (N = 24)

• Study results– Intelligence – IQ scores in normal range– Neurocognitive deficits

• Executive function, attention, verbal memory, verbal fluency, expressive naming

• Deficits were more pronounced in patients with high blood phe levels (> 1000 μmol/L)

• Greater correlation between deficits and blood phe level during childhood compared to current blood phe level

Brumm, et al. J Inherit Metab Dis. 2004(27):549-566.Brumm, et al. J Inherit Metab Dis. 2004(27):549-566.

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Neurocognitive Outcomes inEarly-Treated PKU

• Study design– Meta-analysis of 33 primary studies with 200

patient outcomes (time period: 1980-2004)

• Study results– Intelligence – moderately lower IQ scores– Neurocognitive deficits

• Significantly impaired executive functions – working memory, inhibitory control, cognitive flexibility, planning

DeRoche, et al. Dev Neuropsychol. 2008;33(4):474-504.DeRoche, et al. Dev Neuropsychol. 2008;33(4):474-504.

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Executive Function in Patients with PKU vs. Control Group

53

183

58

210

0 50 100 150 200 250

Test 2(composite

scores)

Test 1(composite

scores)

Control (N = 14)

PKU (N = 14)

Leuzzi, et al. J Inherit Metab Dis. 2004;27(2):115-25.Leuzzi, et al. J Inherit Metab Dis. 2004;27(2):115-25.

P < 0.001P < 0.001

P < 0.05P < 0.05

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Working Memory in Patients with PKU vs. Control Group

5.2

4.6

3.9

3.43.8

3.3

0

1

2

3

4

5

6

Verbal Domain Object Domain Spatial Domain

ControlGroup

PKU

P < 0.05(all domains)P < 0.05(all domains)

Mea

n S

pan

Mea

n S

pan

White, et al. J Int Neuropsychol Soc. 2002;8:1-11.White, et al. J Int Neuropsychol Soc. 2002;8:1-11.

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Inhibitory Control in Patients with PKU vs. Control Group

1

25

32

2

0

5

10

15

20

25

30

35

Go No-Go

Control (N = 23)PKU (N = 26)

* P < 0.05 vs. control* P < 0.05 vs. control**

Num

ber

of

Err

ors

Num

ber

of

Err

ors

Christ, et al. Dev Neuropsychol. 2006;30(3):845-64.Christ, et al. Dev Neuropsychol. 2006;30(3):845-64.

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Strategic Planning in Patients with PKU vs. Normative Data

10

8.37.6

8.68.1

0

1

2

3

4

5

6

7

8

9

10

NormativeData

VisualScanning

NumberSequencing

LetterSequencing

Switching

P < 0.05vs. normativedata

P < 0.05vs. normativedata

** **

N = 15 N = 15

VanZutphen, et al. Clin Genet. 2007;72(1):13-8.VanZutphen, et al. Clin Genet. 2007;72(1):13-8.

Tes

t S

core

Tes

t S

core

23

Information Processing Speed in Patients with PKU vs. Control Group

11.4

8.4

10.5

7.8

0

2

4

6

8

10

12

Symbol Search Coding

50.9

66.2

0

10

20

30

40

50

60

70

Contingency Naming

ControlGroup

PKU

Anderson, et al. Dev Neuropsychol. 2007;32(2):645-68.Anderson, et al. Dev Neuropsychol. 2007;32(2):645-68.

Tes

t S

core

Tes

t S

core

Tim

e to

Rap

id

Ret

riev

alT

ime

to R

apid

R

etri

eval

P < 0.01 vs. control(all domains)


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Memory and Learning Impairments in Patients with PKU

6.3

13.6

12

7.59 8.3

7.3

5.5

0

2

4

6

8

10

12

14

16

Trial 1 Trial 5 Trial 1 Trial 5

Control (N = 23)

PKU (N = 23)

White, et al. Neuropsychol. 2001;15(2):221-9.White, et al. Neuropsychol. 2001;15(2):221-9.

Wor

ds

Rec

alle

dW

ords

R

ecal

led


California Verbal Learning TestCalifornia Verbal Learning Test

Patients up to 11 y.o.Patients up to 11 y.o. Patients ≥ 11 y.o.Patients ≥ 11 y.o.

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Motor Issues and Perception

• Motor skills– Dexterity; hand-wrist steadiness and speed

• Perception and visual-spatial difficulties– Sensitivity to visual contrast

Janzen, et al. Mol Genet Metabol. 2010;99(S1):47-51.Janzen, et al. Mol Genet Metabol. 2010;99(S1):47-51.

26

Preserved Functional Areas

• Developmental milestones• Language

– Expressive and receptive language skills

• Gross motor coordination

Janzen, et al. Mol Genet Metabol. 2010;99(S1):47-51.Janzen, et al. Mol Genet Metabol. 2010;99(S1):47-51.

27

Academic Performance

Academic difficulties due to:• Executive functioning

deficits• Information processing

speed deficits• ADHD

Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.

28

Academic Difficulties in Patients with PKU vs. Control Group

24

50

19

39

5

12

0

5

10

15

20

25

30

35

40

45

50

General SchoolProblems

Special Tutoring Repeat Classes

Control (N = 21)PKU (N = 26)


%

Stu

den

ts%

S

tude

nts

Gassio, et al. Pediatr Neurol. 2005;33(4):267-71.Gassio, et al. Pediatr Neurol. 2005;33(4):267-71.

29

Maternal PKU

Risks to children born to women with untreated maternal PKU:• Mental retardation (92% risk) • Microcephaly• Congenital heart disease• Low birth weightOther issues:• Postnatal growth retardation• Mild craniofacial dysmorphism• Neurological abnormalities• Behavioral problems

Metabolic control must be achieved early and consistentlythroughout the pregnancy to prevent or minimize complications

Brumm, et al. Mol Genet Metabol. 2010;99(S1):18-21. Koch, et al. Mol Genet Metabol. 2010;99 (S1):68-74.Brumm, et al. Mol Genet Metabol. 2010;99(S1):18-21. Koch, et al. Mol Genet Metabol. 2010;99 (S1):68-74.

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Neurocognitive Testing

Neurocognitive Domain Test / Assessment

Intelligence / IQ Wechsler intelligence scale

Executive function• Working memory, attention

• Inhibitory control, cognitive flexibility

• Planning / organization

Behavior rating inventory of executive function (BRIEF*)

• Digit span; self-ordered pointing test; trail making test

• Stroop color-word test; Wisconsin card sorting test; tower tasks; test of everyday attention for children

• Rey-Osterreith complex figure test; tower tasks

Non-executive function• Information processing speed

• Motor skills

• Memory and learning

• Symbol digit coding; finger tapping test; trail making test

• Purdue test; Peabody developmental motor scales

• California verbal learning test; Rey learning tests

Academic performance Teacher/parent reports; academic testing

Social-emotional adjustment Quality of life questionnaires

* BRIEF-P (preschool version) is available for children aged 2-5 years old. Christ, et al. Mol Genet Metabol. 2010;99(S1):22-32. Janzen, et al. Mol Genet Metabol. 2010;99(S1):47-51. * BRIEF-P (preschool version) is available for children aged 2-5 years old. Christ, et al. Mol Genet Metabol. 2010;99(S1):22-32. Janzen, et al. Mol Genet Metabol. 2010;99(S1):47-51.

31

Lecture Overview

• Review of PKU


• Psychiatric issues– Psychosocial impact of neurocognitive impairment

– Psychiatric and psychological comorbidities

– Psychiatric symptoms

– ADHD

– Psychiatric evaluation

– Patient referral and management


32

Psychosocial Impact of PKU-Related Neurocognitive Impairment

• Self-esteem• Interpersonal skills• Social competence• Relationships• Academic difficulties• Quality of life

Gentile, et al. Mol Genet Metabol. 2010;99(S1):64-67. Feillet, et al. Mol Genet Metabol. 2010;99(S1):79-85.Gentile, et al. Mol Genet Metabol. 2010;99(S1):64-67. Feillet, et al. Mol Genet Metabol. 2010;99(S1):79-85.

33

Common Psychiatric and Psychological Comorbidities

• ADHD• Depression• Anxiety and phobias• Other:

Behavior problems, social dysfunction

Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.Brumm, et al. Mol Genet Metabol. 2010;99(S1):59-63.Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.Brumm, et al. Mol Genet Metabol. 2010;99(S1):59-63.

34

Psychiatric Symptoms in PKU

↓ Positive Emotions Less joy, happiness,

confidence, autonomy, social competence

↑ Negative EmotionsMore depression, anxiety, phobias, social isolation

Brumm, et al. Mol Genet Metabol. 2010;99(S1):59-63. Feillet, et al. Mol Genet Metabol. 2010;99(S1):79-85.Brumm, et al. Mol Genet Metabol. 2010;99(S1):59-63. Feillet, et al. Mol Genet Metabol. 2010;99(S1):79-85.

35

Psychiatric Symptoms in PKU

Untreated Individual Early-Treated Child Early-Treated Adult

Aggression Attention problems Decreased positive emotions

Anxiety Decreased autonomy Depression

Autistic behaviors Decreased social competence Generalized anxiety

Depression Less achievement motivation Lack of autonomy

Hyperactivity Low self-esteem Low self-esteem

Impaired social skills School problems Phobias

Psychotic symptoms Social isolation/withdrawal

Social withdrawal Social maturity deficits


36

Psychiatric Symptoms in Patients with PKU vs. Control Group

6

14

14

31

37

1

5

5

16

19

0 10 20 30 40

Work Anxiety

Hypochondria

Anxiety

Phobias

Depression

Control (N = 181)

PKU (N = 35)

Pietz, et al. Pediatrics. 1997;99(3):345-50.Pietz, et al. Pediatrics. 1997;99(3):345-50.

Percent of Adult Patients Reporting SymptomPercent of Adult Patients Reporting Symptom



%%%%

%%%%

%%%%

%%%%

%%%%

37

ADHD

• ADHD and PKU are theoretically linked by low levels of dopamine in the PFC

• Academic underachievement

• Difficulties with math skills

Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.

38

Stimulant Use for ADHD in Patients with PKU vs. Control Group

7%

93%

26%

74%

Control group = patients with diabetes mellitusArnold, et al. J Inherit Metab Dis. 2004;27(2)137-43.Control group = patients with diabetes mellitusArnold, et al. J Inherit Metab Dis. 2004;27(2)137-43.

Control Group (N = 76)Control Group (N = 76) PKU (N = 38)PKU (N = 38)

Percent of patients usingstimulants for ADHD

(P < 0.006)

Percent of patients usingstimulants for ADHD

(P < 0.006)

ADHD symptoms were associatedwith higher blood phe levels

ADHD symptoms were associatedwith higher blood phe levels

39

Psychological Issues in Patients with PKU

“The prevalence and severity of problems generally correlates with the

timing and degree of exposure to elevated blood phe levels.”


40

Psychological Issues in Patients with PKU:Clinical Features and Presentation

• Stress of chronic illness• Burden of dietary restrictions• Symptom overlap vs. independent condition• Diagnostic overshadowing*

– Symptoms are misattributed to one condition without consideration of a second comorbid condition

• Delayed diagnosis, misdiagnosis

* Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.* Antshel, et al. Mol Genet Metabol. 2010;99(S1):52-8.

41

Psychiatric Evaluation

• Monitor the emotional and behavioral well-being of patients with PKU

• Intervene and refer before psychiatric symptoms and counterproductive behaviors initiate a vicious cycle of poor dietary control, elevated blood phe levels, and worsening symptoms


Poor dietarycontrol

Elevatedblood

phe levels

Psychiatricsymptoms

42

Assessment by Non-Psychologists

Psychological Realm Test / Assessment

Adaptive functioning Adaptive behavior assessment system (ABAS-II)

Behavior Behavior assessment system for children (BASC-II)

Executive function Behavior rating inventory of executive function (BRIEF)

(BRIEF-P = preschool version for children aged 2-5 years old)

43

Patient Referral and Management

• Referral to:– Psychologist– School psychologist (children)– Psychiatrist– Other mental health professional (e.g. social worker,

licensed professional counselor)

• Management plan

Schmidt, et al. J Clin Exp Neuropsychol. 1994;16(5):681-8.Brumm, et al. Mol Genet Metabol. 2010;99(S1):59-63.Schmidt, et al. J Clin Exp Neuropsychol. 1994;16(5):681-8.Brumm, et al. Mol Genet Metabol. 2010;99(S1):59-63.

Reintroduction of strict dietary control is recommended for patients displaying neurocognitive or psychiatric symptomsReintroduction of strict dietary control is recommended for patients displaying neurocognitive or psychiatric symptoms

44

Lecture Overview

• Review of PKU




45

Management of Neurocognitive and Psychiatric Issues

Recognition• Dietary restrictions have improved patient

outcomes, but often this intervention alone is not enough.

46


Empowerment• All healthcare professionals can take action

to screen patients for problems, to help patients be more compliant with dietary restrictions, and to refer patients to a psychologist or psychiatrist.

47


Continuation• Early and ongoing monitoring and intervention

helps break the cycle of suboptimal performance. Life-long observation, management and support of patients is critical.

48

Summary of Key Points

• Awareness– Even patients following dietary restrictions can experience

PKU-related neurocognitive and psychiatric issues

• Assessment– Patient assessment is the first step in the management

process

• Treatment– Strategies for improving patient functioning exist – Control blood phe levels– Address comorbid conditions

pku neuro psych webinar

Documents

control blood phe levels

impact of blood phe

blood phe levels fsiq

mol genet metabol

stability of blood phe

phenylalanine phe

low blood phe variability

neurocognitive function