Transcript Neurocognitive and Behavioral Outcomes with PKU: Raising

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
KEY POINT # 1: EVEN TREATED CHILDREN
AND ADULTS EXPERIENCE LEARNING
DIFFICULTIES AND OTHER
NEUROPSYCHOLOGICAL EFFECTS
NEUROCOGNITIVE DEFICITS IN
TREATED PKU
Especially if
Blood
Phe not
consistently in
target
range
REDUCTIONS IN:
•Executive Functioning
• Memory
• Planning
• Attention
• Organization
• Mental Processing Speed
• Behavior and Mood
ADHERENCE TO TREATMENT
• Nearly one in three PKU children under the age of 10 have blood
Phe above recommended target range
• Noncompliance increases as patients enter adolescence
Proportion Above
Recommended Level (%)
90
79%
80
70
60
50%
50
40
30
28%
27%
(n = 178)
(n = 137)
0–4
5–9
20
10
0
(n = 98)
(n = 77)
10–14
15–19
Age Groups (in Years)
Adapted from Table 2 of Walter JH, et al. Lancet. 2002;360:55–57.
WHY PROBLEMS?
• THE DOPAMINE HYPOTHESIS
EXECUTIVE FUNCTIONING AND THE
DOPAMINE HYPOTHESIS
Periphery
(mostly liver)
Phenylalanine
PAH
BH4
Blood
Brain
Barrier
Tyrosine
Tyrosine
Brain
TH
BH4
BH4 = tetrahydrobiopterin
PAH = phenylalanine hydroxylase
TH = tyrosine hydroxylase
AADC = aromatic amino acid decarboxylase
L-dopa
AADC
Dopamine
DOPAMINE: EXECUTIVE FUNCTION,
EMOTION AND SOCIAL BEHAVIOR
• Neurotransmitter
related to attention,
mood, and
movement
• Precursor to
norepinephrine,
epinephrine, and
other
neurotransmitters
basal ganglia
frontal lobe
prefrontal
cortex
dopamine
pathways
Image from http://nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html
DOPAMINE AND EXECUTIVE FUNCTION
DEFICITS
Infants2
• Working memory
• Behavioral inhibition
Children (7–14)3
• Impulse control
• Attentional flexibility
Zutphen KH, et al. Clin Genet. 2007;72:13-18.
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.
1Van
2Diamond
Adults4
• Attention
• Working memory
• Verbal Fluency
Children with PKU on diet have significantly lower
IQ than unaffected peers
and sibling controls
130
P = 0.001
P < 0.0001
120
Wechsler Intelligence Scale
Wechsler Intelligence Scale
120
110
100
90
80
n = 21
n = 26
Peers*
PKU
70
†
110
100
90
80
n = 55
n = 55
70
Siblings
PKU
*Controls were age- and sex-matched
†PKU patients (ages 7–19 years old) managed early
and continuously with Phe-restricted diet
Gassio R, et al. Pediatr Neurol. 2005;33:267–271.
Koch R, et al. J Inherit Metab Dis. 1984;7:86-90.
% Children in Severe Range**
EXECUTIVE FUNCTIONING
DEFICITS
25
21*
20
18*
15
10
5
0
5
Control
(n = 80)
Hydrocephalus
(n = 45)
PKU
(n = 44)
*P < 0.001 compared to control
**Based on Behavior Rating Inventory of Executive Function (BRIEF) global executive
composite score. Severe range is > 1 SD above the mean
Anderson VA, et al. Child Neuropsychol. 2002;8(4):231-240.
ATTENTION PROBLEMS
Stimulant Treatment
for Attentional Dysfunction
30
26%*
25
20
15
10
7%
5
0
(n = 38)
(n = 76)
PKU
Diabetes Mellitus
Group
*P < 0.006 as compared to children with diabetes mellitus
Arnold GL, et al. J Inherit Metab Dis. 2004;27:137–143.
WORKING MEMORY
Control
6
n = 20
5.2
Mean Span
5
PKU
n = 20
4.6*
3.9
4
3.4*
3.8
3.3*
3
2
1
0
Verbal
Object
*P < .05 compared to control
White DA, et al. J Int Neuropsychol Soc. 2002;8:1-11.
Spatial
ORGANIZATION AND MEMORY
Control
16
PKU
n = 23
n = 23
Words Recalled
14
13.6
12
12
10
9
8
6
4
*
6.3
8.3
7.5
7.3
5.5
2
0
Trial 1
Trial 5
Trial 1
Trial 5
Younger < 11 yr
Older ≥ 11 yr
California Verbal Learning Test
*P < 0.05 compared to control
White DA, et al. Neuropsychol. 2001;15(2):221-229.
IMPULSE CONTROL
50
Control
Number of Errors
(n = 23)
*
PKU
(n = 26)
40
30
32
25
20
10
0
Go
*p < 0.05 compared to control
Christ et al., 2006
No-Go
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
PSYCHIATRIC OUTCOMES IN
ADULTS WITH PKU
*P < 0.05 as compared to 18-year-old controls
Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:345–350.
AGORAPHOBIA
Score on AAL Scale†
Blood Phe level and score on AAL Scale† are
significantly correlated
4.0
3.5
3.0
2.5
2.0
rs = 0.43
1.5
1.0
0.5
0.0
600
†From
900
1200
1500
1800
2100
Blood Phenylalanine Level (μmol/L)
the Mobility Inventory, measuring avoidance behavior when alone (AAL)
Waisbren SE and Levy HL. J Inherit Metab Dis. 1991;14:755-764.
2400
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.
META-ANALYSIS SUMMARY
Meta-analysis of 11 studies demonstrates deficits in
multiple cognitive domains
1.4
1.2
Effect Size*
1
large
0.8
0.6
medium
0.4
0.2
small
0
-0.2
IQ
Processing
Speed
Attention
Inhibition
Motor
Control
Working
Memory
Cognitive Domain
Range: Control 91–221; PKU 100–218
*Hedge’s g effect size with 95% confidence intervals
Adapted from Figure 1 of Moyle JJ, et al. Neuropsychol Rev. 2007;17(2):91–101.
SCHOOL PROBLEMS
*P
= 0.028 vs controls
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
STABILITY OF BLOOD PHE
• 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
Example Low Variability IQ = 116
Example High Variability IQ = 92
2000
Mean* (412 μmol/L)
± SD† (166 μmol/L)
1600
1200
800
400
Blood Phe Level (umol/L)
Blood Phe Level (umol/L)
2000
Mean* (389 μmol/L)
± SD† (325 μmol/L)
1600
1200
800
400
0
0
0
10
20
30
40
50
60
70
Phe Specimen Number in 7yo female
*Lifetime blood Phe levels
†Mean standard deviations for lifetime blood Phe levels
Anastasoaie V, et al. Mol Genet Metab. 2008;95:17-20.
0
10
20
30
40
50
60
Phe Specimen Number in 6yo male
70
ADOLESCENTS & YOUNG ADULTS
•
•
•
•
•
TUTORS
EXTENDED TIME OR UNTIMED TESTING
CHOOSE CLASSES CAREFULLY
PSYCHOTHERAPY
REDUCE BLOOD PHE
SAM
SOCIAL SUPPORT
POSITIVE ATTITUDES
MANAGEABILITY
Finkelson L, Bailey I, Waisbren SE. J
Inherit Metab DIs. 2001; 24: 515-516.
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!