NEUROCOGNITIVE, OUTCOMES IN PKU: IT S TIME TO RAISE THE BAR

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1 NEUROCOGNITIVE, OUTCOMES IN : IT S TIME TO RAISE THE BAR KEY POINTS 1. High Phenylalanine (Phe) levels harm the brain.. Traditional therapies do not completely protect individuals with. 3. New approaches may improve outcomes in. KEY POINT #1: PHE IS HARMFUL BLOOD PHE AND IQ ARE CORRELATED IN PATIENTS WITH Observation period Critical period ( 1 years old) Lifetime (all ages) Range of blood Phe (μmol/l) Lifetime IQ loss for each 1 μmol/l increase in blood Phe (IQ points) OUTCOMES FOR ADULTS WITH WORSE FOR THOSE WHO DISCONTINUED DIET Outcome Medical Problems (per patient) College Degree Socioeconomic Class I or II* Discontinued Diet. ± 1.8 3% 19% Continued Diet.9 ± 1. 78% % *Two highest socioeconomic classes in the Hollingshed classification system Waisbren SE, et al. Mol Genet Metab. 7;9:3 7. Koch R, et al. J Inherit Metab. ;:

2 Blood Phe Level (umol/l) STABILITY OF BLOOD PHE Correlation of SD of blood Phe levels with FSIQ was -.3 (p=.8) FSIQ decreased.3 points with 1 point increase in SD of blood Phe Example Low Variability IQ = 11 Example High Variability IQ = 9 Mean* (1 μmol/l) ± SD (1 μmol/l) Phe Specimen Number in 7yo female Blood Phe Level (umol/l) Mean* (389 μmol/l) ± SD (3 μmol/l) Phe Specimen Number in yo male DOPAMINE: EXECUTIVE FUNCTION, EMOTION AND SOCIAL BEHAVIOR Neurotransmitter related to attention, mood, and movement Precursor to norepinephrine, epinephrine, and other neurotransmitters frontal lobe prefrontal cortex dopamine pathways basal ganglia *Lifetime blood Phe levels Mean standard deviations for lifetime blood Phe levels Anastasoaie V, et al. Mol Genet Metab. 8;9:17-. Image from DOPAMINE IS SYNTHESIZED FROM TYROSINE THAT IS CONVERTED TO L-DOPA Periphery (mostly liver) Blood Brain Barrier Brain DOPAMINE ACTIVITY IS REDUCED IN ADULTS WITH FDOPA uptake in first minutes after injection is reduced in % Phenylalanine PAH Tyrosine Tyrosine TH AADC L-dopa Dopamine Control (n = 7) (n = 7) BH BH BH = tetrahydrobiopterin PAH = phenylalanine hydroxylase TH = tyrosine hydroxylase AADC = aromatic amino acid decarboxylase Rate of FDOPA utilization is reduced in striatum of patients FDOPA = -[ 18 F]-L-dopamine s k 3 = rate of FDOPA utilization Landvogt C, et al. J Cereb Blood Flow Metab. 8;8(): s k3 CONTRIBUTIONS OF PREFRONTAL CORTEX TO MENTAL FUNCTION Executive Functions Cognitive abilities that control and regulate other abilities and behaviors Include Planning Attention Working memory Problem solving Impulse control Social Behaviors Emotional Responses MYELIN INSULATES AXONS WHICH INCREASES THE SPEED OF PROCESSING OF NERVE SIGNALS White matter contains nerve fibers surrounded by myelin Image from:

3 WHITE MATTER HYPOTHESIS KEY POINT #: TRADITIONAL THERAPIES NOT COMPLETELY PROTECTIVE Individuals with 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 Anderson P, et al. Devel Neuropsychol. 7;3():-8. ADHERENCE TO TREATMENT Nearly one in three children under the age of 1 have blood Phe above recommended target range Noncompliance increases as patients enter adolescence Children with on diet have significantly lower IQ than unaffected peers and sibling controls P =.1 P < Proportion Above Recommended Level (%) % 7% % Age Groups (in Years) 79% (n = 178) (n = 137) (n = 98) (n = 77) Wechsler Intelligence Scale n = 1 Peers* n = *Controls were age- and sex-matched patients (ages 7 19 years old) managed early and continuously with Phe-restricted diet Wechsler Intelligence Scale n = n = Siblings Adapted from Table of Walter JH, et al. Lancet. ;3: 7. Gassio R, et al. Pediatr Neurol. ;33:7 71. Koch R, et al. J Inherit Metab Dis. 198;7:8-9. NEUROCOGNITIVE DEFICITS IN TREATED EXECUTIVE FUNCTION DEFICITS Even with early and continuously treated, executive function gets worse with age and rising Phe level 1 Blood Phe not consistently in target range REDUCTIONS IN: Executive Functioning Memory Planning Attention Organization Mental Processing Speed Behavior and Mood Success in school and life Infants Working memory Behavioral inhibition Children (7 1) 3 Impulse control Attentional flexibility 1 Van Zutphen KH, et al. Clin Genet. 7;7: Diamond A, et al. Monogr Soc Res Child Dev. 1997;: Huijbregts SC, et al. NeuroSci Biobehav Rev. ;: Adults Attention Working memory Verbal Fluency Channon S, et al. Neuropsychology. ;18:13-. 3

4 % Children in Severe Range** EXECUTIVE FUNCTIONING DEFICITS * 1* Control Hydrocephalus (n = 8) (n = ) (n = ) *P <.1 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. ;8():31-. Stimulant Treatment for Attentional Dysfunction ATTENTION PROBLEMS %* Arnold GL, et al. J Inherit Metab Dis. ;7: Group 7% (n = 38) (n = 7) *P <. as compared to children with diabetes mellitus Diabetes Mellitus WORKING MEMORY STRATEGIC PLANNING Mean Span.*. n = n = * 3.3* 3 1 Verbal Object Spatial *P <. compared to control White DA, et al. J Int Neuropsychol Soc. ;8: Normative Data N = 1 (11 on dietary treatment) Visual Scanning Normative sample scores for all subtests set to 1 ± 3 (mean ± SD) *P <. compared to normative data VanZutphen KH, et al. Clin Genet. 7;7: Number Sequencing Trail Making Tests * Normative Data Letter Sequencing * Switching ORGANIZATION AND MEMORY IMPULSE CONTROL 1 n = 3 n = * Trial 1 Trial Trial 1 Trial Younger < 11 yo Older 11 yo California Verbal Learning Test *P <. compared to control Words Recalled Number of Errors 3 1 (n = 3) (n = ) Go *p <. compared to control * 3 No-Go White DA, et al. Neuropsychol. 1;1():1-9. Christ et al.,

5 RESPONSE MONITORING EXECUTIVE FUNCTIONING IN Reaction Time (msec) (P <.) Simple RT Go RT Post-Error RT 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 Araujo et al., in press (request reprint from D. White) MENTAL PROCESSING SPEED META-ANALYSIS SUMMARY Test Score (Mean + SE) Time to Rapid Retrival (FCC) Symbol Search Coding Processing Speed Test Contingency Naming Effect Size* Meta-analysis of 11 studies demonstrates deficits in multiple cognitive domains IQ Processing Speed Attention Inhibition Motor Control Cognitive Domain Working Memory large medium small *Dietary restrictions varied from strict () to moderate (11) to none (3) P <.1 for control group compared to group Anderson PJ, et al. Dev Neuropsychol. 7;3():-8. Range: Control 91 1; 1 18 * Hedge s g effect size with 9% confidence intervals Adapted from Figure 1 of Moyle JJ, et al. Neuropsychol Rev. 7;17(): SCHOOL PROBLEMS EMOTIONAL AND BEHAVIORAL OUTCOMES %* Total school problems Required special tutoring Repeated classes 39% 3 1 * P =.8 vs controls 1% % 19% % Students (n = ) Unaffected Peers (n = 1) School Problems DEPRESSION ANXIETY Gassio R, et al. Pediatr Neurol. ;33:7 71.

6 PSYCHIATRIC OUTCOMES IN ADULTS WITH % 37%* 1% 31%* % 1%* Depressed Mood Phobias Generalized Anxiety *P <. as compared to 18-year-old controls Psychiatric Disorder Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:3 3. Control (n = 181) (n = 3) % 1%* Hypochondriac Worries 1% %* Anxiety at Work Score on AAL Scale AGORAPHOBIA Blood Phe level and score on AAL Scale are significantly correlated Blood Phenylalanine Level (μmol/l) From the Mobility Inventory, measuring avoidance behavior when alone (AAL) Waisbren SE and Levy HL. J Inherit Metab Dis. 1991;1:7-7. r s =.3 KEY POINT #3: IMPROVEMENTS IN OUTCOME MAY BE POSSIBLE GREATER VARIETY OF FORMULAS AND FOODS GREATER UNDERSTANDING OF PSYCHOLOGICAL FACTORS SOCIAL SUPPORT POSITIVE ATTITUDES NEW THERAPIES Large Neutral Amino Acids (LNNA s) Available Tetrahydrobiopterin Therapy (BH) MANAGEABILITY Finkelson L, Bailey I, Waisbren SE. J Inherit Metab DIs. 1; : 1-1. Ammonia Lyase Enzyme Replacement Therapy Gene Therapy In research

7 ASSESSMENT OF OUTCOMES UNIFORM ASSESSMENT METHOD Identify deficits associated with Track changes over time (impact of changes in blood level or therapeutic strategies) Uniform set of tests Can be administered by non-psychologists DOMAIN Adaptive Behavior Executive Functioning Social/Emotional Functioning INFANTS (- YRS) ABAS-II CHILDREN (3-17 YRS) ABAS-II BRIEF BASC-II ADULTS (18+ YRS) ABAS-II BRIEF BDI-II & BDI-II ABBREVIATIONS & SOURCES ABAS-II : Adaptive Behavior Assessment System- Second Edition (Harrison, Oakland 3) FOR MORE INFORMATION AND SCORING susan.waisbren@childrens.harvard.edu BRIEF: Behavior Rating Inventory of Executive Function (Gioia, Isquith, Guy, Kenworthy, ) BASC-II: Behavior Assessment System for Children- Second Edition (Reynolds, Kamphus,) BAI: Beck Anxiety Inventory (Beck, Steer,1993) BDI-II: Beck Depression Inventory-Second Edition (Beck, Steer, Brown,199) THANK YOU! 7