Impact and Outcomes of Dietary Management of Phenylketonuria (PKU)

1
Impact and Outcomes of Dietary Management of
Phenylketonuria (PKU)
2
Overview

• PKU and its consequences
• Outcomes of dietary management
• Dietary compliance issues
• Nutritional issues
• Cognitive and behavioral outcomes in
  diet-managed patients
• Conclusions

3
What is phenylketonuria?

• Persistent elevated blood phenylalanine (Phe)
  caused by a deficiency of the phenylalanine
  hydroxylase (PAH) enzyme1
• The term PKU is reserved for primary dysfunction
  of the PAH enzyme due to mutations in the PAH
  gene2
• The degree of impairment varies greatly among
  patients resulting in a broad continuum of
  phenotypes1
• Categories based on blood Phe at diagnosis3
• Classic PKU gt 1200 µmol/L (20 mg/dL)
• Moderate PKU 9001200 µmol/L (1520 mg/dL)
• Mild PKU 600900 µmol/L (1015 mg/dL)
• Mild HPA 300600 µmol/L (510 mg/dL)

1NIH Consensus Development Panel. National
Institutes of Health consensus development
conference statement Phenylketonuria screening
and management, October 1618, 2000. Pediatrics.
2000108972982. 2Scriver S. Consensus
Development Conference on Phenylketonuria (PKU)
Screening and Management.October 1618,
20001923. 3Mitchell J, et al. Mol Genet Metab.
200586S81S85.
4
PKU is a relatively common metabolic disorder

• Most frequent disorder of amino acid metabolism
• Incidence of PKU in the USA1
• 1 per 13,500 to 1 per 19,000 newborns
• Higher in Whites and Native Americans
• Lower in Blacks, Hispanics, and Asians

1NIH Consensus Development Panel. National
Institutes of Health consensus development
conference statement Phenylketonuria screening
and management, October 1618, 2000. Pediatrics.
2000108972982.
5
Simplified biochemistry of phenylalanine
metabolism
PAH Enzyme
DEFECTIVE
Phenylalanine
Tyrosine
BH4 Cofactor
PAH phenylalanine hydroxylase BH4 cofactor
tetrahydrobiopterin
6
History of PKU Timeline
http//www.pahdb.mcgill.ca Scriver, CR. PKU The
Journey not the Arrivalyet. In Blau N.PKU and
BH4Advances in Phenylketonuria and
Tetrahydrobiopterin. 1st ed. SPS
Publications2006.
7
Earliest reports of dietary treatment

• Bickel, Gerrard, and Hickmans, 19531
• Treated 2-year old PKU child with low-Phe diet
• Cognitive and behavioral deficits improved
• Armstrong and Tyler, 19542
• Treated five PKU children (ages 7 months to 4½
  years)
• The 4½ year olds showed some behavioral and
  physical improvement
• In the younger patients, the diet led to reduced
  seizures and normal development
• Woolf, Griffiths, and Moncrieff, 19553
• Treated three PKU children (ages 2 to 5) with low
  Phe diet
• All three showed marked intellectual improvement

1Bickel H, Gerrard J, Hickmans EM.
Lancet.1953265(6790)812-813. 2Armstrong MD,
Tyler FH. J Clin Invest.195534(4)565-580. 3Woolf
LI, Griffiths R, Moncrieff A. Br Med
J.19551(4905)57-64.
8
Success of the diet followed newborn screening

• It is reasonable to presume that the best
  results of dietetic treatment of PKU will be
  obtained if treatment is started in infancy and
  particularly in the neonatal period1
• The first method of testing for PKU was the
  ferric chloride test2
• Detected ketones in urine
• Limited use in newborns because appearance of
  ketones can be delayed
• The Guthrie test3
• Developed by Robert Guthrie in the late 1950s
• Bacteria inhibition assay worked on newborn blood
• Simplicity (dried blood spot on filter paper) was
  ideal for mass screening

1Bickel H, et al. Acta Pediatr.19544364-77. 2Dh
ondt J-L. Laboratory Diagnostics in
Phenylketoneuria. In Blau N.PKU and
BH4Advances in Phenylketonuria and
Tetrahydrobiopterin. 1st ed. SPS
Publications2006. 3Guthrie R, Susi A.
Pediatrics. 196332318-343.
9
Evidence that the diet continues to workThe US
Collaborative Study

• From 1967 to 1999, this longitudinal study
  produced several milestone results
• At age 4 IQ was within the range of the general
  population1
• At age 6 IQ was significantly related to the age
  ofstarting dietary treatment2
• At age 8 Subjects on-diet performed better on IQ
  and school achievement tests than subjects
  off-diet2
• As adults Subjects on-diet had fewer medical and
  mental disorders and higher cognitive test
  scores than subjects off-diet3
• As a whole, these findings have led to the
  philosophy of a Diet for Life at most clinics
  in the United States3

1Dobson JC, et al. Pediatrics. 197760822-827. 2K
och R, et al. J Inher Metab Dis.
1984786-90. 3Koch R, et al. Consensus
Development Conference on Phenylketonuria (PKU)
Screening and Management. October 1618,
200059-65.
10
Consequences of elevated blood phenylalanine
levels vary by age
Penrose LS. Lancet. 1946June 29949953. Gassio
R, et al. Pediatr Neurol. 200533267271. Welsh
MC, et al. Child Dev. 19906116971713.
11
Overview

• PKU and its consequences
• Outcomes of dietary management
• Dietary compliance issues
• Nutritional issues
• Cognitive and behavioral outcomes indiet-managed
  patients
• Conclusions

12
Comparison of NIH consensus recommendedblood Phe
for diet-managed PKU patientswith the general
population
1Scriver CR and Kaufman S. Hyperphenylalaninemia
Phenylalanine Hydroxylase Deficiency. In Scriver
CR, Beaudet AL, Valle D and Sly WS. The Metabolic
and Molecular Bases of Inherited Disease.
McGraw-Hill, New York2001. 2NIH Consensus
Development Panel. National Institutes of Health
consensus development conference
statement Phenylketonuria screening and
management, October 1618, 2000. Pediatrics.
2000108972982.
13
Significant correlation exists betweenPhe and IQ
in patients with PKU

• Meta-analysis of published PKU trials with Phe,
  neurological and dietary outcome measures
• Results Correlations between blood Phe and IQ
• The statistically significant correlations
  suggest that blood Phe can be used as a surrogate
  marker for IQ

Waisbren SE, et al. Mol Genet Metab.
2007926370.
14
Dietary compliance in PKU a serious issue

• Nearly one in three PKU children under the age of
  10 have blood Phe above recommended target range
• Noncompliance increases as patients enter
  adolescence

Adapted from Table 2 of Walter JH, et al. Lancet.
20023605557.
15
Even patients who claim to be on diet are not
achieving blood Phe targets
59 of adult PKU patients on diet had blood Phe
above recommended target range
Recommended target range for this study was lt
726 µmol/L 1Modan-Moses D, et al. J Inherit
Metab Dis. 2007300202208.2Modan-Moses D.
E-mail communication. September 18, 2007
16
Overview

• PKU and its consequences
• Outcomes of dietary management
• Dietary compliance issues
• Nutritional issues
• Cognitive and behavioral outcomes indiet-managed
  patients
• Conclusions

17
Potential health consequencesassociated with PKU
diets
1Pryzrembel H, et al. Eur J Pediatr.
2000159(suppl 2)S129S135. 2Giovannini M,
et al. J Inherit Metab Dis. 200730145152. 3Aco
sta PB, et al. J Am Diet Assoc.
200310311671173. 4Modan-Moses D, et al. J
Inherit Metab Dis. 200730202208. 5Moyle JJ,
et al. Neuropsychol Rev. 200717(2)91101. 6Robin
son M, et al. J Pediatrics. 2000136(4)545547.
18
There is a strong correlation between plasma
protein levels and growth
N 38 children (ages 218, mean 8.9) with early
and continuously treated PKU Arnold GL, et al. J
Pediatrics. 2002141(2)243246.
19
Nutrition and growth in PKU patients

• Growth retardation has been observed in PKU
  patients on diet meeting age-specific RDAs for
  protein1
• In studies in which height is not different, PKU
  patients often have significantly higher weight
  than controls2
• In response, it has been recommended that protein
  intake for PKU patients should exceed RDIs by
  13293
• Following a diet regimen with protein intake
  exceeding RDAs, most studies of growth and
  protein intake show no impairment1

1Huemer M, et al. J Inherit Metab Dis.
200730(5)694699. 2McBurnie MA, et al. Ann Hum
Biol. 199118357368. 3Acosta PB, et al. J
Pediatr Gastroenterol Nutr. 1998276287291.
20
Summary of protein intake and growth studies in
control and PKU populations
Adapted from Table 3 of Huemer M, et al. J
Inherit Metab Dis. 200730(5)694699.
21
Increase of natural protein in diet may be of
value to PKU patients

• Typical PKU diets, with 7590 of total protein
  intake from synthetic amino acids in medical
  foods, shift away from natural protein sources1
• Natural protein intake, rather than total
  protein, is most closely correlated with fat-free
  muscle mass2
• There is significant correlation between natural
  protein (not synthetic protein) and head
  circumference growth in the first three years of
  life3
• An improvement of protein quality may be the key
  to normal growth and body composition in PKU
  children2

1McBurnie MA, et al. Ann Hum Biol.
199118357368. 2Huemer M, et al. J Inherit
Metab Dis. 200730(5)694699. 3Hoeksma M, et
al. J Inherit Metab Dis. 200528845854.
22
Trace element status in PKU
Acosta PB, et al. J Parenter Enteral Nutr.
19815(5)406409. Fisberg RM, et al. Nutrition.
199915(6)449452. Taylor CJ, et al. J Inherit
Metab Dis. 19847(4)160164. van Bakel MM, et
al. Am J Clin Nutr. 200072(4)976981. Reilly C,
et al. Am J Clin Nutr. 199052159165. Artuch
R, et al. Clin Biochem. 200437(3)198-203. Bodley
JL, et al. Eur J Pediatr. 1993152140143. Acost
a PB, et al. Genet Med. 20046(2)96101.
23
Decreases in bone mass can occurat early age in
patients with PKU
Significantly lower than expected in the normal
population (P lt 0.005) BMD Bone Mineral Density
Mean age of patients 25 5.3 years, N
31 Modan-Moses D, et al. J Inherit Metab Dis.
200730202208.
24
Overview

• PKU and its consequences
• Outcomes of dietary management
• Dietary compliance issues
• Nutritional issues
• Cognitive and behavioral outcomes in
  diet-managed patients
• Conclusions

25
Inadequate blood Phe control associated with
suboptimal outcomes
Channon S, et al. Neuropsychology.
200519679686. Anderson PJ, et al. Develop
Neuropsych. 200732(2)645668. Moyle JJ, et al.
Neuropsych Rev. 200717(2)91101.
26
Paired comparisons on the Wechsler
IntelligenceScale (IQ) for children with PKU and
matched sibling controls at 8 years of age
Koch R, et al. J Inherit Metab Dis.
19847(2)86-90.
27
Children on early and continuouslyPhe-restricted
diet have reduced executive function compared to
unaffected peers
Mean age in years was 10.9 for control (range
813) and 10.8 for PKU (range 813) Phe measured
on day of testing and calculated from age 0 to 4
years using medical records Adapted from Table 1
of Leuzzi V, et al. J Inherit Metab Dis.
200427115125.
28
Children with PKU demonstrate developmental
deficit in workingmemory despite Phe-restricted
diet
Subjects in the PKU group (ages 617) were on a
diet control program to limit Phe
intake Control subjects matched for age, sex
and years of education Test for separate slopes
t(15) -3.05, P lt .005 White DA, et al. J Int
Neuropsychol Soc. 20028111.
29
Meta-analysis of PKU studies reveals cognitive
deficits despite Phe-restricted diet
Control n 107 221
NP 91 100
120PKU n 113
218 NP 100
104 122
NP not provided Hedges g effect size with
95 confidence intervals Adapted from Figure 1
of Moyle JJ, et al. Neuropsychol Rev.
200717(2)91101.
30
Children with PKU present more school problems
than unaffected peers
P 0.028 vs controls Gassio R, et al. Pediatr
Neurol. 200533267271.
31
Significant increase in treatment with
stimulants for attentional dysfunction in
children with PKU
P lt 0.006 as compared to children with diabetes
mellitus
Arnold GL, et al. J Inherit Metab Dis.
200427137143.
32
Increase in psychiatric symptoms inadults with
PKU on Phe-restricted diets

P lt 0.05 as compared to 18-year old
controls Adapted from Table 3 of Pietz J, et al.
Pediatrics. 199799345350.
33
Overview

• PKU and its consequences
• Outcomes of dietary management
• Dietary compliance issues
• Nutritional issues
• Cognitive and behavioral outcomes in
  diet-managed patients
• Conclusions

34
Conclusions

• The combination of newborn screening and
  Phe-restricted diets has nearly eliminated the
  severe neurocognitive and motor deficits that
  occur with untreated PKU
• In some studies, difficulty in following the diet
  and maintaining adequate Phe control resulted in
  poor outcomes
• Nutritional deficiencies have been associated
  with low-Phe diets, suggesting that increasing
  natural sources of protein may be of value
• Despite the overall success of the PKU diet,
  adherence into adulthood continues to be a problem