1. LARGE NEUTRAL AMINO ACIDS PHENYLKETONURIA: Kathryn Moseley Assistant Professor of Pediatrics Department of Pediatrics, Genetics Division USC/Keck School of Medicine High Hopes NPKUA Conference Jan. 2010

2. Objectives Present past and current information on the use of LNAA and the rationale for treatment Describe current experiences and present clinical data from recent studies Summarize the most recent developments of this treatment and the cost/benefit of treatment

3. LNAA Christensen, HN, 1953 Andersen, AE, 1976 Pratt, OE, 1980 Berry, HK, 1990 Lou, HC, 1994 Pietz, J 1999 Pietz, J. Lutz, 2003 Koch, R 2003 Matalon, R, 2006 Matalon, R. 2007 Schindeler, S, 2007

4. LARGE NEUTRAL AMINO ACID THERAPY Valine Methonine Isoleucine Leucine Histidine Threonine Tryptophan Tyrosine Phenylalanine

5. Phenylketonuria Genetics: AR, 1: 12,000 Phenylalanine Hydroxylase def. The enzyme expressed in the liver not in the brain. Clinical presentation: MR, eczema, reduced skin pigmentation, behavioral abn. DX –NBS (Phe/Tyr ratio >1.5). Therapy: 1. Dietary therapy with phe restricted diet and special formula /LNAA Tx. (life long to prevent CNS insults) 2. BH4. Monitoring: ~ monthly Phe/Tyr monitoring, Prognosis: excellent if Tx initiated early and well controlled.

7. What causes the mental retardation???

8. Denmark 1985 Offered as an alternative for young adults age 15 years Comprised of LNAA with large doses of Tyrosine and Tryptophan Semi-free diet. Regular bread, unlimited potatoes, rice, pasta. Small portions of meat are also allowed (50gm). Not recommended for children or MPKU

9. LNAA The main difference between LNAA therapy and standard therapy; 80% of protein comes from natural food, 20% comes from medical product

10. LNAA in the United States PheBloc tablets NeoPhe tablets and powder Lanaflex powder PreKUnil tablets

11. Large neutral amino acid therapy and phenylketonuria: a promising approach to treatment Richard Koch, Kathryn Moselely, Shoji Yano, Marvin Nelson Jr, Rex A Moats 2003

16. Large Neutral Amino Acids and Late Diagnosed Phenylketonuria: the California Late Treatment Project K Moseley, S Yano, C Azen, R Boles, R Koch

17. INTRODUCTION It is estimated that there are approximately 200 individuals with PKU residing in state institutions and group homes that are untreated. Many of these individuals exhibit mental retardation, seizures, hypotonia, and neurological deterioration. However, based on our recent experience in treating these individuals, proper treatment can reduce negative behaviors, improve overall health and reduce costs related to care.

18. OBJECTIVES Assess health outcomes, behaviors and cost benefit analyses in known PKU adults residing in California who are being treated with LNAA therapy. Provide treatment intervention protocols and training manuals to facilitate community placement of those untreated with PKU To provide continuing education and resources to health professionals and care providers

19. METHODS 14 late diagnosed individuals with PKU were enrolled in this observational study to evaluate the use of LNAA therapy (11 completed) Informational data gathered included medical history, past and current medications, current diet, IQ, behavioral data and health care costs. Vineland Adaptive Behavior Scales was obtained before the intervention and after one year.

20. METHODS CONTINUED Care providers used intermediate monthly behavior check list to document behaviors. Phe/tyr obtained monthly. Dietary intervention: Subjects reduced natural protein intake to the RDI of 0.8g/kg. ◦ LNAA tablets implemented to supply enhanced amounts of tyrosine and tryptophan.

24. CHANGE IN BLOOD LEVELS No significant change in blood phe levels ◦ 36+/-591umol (p=0.84) Significant increase in blood tyrosine levels  19+/-28umol (p=0.05) Significant decrease in phe/tyr ratio  -9+/-13umol (p=0.05)

25. CHANGE IN BEHAVIOR VS CHANGE IN BLOOD LEVELS ◦ Correlation between increased tyrosine and improvement in daily living skills (p=0.027) ◦ Sig correlation between increased tyrosine and less aggression towards others (p=0.037) ◦ Decrease in phe/tyr ratio correlated with improvement in daily living skills (p=0.012)

26. PKU Late Tx Project Behavior Outcomes VINELAND - No sig improvement in the group as a whole ◦ Biggest change in DLS 7+/-13 (p=0.19) 1 pt declined, 2 had no change, 4 improved OBSERVED BEHAVIORS – No sig improvement in the group as a whole ◦ Trends toward reduced numbers of SIB and agression

27. Cost Benefit Analysis-Drugs Cost before PreKunil Cost after PreKUnil % change $3672$1810~50% Savings/yr ~22,344

28. Cost/Benefit Analysis Average cost living in Developmental Center $236,700 annually Average cost living in a Board and Care facility $122,280 Yearly savings$114,420

29. SUMMARY Improvement in daily living skills was significantly correlated with increased tyrosine and decreased phe/tyr ratio. The cost for psychotropic medications decreased approximately 50%. The cost of living in a board and care facility is less than half the cost of living in a development center.

30. SUMMARY CON’T The use of LNAA has been shown to improve blood amino acid profiles Increase tyrosine and tryptophan blood levels Decrease brain phe levels Well accepted by patients

31. ACKNOWLEDGEMENTS Frank D. Lanterman Regional Center ◦ Diane Campbell Anand, Director California Department of Human Subjects