Neurocognitive and Behavioral Issues in PKU

Susan Waisbren, PhDAssociate Professor of Psychology

Harvard Medical SchoolChildren’s Hospital Boston

Boston, MassachusettsContent developed in conjunction with Desiree A. White, PhD, Associate Professor,

Department of Psychology, Washington University, St. Louis, Missouri

Faculty DisclosureIt is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, and staff participating in this activity will disclose any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all faculty conflicts of interest prior to the release of this activity.

Susan Waisbren, PhD, has received research grants/support from and served as a consultant for BioMarin.

Desiree White, PhD, has received research grants/support from, served as a consultant for, and received honoraria from BioMarin.

• Describe the impact of elevated Phe on long-term patient outcomes

Educational Learning Objective

KEY POINTS1. High Phenylalanine (Phe) levels harm the

brain

2. Traditional therapies do not completely protect individuals with PKU

3. Neuropsychological follow-up is important in identifying deficits associated

with even well-treated PKU

KEY POINT #1

High Phenylalanine (Phe) levels harm the brain.

1. Evidence2. Dopamine hypothesis3. White matter hypothesis

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

Blood Phe and IQ Are Correlatedin Individuals With PKU

Observation period

Correlation between blood

Phe and IQ

Lifetime IQ loss for each 100 µmol/L (1.6

mg/dL) increase in blood Phe (IQ points)

Critical period(0–12 years old) r = -0.35* 1.3–3.1

Lifetime(all ages) r = -0.34* 1.9–4.1

* P < 0.05

Outcomes for Adults with PKU Are Worse if Discontinue Diet

OutcomeDiscontinued

DietContinued

Diet

Medical Problems 2.4 ± 1.8 0.9 ± 1.4

College Degree 32% 78%

Socioeconomic Class I or II*

19% 44%

Koch R, et al. J Inherit Metab. 2002;25:333-346.

*Two highest socioeconomic classes in the Hollingshed classification system

Prefrontal Cortex Is Sensitive to Reductions

in Dopamine

PAH = phenylalanine hydroxylase BH4 = tetrahydrobiopterin

TH = tyrosine hydroxylaseAADC = aromatic amino acid decarboxylase

Periphery(mostly liver)

Blood Brain Barrier

Brain

Figure adapted from Youdim MB, et al. Nature Rev Neurosci. 2006;7:295-309.Image from http://nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html. Accessed Oct ober 2010.

DopaminePathways

White Matter

Image from: http://kvhs.nbed.nb.ca/gallant/biology/schwann_myelin.html. Accessed October 2010.

Myelin insulates axons to increase speed

of neural signal transmission

Image from: RC McKinstryWashington University

Mallinckrodt Institute of Radiology

KEY POINT #2

Traditional therapies do not completely protect individuals with PKU.

1. Adherence2. Cognitive abilities3. School achievement4. Executive functioning5. Processing speed6. Emotional issues

• ~1 in 3 children less than 10 years of age have blood Phe above recommended range

• Noncompliance increases in adolescence

Adapted from Table 2 of Walter JH, et al. Lancet. 2002;360:55-57.

Adherence to Diet Is Difficult

Series10

10

20

30

40

50

60

70

80

90

28% 27%

50%

79%

% A

bo

ve

Re

co

mm

en

de

d R

an

ge

.

0–4 years 5–9 years 10–14 years

15–19 years

Children with PKU on Diet Are at Risk for Lowered IQ

Peers PKU70

80

90

100

110

120

130 P < 0.0001

Wec

hsl

er I

nte

llig

ence

Sca

le I

Q

.

Siblings PKU70

80

90

100

110

120

P < 0.001

We

ch

sle

r In

tell

ige

nc

e S

ca

le I

Q

.

Gassio et al 2005

Koch et al 1984

• Blood Phe and IQ are correlated Waisbren et al 2007

• Variability in Blood Phe may be important Anastasoaie et al 2008

Gassio R, et al. Pediatr Neurol. 2005;33:267–271. Waisbren SE, et al. Mol Genet Metab. 2007;92:63-70.Koch R, et al. J Inherit Metab Dis. 1984;7:86-90. Anastasoaie V, et al. Mol Genet Metab. 2008;95:17-20.

PKU Students Unaffected Peers0

10

20

30

40

50

60

50%

24%

39%

19%

12%

5%

Total school problemsRequired special tutoringRepeated classes

% S

tud

en

ts W

ith

Sc

ho

ol P

rob

lem

s

.

P < 0.03

Children with PKU on Diet Present More School Problems than

Unaffected Peers

Gassio R, et al. Pediatr Neurol. 2005;33:267-271.

Executive Functioning Deficits

• We don’t know if he’s missing or just lost under all that paper!

• Planning• Organization• Working memory• Initiation• Inhibition of usual

response• Cognitive flexibility

8

2

3

4

5

6

7

5 6 7 8 9 10 11 12 13 14 15 16 17 18

Age (years)

Su

mm

ary

Mem

ory

Sco

re Control

PKU

Executive Deficits Across the Lifespan

that May Worsen with Age

Diamond A, et al. Monogr Soc Res Child Dev. 1997;62:1-208.Huijbregts SC, et al. Neuropsychology. 2003:17,369–379. Araujo GC, et al. Neuropsychology. 2009;23:130-134. Channon S, et al. Neuropsychology. 2004;4:613-620. VanZutphen KH, et al. Clin Genet. 2007;72:13-18. White DA, et al. J Int Neuropsychol Soc. 2002;8:1-11. White DA, et al. Neuropsychology. 2001;15(2):221-229.

White et al 2001

Executive Deficits Make Diet Adherence Difficult

• Planning diet• Remembering Phe intake for records• Remembering to take formula• Inhibiting impulse to eat foods not

allowed on diet• Maintaining medical food supplies• Monitoring blood Phe and making

appropriate adjustments in intake

Speed of Processing Is Reduced in Children with PKU

Anderson PJ, et al. Dev Neuropsychol. 2007;32(2):645-668.

Symbol Search Coding0

2

4

6

8

10

12

Control PKU

Te

st

Score

.

Contingency ...0

10

20

30

40

50

60

70

Tim

e t

o R

ap

id R

etr

ival .

P < 0.01P < 0.01

P < 0.01

Depressed Mood

Phobias Generalized Anxiety

Hypochon-driac Worries

Anxiety at Work

0

5

10

15

20

25

30

35

40

19%16%

5% 5%

1%

37

31

14 14

6

Control PKU

Psychiatric Symptoms

% P

atie

nts

Rep

ort

ing

Sym

pto

m

.

*P < 0.05 compared with 18-year-old controls

Adults with PKU DemonstrateIncrease in Psychiatric Symptoms

Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:345-350.

KEY POINT #3 Neuropsychological follow-up is important

in identifying subtle deficits associated with even well treated PKU.

1. Case study2. Screening by non-psychologists3. The Genetics and Metabolism

Psychology Network

Case Study: A.D.

History• Male with PKU, now age 11 years

– Newborn screening level 30 mg/dL

• Over-treated until 17 months – Failure to thrive and mild microcephaly

• Poor metabolic control from ages 2–4 years, until g-tube placed for intake of

formula • Levels varied until age 10 years

– 3.6–16.9 mg/dL

• ADHD medication required• IQ = 81 (100 is average)

Case StudyRecent and Current

• Began treatment with sapropterin at age 10• Blood Phe steady at 5.4 mg/dL• No longer needs ADHD medication• Height 5th percentile; weight 2nd

percentile• IQ = 105 (Increase of 24 points)

Case StudyCurrent

• 11-year-old boy in 4th grade• Continues with g-tube• Eczema and bedwetting• Receives occupational therapy • Has attention problems and requires one-on-

one aide in classroom • Kind, imaginative, eager to please• Enjoys socializing, video games, sports

• Polite, cheerful, talkative• Concentrated fairly well, but hummed as

worked• Enjoyed relating facts about spiders • Told far-fetched stories about school and

home, stating these capture interest of other children

• Did not appear to believe stories, but rather to intentionally elaborate

Assessment Observations

Intellectual PerformanceWechsler Abbreviated Scale of Intelligence (WASI)

Vocabulary Matrix Reasoning Full Scale IQ0

20

40

60

80

100

120

AverageAD

WA

SI

Sco

re

Executive Functioning• Example List

– Carrot– Taxi– Elephant– Car– Airplane– Lettuce– Cat– Potato– Butterfly– Spinach– Boat– Tiger– Scooter– Squash– Parrot

California Verbal Learning Test

Trial 1: 4 wordsTrial 5: 9 words(Used categories)

Previous YearTrial 1: 3 wordsTrial 5: 5 words

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Processing SpeedExample of a Symbol Search Task

YES

YES

NO

NO

Wechsler Intelligence Scale for Children

Symbol Search Coding0

2

4

6

8

10

12

Average AD

WIS

C-I

V S

ub

test

Sco

re

Academic Achievement (WIAT)

WIAT: Wechsler Individual Achievement Test

Reading Recognition: 5th grade level

Reading increased 1 grade in last year

Numerical Operations: 3rd grade level

Careless errors, could not borrow or carry, did not attempt adding long columns of numbers

Math increased 1/2 grade in last year

Visual Motor Integration

Berry Visual Motor Integration Test (VMI): Standard Score = 70 (100 is average) Drew with confidence, but poor organization so details misplaced.

Same score as last year.

• Continue with extra help and occupational therapy

• Teach compensatory strategies in arithmetic• Psychological counseling• Behavioral therapy for weaning from g-tube• Medical evaluation for eczema and bedwetting• Re-evaluation in one year

Recommendations

Screening Tests That Can BeAdministered by Non-

Psychologists

PSYCHOLOGICAL REALM TEST

Adaptive Functioning

Adaptive Behavior Assessment System (ABAS-II)

Behavior

Behavior Assessment System for Children (BASC-II)

Executive Functioning

Behavior Rating Inventory of Executive Function (BRIEF)

Abbreviations & Sources

• ABAS-II: Adaptive Behavior Assessment System-Second Edition (Harrison, Oakland 2003)

• BRIEF: Behavior Rating Inventory of Executive Function (Gioia, Isquith, Guy, Kenworthy, 2000)

• BASC-II: Behavior Assessment System for Children-Second Edition (Reynolds, Kamphus, 2004)

• BAI: Beck Anxiety Inventory (Beck, Steer,1993)

• BDI-II: Beck Depression Inventory-Second Edition (Beck, Steer, Brown,1996)

Genetics and Metabolism Psychology Network

KEY POINTS1. High Phenylalanine (Phe) levels harm the

brain

2. Traditional therapies do not completely protect individuals with PKU

3. Neuropsychological follow-up is important in identifying deficits associated

with even well-treated PKU

Questions & Answers