Neurocognitive Functioning in PKU

Susan Waisbren, PhDChildren’s Hospital Boston

HIGH HOPES!

KEY POINTS

• EVEN TREATED CHILDREN AND ADULTS EXPERIENCE NEUROPSYCHOLOGICAL EFFECTS

• PSYCHOLOGICAL ASSESSMENTS ARE IMPORTANT

• THERE ARE STRATEGIES FOR IMPROVING FUNCTIONING IN PKU

KEY POINT # 1: EVEN TREATED CHILDREN AND ADULTS EXPERIENCE LEARNING

DIFFICULTIES AND OTHER NEUROPSYCHOLOGICAL EFFECTS

NEUROCOGNITIVE DEFICITS IN TREATED PKU

REDUCTIONS IN:

•Executive Functioning• Memory• Planning• Attention• Organization

• Mental Processing Speed• Behavior and Mood

Especially if Blood

Phe not consistently in

target range

• Nearly one in three PKU children under the age of 10 have blood Phe above recommended target range

• Noncompliance increases as patients enter adolescence

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

ADHERENCE TO TREATMENT

28% 27%

50%

79%

0

10

20

30

40

50

60

70

80

90

Age Groups (in Years)

Pro

port

ion A

bove

R

ecom

mended L

eve

l (%

)

0–4 5–9 10–14 15–19

(n = 137) (n = 98) (n = 77)(n = 178) (n = 137) (n = 98) (n = 77)

WHY PROBLEMS?

• THE DOPAMINE HYPOTHESIS

EXECUTIVE FUNCTIONING AND THE DOPAMINE HYPOTHESIS

BH4

PhenylalaninePAH

DopamineTyrosine L-dopaTH

BH4

AADCTyrosine

Periphery(mostly liver)

BloodBrain

Barrier Brain

BH4 = tetrahydrobiopterinPAH = phenylalanine hydroxylaseTH = tyrosine hydroxylaseAADC = aromatic amino acid decarboxylase

DOPAMINE: EXECUTIVE FUNCTION, EMOTION AND SOCIAL BEHAVIOR

• Neurotransmitter related to attention, mood, and movement

• Precursor to norepinephrine, epinephrine, and other neurotransmitters

Image from http://nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html

prefrontalcortex

dopaminepathways

frontal lobebasal ganglia

DOPAMINE AND EXECUTIVE FUNCTION DEFICITS

1Van Zutphen KH, et al. Clin Genet. 2007;72:13-18.2Diamond A, et al. Monogr Soc Res Child Dev. 1997;62:1-208.3Huijbregts SC, et al. NeuroSci Biobehav Rev. 2002;26:697-712.4Channon S, et al. Neuropsychology. 2004;18:613-620.

Infants2

• Working memory• Behavioral inhibition

Children (7–14)3

• Impulse control• Attentional flexibility

Adults4

• Attention• Working memory• Verbal Fluency

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

*Controls were age- and sex-matched†PKU patients (ages 7–19 years old) managed early and continuously with Phe-restricted diet

P < 0.0001

70

80

90

100

110

120

130

Peers* PKU

We

ch

sle

r In

telli

ge

nc

e S

ca

le

n = 26n = 21

Children with PKU on diet have significantly lower IQ than unaffected peers

P = 0.001

70

80

90

100

110

120

Siblings PKU

We

ch

sle

r In

telli

ge

nc

e S

ca

le n = 55 n = 55

Koch R, et al. J Inherit Metab Dis. 1984;7:86-90.

†

and sibling controls

5

18*

21*

0

5

10

15

20

25

Control Hydrocephalus PKU

% C

hil

dre

n i

n S

ev

ere

Ra

ng

e**

EXECUTIVE FUNCTIONING DEFICITS

Anderson VA, et al. Child Neuropsychol. 2002;8(4):231-240.

**Based on Behavior Rating Inventory of Executive Function (BRIEF) global executive composite score. Severe range is > 1 SD above the mean

(n = 80) (n = 45) (n = 44)

*P < 0.001 compared to control

Arnold GL, et al. J Inherit Metab Dis. 2004;27:137–143.

7%

26%*

0

5

10

15

20

25

30

PKU Diabetes MellitusGroup

Stim

ula

nt T

reatm

ent

for

Att

entional D

ysfu

nction

(n = 38) (n = 76)

ATTENTION PROBLEMS

*P < 0.006 as compared to children with diabetes mellitus

WORKING MEMORY

5.2

3.9 3.83.3*3.4*

4.6*

0

1

2

3

4

5

6

Verbal Object Spatial

Mea

n S

pan

Control PKU

*P < .05 compared to control

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

n = 20 n = 20

13.6

7.5

9

6.3

12

7.3

5.5

8.3

0

2

4

6

8

10

12

14

16

Trial 1 Trial 5 Trial 1 Trial 5

Wor

ds R

ecal

led

Control PKU

*

Younger < 11 yr Older ≥ 11 yr

White DA, et al. Neuropsychol. 2001;15(2):221-229.

n = 23 n = 23

*P < 0.05 compared to control

ORGANIZATION AND MEMORY

California Verbal Learning Test

IMPULSE CONTROL

25

32

0

10

20

30

40

50

Go No-Go

Nu

mb

er o

f E

rro

rs

Control PKU

*p < 0.05 compared to control

Christ et al., 2006

(n = 23) (n = 26)

*

EXECUTIVE FUNCTIONING IN PKU

• Planning diet• Remembering Phe intake for records• Remembering to take formula• Helps with inhibiting responses, resisting

foods not allowed on diet• Maintaining supplies• Monitoring blood Phe and making

appropriate adjustments in intake

EMOTIONAL AND BEHAVIORAL OUTCOMES

DEPRESSION ANXIETY

1%

5%5%

16%19%

6%*

14%*14%*

31%*

37%*

0

5

10

15

20

25

30

35

40

Depressed Mood Phobias GeneralizedAnxiety

HypochondriacWorries

Anxiety at Work

Psychiatric Disorder

Pati

en

ts R

ep

ort

ing

Sym

pto

m (

%) Control (n = 181) PKU (n = 35)

*P < 0.05 as compared to 18-year-old controls

PSYCHIATRIC OUTCOMES IN ADULTS WITH PKU

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

AGORAPHOBIABlood Phe level and score on AAL Scale† are

significantly correlated

†From the Mobility Inventory, measuring avoidance behavior when alone (AAL)

Blood Phenylalanine Level (μmol/L)

Sco

re o

n A

AL

Sca

le†

Waisbren SE and Levy HL. J Inherit Metab Dis. 1991;14:755-764.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

600 900 1200 1500 1800 2100 2400

rs = 0.43

WHY?

• THE MYELIN HYPOTHESIS

MYELIN INSULATES AXONS WHICH INCREASE THE SPEED OF PROCESSING

OF NERVE SIGNALS

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

WHITE MATTER HYPOTHESIS

• Individuals with PKU have abnormal white matter

• Abnormalities may be due to– Increased myelin turnover– Elevated water content– Disturbed myelin synthesis

• White matter abnormalities may reduce speed of processing leading to neurocognitive deficits observed with PKU

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

Range: Control 91–221; PKU 100–218*Hedge’s g effect size with 95% confidence intervals

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

IQ ProcessingSpeed

Attention Inhibition MotorControl

WorkingMemory

Cognitive Domain

Eff

ect

Siz

e*

small

medium

large

META-ANALYSIS SUMMARY

Adapted from Figure 1 of Moyle JJ, et al. Neuropsychol Rev. 2007;17(2):91–101.

Meta-analysis of 11 studies demonstrates deficits in multiple cognitive domains

50%*

24%

39%

19%

12%

5%

0

10

20

30

40

50

60

PKU Students (n = 26) Unaffected Peers (n = 21)School Problems

Stu

de

nts

(%

)

Total school problemsRequired special tutoringRepeated classes

*P = 0.028 vs controls

SCHOOL PROBLEMS

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

KEY POINT #2: PSYCHOLOGICAL ASSESSMENT IS IMPORTANT

6, 12, 18, 30 MONTHS Developmental Assessments

• Bayley Scales of Infant Development

• Emergent Language Skills

• Adaptive Behavior

• [Scores < 85 or Discrepancy between scores indicate need for Early Intervention]

4 YEARS Pre-School Assessments

• Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

• Visual-motor skills

• Behavior

• Attention

SCHOOL AGE (6-7 YEARS AND EVERY 3 YEARS THEREAFTER)

• Wechsler Intelligence Scale for Children (WISC-IV) or Wechsler Abbreviated Intelligence Scale (WASI)

• Achievement• Executive Functioning and Attention• Processing Speed• Visual-Motor• Adaptive behavior and mood

ADOLESCENCE & ADULTHOOD

• Wechsler Abbreviated Scale of Intelligence• Achievement• Executive Functioning• Processing Speed• Anxiety & Depression• Adaptive Behavior• Transition to Adult Care • Maternal PKU

KEY POINT #3: STRATEGIES FOR MANAGING CHALLENGES IN PKU

INFANTS AND TODDLERS

• EARLY INTERVENTION

• PLAY THERAPY

• PARENT AS EDUCATOR

SCHOOL AGE

• REMEDIAL HELP• CHUNKING• DICTATING• LISTS & CALENDARS• VERBAL LEARNERS• SLOW DOWN INSTRUCTIONS• TEST MODIFICATIONS• MONITOR BLOOD PHE

0

400

800

1200

1600

2000

0 10 20 30 40 50 60 70

Phe Specimen Number in 6yo male

Blo

od P

he L

evel

(um

ol/L

)

STABILITY OF BLOOD PHE

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

0

400

800

1200

1600

2000

0 10 20 30 40 50 60 70

Phe Specimen Number in 7yo female

Blo

od P

he L

evel

(um

ol/L

)

Mean* (412 μmol/L)± SD† (166 μmol/L)

Mean* (389 μmol/L)± SD† (325 μmol/L)

*Lifetime blood Phe levels†Mean standard deviations for lifetime blood Phe levels

Example Low Variability IQ = 116 Example High Variability IQ = 92

•Correlation of SD of blood Phe levels with FSIQ was -0.36 (p=.058)•FSIQ decreased 4.3 points with 1 point increase in SD of blood Phe

ADOLESCENTS & YOUNG ADULTS

• TUTORS• EXTENDED TIME OR UNTIMED TESTING• CHOOSE CLASSES CAREFULLY• PSYCHOTHERAPY• REDUCE BLOOD PHE

SOCIAL SUPPORT

POSITIVE ATTITUDES

MANAGEABILITY

Finkelson L, Bailey I, Waisbren SE. J Inherit Metab DIs. 2001; 24: 515-516.

SAM

TAKE AWAY MESSAGES

• EVEN TREATED INDIVIDUALS FACE CHALLENGES – DON’T BLAME THE VICTIM

• ASSESSMENT IS THE FIRST STEP TOWARD MANAGING THE CHALLENGES

• STRATEGIES EXIST FOR NEARLY EVERY SITUATION – THERE IS NEVER NOTHING MORE TO BE DONE BECAUSE WE HAVE HIGH HOPES!

THANK YOU!