neurocognitive functioning in pku susan waisbren, phd children’s hospital boston
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Neurocognitive Functioning in PKU Susan Waisbren, PhD Children’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. - PowerPoint PPT PresentationTRANSCRIPT
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Neurocognitive Functioning in PKU
Susan Waisbren, PhDChildren’s Hospital Boston
HIGH HOPES!
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KEY POINTS
• EVEN TREATED CHILDREN AND ADULTS EXPERIENCE NEUROPSYCHOLOGICAL EFFECTS
• PSYCHOLOGICAL ASSESSMENTS ARE IMPORTANT
• THERE ARE STRATEGIES FOR IMPROVING FUNCTIONING IN PKU
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KEY POINT # 1: EVEN TREATED CHILDREN AND ADULTS EXPERIENCE LEARNING
DIFFICULTIES AND OTHER NEUROPSYCHOLOGICAL EFFECTS
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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
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• 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)
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WHY PROBLEMS?
• THE DOPAMINE HYPOTHESIS
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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
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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
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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
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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
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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
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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
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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
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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
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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)
*
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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
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EMOTIONAL AND BEHAVIORAL OUTCOMES
DEPRESSION ANXIETY
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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.
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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
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WHY?
• THE MYELIN HYPOTHESIS
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MYELIN INSULATES AXONS WHICH INCREASE THE SPEED OF PROCESSING
OF NERVE SIGNALS
Image from: http://kvhs.nbed.nb.ca/gallant/biology/schwann_myelin.html
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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.
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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
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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.
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KEY POINT #2: PSYCHOLOGICAL ASSESSMENT IS IMPORTANT
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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]
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4 YEARS Pre-School Assessments
• Wechsler Preschool and Primary Scale of Intelligence (WPPSI)
• Visual-motor skills
• Behavior
• Attention
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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
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ADOLESCENCE & ADULTHOOD
• Wechsler Abbreviated Scale of Intelligence• Achievement• Executive Functioning• Processing Speed• Anxiety & Depression• Adaptive Behavior• Transition to Adult Care • Maternal PKU
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KEY POINT #3: STRATEGIES FOR MANAGING CHALLENGES IN PKU
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INFANTS AND TODDLERS
• EARLY INTERVENTION
• PLAY THERAPY
• PARENT AS EDUCATOR
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SCHOOL AGE
• REMEDIAL HELP• CHUNKING• DICTATING• LISTS & CALENDARS• VERBAL LEARNERS• SLOW DOWN INSTRUCTIONS• TEST MODIFICATIONS• MONITOR BLOOD PHE
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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
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ADOLESCENTS & YOUNG ADULTS
• TUTORS• EXTENDED TIME OR UNTIMED TESTING• CHOOSE CLASSES CAREFULLY• PSYCHOTHERAPY• REDUCE BLOOD PHE
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SOCIAL SUPPORT
POSITIVE ATTITUDES
MANAGEABILITY
Finkelson L, Bailey I, Waisbren SE. J Inherit Metab DIs. 2001; 24: 515-516.
SAM
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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!
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THANK YOU!