Transcript EXPERIENCES WITH LARGE NEUTRAL AMINO ACIDS IN THE

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
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
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LNAA
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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
LARGE NEUTRAL AMINO ACID
THERAPY
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Valine
Methonine
Isoleucine
Leucine
Histidine
Threonine
Tryptophan
Tyrosine
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 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
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LNAA
The main difference between LNAA
therapy and standard therapy;
 80% of protein comes from natural food,
20% comes from medical product
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LNAA in the United States
PheBloc tablets
 NeoPhe tablets and powder
 Lanaflex powder
 PreKUnil tablets
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Large neutral amino acid therapy
and phenylketonuria: a promising
approach to treatment
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Richard Koch, Kathryn Moselely, Shoji
Yano, Marvin Nelson Jr, Rex A Moats
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2003
Large Neutral Amino Acids and
Late Diagnosed Phenylketonuria:
the California Late Treatment
Project
K Moseley, S Yano, C Azen, R Boles, R Koch
INTRODUCTION
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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.
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
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METHODS
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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.
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.
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◦ LNAA tablets implemented to supply
enhanced amounts of tyrosine and
tryptophan.
Phe
1400
1200
Mean + s.e.
1000
800
600
400
200
0
Pre
Post
LNAA Status
Tyrosine
100
Mean + s.e.
80
60
40
20
0
Pre
Post
LNAA Status
Phe/Tyrosine Ratio
35
30
Mean + s.e.
25
20
15
10
5
0
Pre
Post
LNAA Status
CHANGE IN BLOOD LEVELS
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No significant change in blood phe levels
◦ 36+/-591umol (p=0.84)
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Significant increase in blood tyrosine levels
 19+/-28umol (p=0.05)
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Significant decrease in phe/tyr ratio
 -9+/-13umol (p=0.05)
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)
PKU Late Tx Project
Behavior Outcomes
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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
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OBSERVED BEHAVIORS – No sig
improvement in the group as a whole
◦ Trends toward reduced numbers of SIB and
agression
Cost Benefit Analysis-Drugs
Cost before
PreKunil
Cost after
PreKUnil
% change
$3672
$1810
~50%
Savings/yr
~22,344
Cost/Benefit Analysis
Average cost living in Developmental
Center $236,700 annually
 Average cost living in a Board and Care
facility $122,280
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Yearly savings
$114,420
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.
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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
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ACKNOWLEDGEMENTS
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Frank D. Lanterman Regional Center
◦ Diane Campbell Anand, Director
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California Department of Human Subjects