Impact and Outcomes of Dietary Management of Phenylketonuria (PKU)

• PKU and its consequences

• Outcomes of dietary management– Dietary compliance issues

– Nutritional issues

• Cognitive and behavioral outcomes in diet-managed patients

• Conclusions

Overview

• 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 > 1200 µmol/L (20 mg/dL)

– Moderate PKU = 900–1200 µmol/L (15–20 mg/dL)

– Mild PKU = 600–900 µmol/L (10–15 mg/dL)

– Mild HPA = 300–600 µmol/L (5–10 mg/dL)

What is phenylketonuria?

1NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, 2000. Pediatrics. 2000;108:972–982.

2Scriver S. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management.October 16–18, 2000;19–23.

3Mitchell J, et al. Mol Genet Metab. 2005;86:S81–S85.

• 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 16–18, 2000. Pediatrics. 2000;108:972–982.

PKU is a relatively common metabolic disorder

PAH = phenylalanine hydroxylase BH4 = cofactor tetrahydrobiopterin

Simplified biochemistry of phenylalanine metabolism

Phenylalanine Tyrosine

PAH Enzyme

BH4

Cofactor

DEFECT

IVE

History of PKU Timeline

*http://www.pahdb.mcgill.ca

Scriver, CR. PKU: The Journey; not the Arrival…yet. In: Blau N.PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006.

1934: Oligophrenia phenylpyruvicadiscovered

1935: Oligophrenia phenylpyruvica renamed PKU

1950s: Low-Phe diet used to treat PKU

1953: Deficient PAH activity demonstrated in PKU

1960s: Newborn screening test for PKU developed

1980s: Human PAH gene mapped and cDNA cloned

2007: Kuvan™ approved for reducing Phe in PKU

1990s: Extensive PAH geneallelic heterogeneity documentedin online database*

1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s

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.1953;265(6790):812-813.2Armstrong MD, Tyler FH. J Clin Invest.1955;34(4):565-580.3Woolf LI, Griffiths R, Moncrieff A. Br Med J.1955;1(4905):57-64.

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 period”1

• 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.1954;43:64-77.2Dhondt J-L. Laboratory Diagnostics in Phenylketoneuria. In: Blau N.PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006.

3Guthrie R, Susi A. Pediatrics. 1963:32:318-343.

Evidence that the diet continues to work:

The 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. 1977;60:822-827.2Koch R, et al. J Inher Metab Dis. 1984;7:86-90.3Koch R, et al. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management. October 16–18, 2000;59-65.

When PKU is untreated or treated late, the following may occur Mental retardation or reduced IQ Seizures and tremors Difficulties in executive function Psychological and behavioral issues Social difficulties Impaired growth Irritability Eczema

Children

When PKU is poorly controlled, the following may occur Difficulties in executive function Psychological and behavioral

issues Social difficulties Neurological complications Irritability Eczema

Adults

Penrose LS. Lancet. 1946;June 29:949–953.Gassio R, et al. Pediatr Neurol. 2005;33:267–271.Welsh MC, et al. Child Dev. 1990;61:1697–1713.

PKU Patients Not on Diet

PKU Patients Not on Diet

Consequences of elevated blood phenylalanine levels vary by age

• PKU and its consequences

• Outcomes of dietary management– Dietary compliance issues

– Nutritional issues

• Cognitive and behavioral outcomes indiet-managed patients

• Conclusions

Overview

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 York;2001.

2NIH Consensus Development Panel. National Institutes of Health consensus development conference statement:Phenylketonuria: screening and management, October 16–18, 2000. Pediatrics. 2000;108:972–982.

Comparison of NIH consensus recommendedblood Phe for diet-managed PKU patients

with the general population

62 ± 181

120–3602

60 ± 131

120–9002

0

100

200

300

400

500

600

700

800

900

1000

Patients ≤ 12 years Patients ≥ 13 years

Blo

od P

he (

µm

ol/L) General population*

NIH recommended range for individuals with PKU

*Values for patients ≤ 12 and ≥ 13 years of age basedon a mean age of 8 and 16, respectively1

Conversion: 60 µmol/L = 1 mg/dL

Waisbren SE, et al. Mol Genet Metab. 2007;92:63–70.

• 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

Significant correlation exists betweenPhe and IQ in patients with PKU

Observation period

Range of blood Phe(µmol/L)

Lifetime IQ loss for each 100 µmol/L increase in blood Phe (IQ points)

Critical period(0–12 years old)

423–750 1.3–3.1

Lifetime(all ages)

394–666 1.9–4.1

• 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. 2002;360:55–57.

Dietary compliance in PKU: a serious issue

Age Dependence of Blood Phe Above Clinically Recommended Levels

28% 27%

50%

79%

0

10

20

30

40

50

60

70

80

90

Age Groups (in Years)

Pro

po

rtio

n o

f P

ati

en

tS

am

ple

s A

bo

ve

R

ec

om

me

nd

ed

Le

ve

l (%

)

0–4 5–9 10–14 15–19

(n = 178) (n = 137) (n = 98) (n = 77)

*Recommended target range for this study was < 726 µmol/L1Modan-Moses D, et al. J Inherit Metab Dis. 2007;300:202–208.2Modan-Moses D. E-mail communication. September 18, 2007

59% of adult PKU patients on diet had blood Phe above recommended target range*

59%

41%

Blood Phe above target(n = 10/17)

Blood Phe at or belowtarget (n = 7/17)

Even patients who claim to be on diet are not achieving blood Phe targets

• PKU and its consequences

• Outcomes of dietary management– Dietary compliance issues

– Nutritional issues

• Cognitive and behavioral outcomes indiet-managed patients

• Conclusions

Overview

Potential health consequencesassociated with PKU diets

1Pryzrembel H, et al. Eur J Pediatr. 2000;159(suppl 2):S129–S135. 2Giovannini M, et al. J Inherit Metab Dis. 2007;30:145–152.3Acosta PB, et al. J Am Diet Assoc. 2003;103:1167–1173.4Modan-Moses D, et al. J Inherit Metab Dis. 2007;30:202–208. 5Moyle JJ, et al. Neuropsychol Rev. 2007;17(2):91–101.6Robinson M, et al. J Pediatrics. 2000;136(4):545–547.

PKU Diet

Bone mass reduction1,4

Weight gain/obesity3 Growth retardation2

Neuropathy/ Myelopathy6

Neurocognitive deficits5

Nutritional Problems2

58%56%

28%

18%

0

10

20

30

40

50

60

70

1st 2nd 3rd 4th

Mean Plasma Prealbumin Quartile

Mea

n H

eig

ht

Per

cen

tile

(%

)

N = 38 children (ages 2–18, mean 8.9) with early and continuously treated PKU

Arnold GL, et al. J Pediatrics. 2002;141(2):243–246.

There is a strong correlation between plasma protein levels and growth

• 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 13–29%3

• 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. 2007;30(5):694–699.2McBurnie MA, et al. Ann Hum Biol. 1991;18:357–368.3Acosta PB, et al. J Pediatr Gastroenterol Nutr. 1998;276:287–291.

Nutrition and growth in PKU patients

Shäffer, et al. 1994.

Verkerk, et al. 1994.

Allen, et al. 1996.

Acosta, et al. 1998.

Arnold, et al. 2002.

Dobbelaere, et al. 2003.

Hoeksma, et al. 2005.

Huemer, et al. 2007.

Moderate growth retardation in first two years of life

Impaired growth

Impaired length and total body nitrogen

Normal growth

No general growth impairment

PKU patients shorter and lighter thanreference population

Significant correlation between headcircumference growth and natural proteinintake

Significant correlation betweenfat free mass and natural protein intake

0–6

0.5–10

N/A

0.5

2–18

0.7–7

0–3

0.2–15

82

112

37

35

38

20

174

34

Adapted from Table 3 of Huemer M, et al. J Inherit Metab Dis. 2007:30(5):694–699.

Summary of protein intake and growth studies in control and PKU populations

Group, Year N ResultsAge

(years)

• Typical PKU diets, with 75–90% 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 children”2

Increase of natural protein in diet may be of value to PKU patients

1McBurnie MA, et al. Ann Hum Biol. 1991;18:357–368.2Huemer M, et al. J Inherit Metab Dis. 2007;30(5):694–699. 3Hoeksma M, et al. J Inherit Metab Dis. 2005;28:845–854.

21

25

20

53

42

24

46

37

Acosta, et al. 1981

Taylor, et al. 1984

Reilly, et al. 1990

Bodley, et al. 1993

Fisberg, et al. 1999

van Bakel, et al. 2000

Artuch, et al. 2004

Acosta, et al. 2004

Plasma zinc copper levels significantly lower than in non-PKU controls

Hair zinc levels lower than siblings;lower plasma zinc in 42% of PKU patients

Plasma selenium (but not copper, zinc, or iron) levels significantly lower inPKU group compared to sibling controls

Serum ferritin concentrations lower thannormal in 28 subjects (53%)

Plasma zinc significantly lower in PKU children ≥ 7 years old compared to control

Plasma selenium significantly lower inin PKU compared to control group

Plasma selenium concentrations were not different from the general population

High transferrin receptor baseline values suggesting iron deficiency in 22% of PKUsubjects

Zinc, Copper

Zinc

Selenium,Iron, Zinc,

Copper

Iron

Zinc

Selenium

Selenium

Iron

Group, Year N Element Results

Acosta PB, et al. J Parenter Enteral Nutr. 1981;5(5):406–409. Fisberg RM, et al. Nutrition. 1999;15(6):449–452.Taylor CJ, et al. J Inherit Metab Dis. 1984;7(4):160–164. van Bakel MM, et al. Am J Clin Nutr. 2000;72(4):976–981.Reilly C, et al. Am J Clin Nutr. 1990;52:159–165. Artuch R, et al. Clin Biochem. 2004;37(3):198-203.Bodley JL, et al. Eur J Pediatr. 1993;152:140–143. Acosta PB, et al. Genet Med. 2004;6(2):96–101.

Trace element status in PKU

Mean age of patients: 25 ± 5.3 years, N = 31

Modan-Moses D, et al. J Inherit Metab Dis. 2007;30:202–208.

Decreases in bone mass can occurat early age in patients with PKU

Skeletal SiteBMD

Z-score

Lumbar (L1–L4)

-0.75 ± 1.04

Femoral Neck

-0.73* ± 0.66

Total Body -0.47* ± 0.72

*Significantly lower than expected in the normal population (P < 0.005)

BMD = Bone Mineral Density

39%

7%

0

10

20

30

40

50

Condition

Pe

rce

nta

ge

of

Pa

tie

nts

Osteopenia Osteoporosis

(n = 11) (n = 2)

• PKU and its consequences

• Outcomes of dietary management– Dietary compliance issues

– Nutritional issues

• Cognitive and behavioral outcomes in diet-managed patients

• Conclusions

Overview

Channon S, et al. Neuropsychology. 2005;19:679–686.Anderson PJ, et al. Develop Neuropsych. 2007;32(2):645–668.Moyle JJ, et al. Neuropsych Rev. 2007;17(2):91–101.

Inadequate blood Phe control associated with suboptimal outcomes

Subtle Changes• Executive function • Processing speed• Attention• Inhibition• Motor control

Diet-managed; Blood Phe in currently

recommended range

Observable Deficits• Verbal/IQ scales• Memory• Attention• Cognitive• Social • Behavior/Mood disorders

Diet-managed; Blood Phe not

consistently in rangePKU patients

Koch R, et al. J Inherit Metab Dis. 1984;7(2):86-90.

Paired comparisons on the Wechsler IntelligenceScale (IQ) for children with PKU and matched

sibling controls at 8 years of age

P = 0.001

0

20

40

60

80

100

120

140

Siblings PKU Patients

Wec

hsl

er I

nte

llig

ence

Sca

le

(n = 55) (n = 55)

Mean age in years was 10.9 for control (range 8–13) and 10.8 for PKU (range 8–13)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. 2004;27:115–125.

P < .001

210

183

0

50

100

150

200

250

Executive Function TestBattery 1

Mea

n T

est

Sco

res

Control PKU P < .0558

53

0

10

20

30

40

50

60

Executive Function TestBattery 2

Mea

n T

est

Sco

res

(n = 14) (n = 14) (n = 14) (n = 14)

Children on early and continuouslyPhe-restricted diet have reduced executive

function compared to unaffected peers

*Subjects in the PKU group (ages 6–17) 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 < .005

White DA, et al. J Int Neuropsychol Soc. 2002;8:1–11.

Children with PKU demonstrate developmental deficit in working

memory despite Phe-restricted diet8

2

3

4

5

6

7

5 6 7 8 9 10 11 12 13 14 15 16 17 18

Age (years)

Su

mm

ary

Mem

ory

Sco

re Control (n = 20)**

slope = 0.29†

slope = 0.08†

PKU (n = 20)*

NP = not provided *Hedge’s g effect size with 95% confidence intervals

Adapted from Figure 1 of Moyle JJ, et al. Neuropsychol Rev. 2007;17(2):91–101.

Control n: 107 221 NP 91 100 120PKU n: 113 218 NP 100 104 122

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

IQ ProcessingSpeed

Attention Inhibition MotorControl

WorkingMemory

Cognitive Domain

Eff

ect

Siz

e*

small

medium

large

Meta-analysis of PKU studies reveals cognitive deficits despite Phe-restricted diet

24%

50%*

19%

39%

5%12%

0

10

20

30

40

50

60

PKU Students (n = 26) Controls (n = 21)

School Problems

Stu

den

ts (

%)

Total school problems Required special tutoring Repeated classes

*P = 0.028 vs controls

Gassio R, et al. Pediatr Neurol. 2005;33:267–271.

Children with PKU present more school problems than unaffected peers

Arnold GL, et al. J Inherit Metab Dis. 2004;27:137–143.

7%

26%*

0

5

10

15

20

25

30

PKU Diabetes Mellitus

Group

Tre

atm

en

t W

ith

Sti

mu

lan

ts

for

Att

en

tio

na

l Dy

sfu

nc

tio

n (

%)

(n = 38) (n = 76)

Significant increase in treatment with stimulants for attentional

dysfunction in children with PKU

*P < 0.006 as compared to children with diabetes mellitus

*P < 0.05 as compared to 18-year old controls

Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:345–350.

Increase in psychiatric symptoms inadults with PKU on Phe-restricted diets

1%5%5%

16%19%

6%*

14%*14%*

31%*

37%*

0

5

10

15

20

25

30

35

40

DepressedMood

Phobias GeneralizedAnxiety

HypochondriacWorries

Anxiety at Work

Psychiatric Disorder

Pat

ien

ts R

epo

rtin

g S

ymp

tom

(%) Control (n = 181) PKU (n = 35)

• PKU and its consequences

• Outcomes of dietary management– Dietary compliance issues

– Nutritional issues

• Cognitive and behavioral outcomes in diet-managed patients

• Conclusions

Overview

• 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

Conclusions