LARGE NEUTRAL AMINO ACIDS LARGE NEUTRAL AMINO ACIDS PHENYLKETONURIA:PHENYLKETONURIA:

Kathryn MoseleyAssistant Professor of PediatricsDepartment of Pediatrics, Genetics DivisionUSC/Keck School of Medicine

High Hopes NPKUA Conference Jan. 2010

ObjectivesObjectivesPresent 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

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

LARGE NEUTRAL AMINO ACID LARGE NEUTRAL AMINO ACID THERAPYTHERAPYValineMethonineIsoleucineLeucineHistidineThreonineTryptophanTyrosine Phenylalanine

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.

What causes the mental retardation???

Denmark 1985Denmark 1985Offered as an alternative for young

adults age 15 yearsComprised of LNAA with large

doses of Tyrosine and TryptophanSemi-free diet. Regular bread,

unlimited potatoes, rice, pasta. Small portions of meat are also allowed (50gm).

Not recommended for children or MPKU

LNAALNAAThe main difference between

LNAA therapy and standard therapy;

80% of protein comes from natural food, 20% comes from medical product

LNAA in the United StatesLNAA in the United StatesPheBloc tabletsNeoPhe tablets and powderLanaflex powderPreKUnil tablets

Large neutral amino acid Large neutral amino acid therapy and therapy and phenylketonuria: a phenylketonuria: a promising approach to promising approach to treatmenttreatment

Richard Koch, Kathryn Moselely, Shoji Yano, Marvin Nelson Jr, Rex A Moats

2003

Large Neutral Amino Large Neutral Amino Acids and Late Diagnosed Acids and Late Diagnosed Phenylketonuria: the Phenylketonuria: the California Late Treatment California Late Treatment ProjectProject

K Moseley, S Yano, C Azen, R Boles, R Koch

INTRODUCTIONINTRODUCTIONIt 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.

OBJECTIVESOBJECTIVESAssess 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

METHODSMETHODS14 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.

METHODS CONTINUEDMETHODS CONTINUEDCare 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.

Phe

LNAA Status

Pre Post

Mea

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0

200

400

600

800

1000

1200

1400

Tyrosine

LNAA Status

Pre Post

Mea

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100

Phe/Tyrosine Ratio

LNAA Status

Pre Post

Mea

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10

15

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25

30

35

CHANGE IN BLOOD CHANGE IN BLOOD LEVELSLEVELS

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)

CHANGE IN BEHAVIOR VS CHANGE IN BEHAVIOR VS CHANGE IN BLOOD CHANGE IN BLOOD LEVELSLEVELS

◦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)

PKU Late Tx ProjectPKU Late Tx ProjectBehavior Outcomes 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

Cost Benefit Analysis-Cost Benefit Analysis-DrugsDrugsCost before PreKunil

Cost after

PreKUnil

% change

$3672 $1810 ~50%

Savings/yr

~22,344

Cost/Benefit AnalysisCost/Benefit AnalysisAverage cost living in

Developmental Center $236,700 annually

Average cost living in a Board and Care facility $122,280

Yearly savings $114,420

SUMMARYSUMMARYImprovement 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.

SUMMARY CON’TThe 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

ACKNOWLEDGEMENTSACKNOWLEDGEMENTSFrank D. Lanterman Regional

Center◦Diane Campbell Anand, Director

California Department of Human Subjects