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Impact and Outcomes of Dietary Management of Phenylketonuria (PKU)

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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 > 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? 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) 1. NIH Consensus Statement 2000: P972 col 2 ¶1 2. Scriver, 2000: P19 ¶3 1NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, 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. 1. NIH Consensus Statement 2000: P973 col 2 ¶3 3. Mitchell, 2005: pS82 col 1 ¶2 1NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, Pediatrics. 2000;108:972–982. 2Scriver S. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management. October 16–18, 2000;19–23. 3Mitchell J, Wilcken B, Alexander I, et al. Tetrahydrobiopterin responsive phenylketonuria: The New South Wales experience. Mol Genet Metab. 2005;86:S81–S85.

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 PKU is a relatively common metabolic disorder USA incidence is based on 1994 Newborn Screening Report of the Council of Regional Networks for Genetic Services (CORN)1 Possible reasons for wide range of incidences2 Different quantification methods used Different ages at testing Differences in diagnostic cut-off value Ethnic composition of population The highest incidences are in Ireland and Northern and Eastern Europe and the lowest incidences are in Japan (1 per 115,083) and in Finland (1 per 71,111)2 Composite estimate of the incidence of non-PKU hyperphenylalaninemia in the USA is 1 per 48,000 newborns1 NIH Consensus Statement 2000: P973 col 1 last sentence 2. Dhondt, 2006: P169 ¶3 2. Dhondt, 2006: P167 ¶3 1NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, Pediatrics. 2000;108:972–982. 2. Dhondt, 2006: P169 ¶3 2. Dhondt, 2006: P169 ¶3 2. Dhondt, 2006: P169 ¶4 1. NIH Consensus Statement 2000: P973 col 2 ¶1 1NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, Pediatrics. 2000;108:972–982. 2Dhondt JL. Laboratory Diagnosis of Phenylketonuria. In: Blau N, ed. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006:161–179.

5 Simplified biochemistry of phenylalanine metabolism
PAH Enzyme DEFECTIVE Phenylalanine Tyrosine BH4 Cofactor Simplified biochemistry of phenylalanine metabolism The enzyme phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of L-phenylalanine (Phe) to L-tyrosine (Tyr) in the presence of the natural cofactor tetrahydrobiopterin (BH4) and oxygen (O2)1,2 PAH activity is the rate-limiting step in the catabolism of Phe1,2 PAH converts approximately 75% of the Phe supplied by the diet and protein catabolism2 Defects in PAH enzyme caused by mutations in the PAH gene lead to reduced or absent activity of the enzyme, which in turn leads to the increase in blood Phe characteristic of hyperphenylalaninemia2 1. Scriver, 2001: P1673 col 2 ¶2 2. Pey, 2006: P67 ¶1 PAH = phenylalanine hydroxylase BH4 = cofactor tetrahydrobiopterin 1. Scriver, 2001: P1672 col 2 ¶1 2. Pey, 2006: P67 ¶1 2. Pey, 2006: P67 ¶1 2. Pey, 2006: P67 ¶1 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. 2Pey AL and Martinez A. The Phenylalanine Hydroxylase System. In: Blau N. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006.

6 History of PKU Timeline
1934: Oligophrenia phenylpyruvica discovered 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 gene allelic heterogeneity documented in online database* 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s History of PKU Timeline In 1934, Asbjørn Følling published his observations on the excretion of phenylpyruvic acid in the urine as an anomaly of metabolism related to mental retardation. He suggested the condition be called “Oligophrenia phenylpyruvica”1 A year after it was discovered by Følling, Penrose renamed the condition PKU2 In the 1950s, Jervis and others demonstrated that PKU patients were deficient in hepatic phenylalanine hydroxylase (PAH) activity2 Also in the early 1950s, Bickel, et al, Woolf, et al, and Armstrong and Tyler showed that blood Phe could be reduced by treatment with a low-Phe diet2 In the late 1950s and early 1960s, Robert Guthrie developed a method for detecting PKU that could be used as a newborn screening test2 In the 1980s, the human PAH gene was mapped and its cDNA cloned by Woo, et al2 During the 1990s, mutation analysis of the PAH gene demonstrated its extensive allelic heterogeneity and an online database of mutations was started2 In 2007, Kuvan™ was approved for reducing blood Phe in PKU 1. Følling, 2006: P51 ¶1 2. Scriver, 2006: P23 ¶1 *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. 2. Scriver, 2006: P23 ¶2 2. Scriver, 2006: P23 ¶2 2. Scriver, 2006: P23 ¶2 2. Scriver, 2006: P24 ¶1 2. Scriver, 2006: P24 ¶1 1Følling I. The discovery of Phenylketonuria by Asbjørn Følling. In: Blau N. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006. 2Scriver, CR. PKU: The Journey; not the Arrival…yet. In: Blau N. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006.

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 Earliest reports of dietary treatment Bickel, Gerrard, and Hickmans, 19531 Treated a 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 1. Bickel, 1953: P812 col1 ¶1; col2 ¶1 2. Armstrong, 1954: P566 col1 ¶2; P578 summary 1Bickel H, Gerrard J, Hickmans EM. Lancet.1953;265(6790): 2Armstrong MD, Tyler FH. J Clin Invest.1955;34(4): 3Woolf LI, Griffiths R, Moncrieff A. Br Med J.1955;1(4905):57-64. 3. Woolf, 1955: P57 col1 ¶3 1Bickel H, Gerrard J, Hickmans EM. Influence of phenylalanine intake on phenylketonuria. Lancet. 1953;265(6790): 2Armstrong MD, Tyler FH. Studies on phenylketonuria. Restricted phenylalanine intake in phenylketonuria. J Clin Invest. 1955;34(4): 3Woolf LI, Griffiths R, Moncrieff A. Treatment of phenylketonuria with a diet low in phenylalanine. Br Med J. 1955;1(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 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 Success of the diet followed newborn screening The first bullet is a prescient quote from the Bickel et al paper in 1954 reporting the first patient with PKU treated with a low Phe diet2 The first method of testing for PKU was the ferric chloride test2 Detected ketones in urine Limited use in newborns because of the frequent delay in the appearance of ketones in the urine of newborns The Guthrie test2 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 2. Dhondt, 2006: P161 ¶2 2. Dhondt, 2006: P161 ¶2 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: 2. Dhondt, 2006: P161 ¶3 1Bickel H, Gerrard J, Hickmans EM. The influence of phenylalanine intake on the chemistry and behaviour of a phenyl-ketonuric child. Acta Pediatr. 1954;43:64-77. 2Dhondt J-L. Laboratory Diagnostics in Phenylketonuria. In: Blau N. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications;2006. 3Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963:32:

9 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 of starting 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 Evidence that the diet continues to work: The US Collaborative Study The US Collaborative Study was a longitudinal study begun in 1967 to assess the effects of Phe-restricted diets on the physical, cognitive, and psychosocial development of children with PKU1 The study started with a group of 216 four year olds with PKU and 228 controls (9 siblings with untreated PKU, 219 nonaffected siblings)1 Over the next 17 years, the study produced several milestone results At 4 years of age, IQ (mean 93) was within the range of the general population (100)2 IQ at 6 years of age was significantly related to the age of initiation of treatment, emphasizing the need to start the diet early3 Subjects remaining on-diet at 8 years of age performed better on IQ and school achievement tests than subjects who resumed a normal diet after age 63 A 15 year follow-up of subjects in the study found a lower frequency of medical and mental disorders and higher cognitive test scores among subjects who discontinued diet4 Taken as a whole, these findings have led to the philosophy of a “Diet for Life” at most clinics in the United States4 1. Williamson, 1977: P815 col 1 ¶1 1. Williamson, 1977: P818 col 2 ¶5 1Dobson JC, et al. Pediatrics. 1977;60: 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. 2. Dobson, 1977: P825 col 2 3. Koch, 1984: P86 col 1 ¶2 3. Koch, 1984: P86 col 1 ¶2 4. Koch, 2000: P65 ¶3 4. Koch, 2000: P59 ¶2 1Williamson M, Dobson JC, Koch R. Collaborative study of children treated for phenylketonuria: Study design. Pediatrics. 1977;60: 2Dobson JC, Williamson ML, Azen C, Koch R. Intellectual assessment of 111 four-year-old children with phenylketonuria. Pediatrics. 1977;60: 3Koch R, Azen C, Friedman EG, Williamson ML. Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inher Metab Dis. 1984;7:86-90. 4Koch R, Burton B, Coldwell J, et al. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management. October 16–18, 2000;59-65.

10 Consequences of elevated blood phenylalanine levels vary by age
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 PKU Patients Not on Diet When PKU is poorly controlled, the following may occur Difficulties in executive function Psychological and behavioral issues Social difficulties Neurological complications Irritability Eczema Adults Consequences of elevated blood phenylalanine levels vary by age Wording from Penrose’s historic presentation to University College, London in 1946 regarding individuals with PKU1 Every case shows intellectual defect Patients may display hyperkinetic mannerisms, epileptiform seizures, dermatitis, excessive sweating, kyphosis, and spasticity1 In adolescent and adult patients with poorly controlled or discontinued diet, there is risk of cognitive and emotional problems, behavioral disorders and neurologic complications such as epilepsy, ataxia, tremor, and spasticity2 Executive function refers to a group of cognitive functions that are influenced by dopaminergic projections to the prefrontal cortex, such as working memory, inhibitory control, conceptual reasoning, planning ability, selective sustained attention, mental flexibility and organizational strategy4 1. Penrose, 1946: P194 ¶1 1. Penrose, 1946: P195 ¶1 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. 2. Gassio, 2005: P267 col 2 ¶1 4. Anderson, 2007: P647 ¶2, P648 ¶1 1Penrose LS. Phenylketonuria—a problem in eugenics Lancet. 1946;June 29:949–953. 2Gassio R, Fusté E, López-Sale A, et al. school performance in Early and continuously treated phenylketonuria. Pediatr Neurol. 2005;33:267–271. 3Welsh MC, Pennington BF, Ozonoff S, Rouse B and McCabe ERB. Neuropsychology of early-treated phenylketonuria: specific executive function deficits. Child Dev. 1990;61:1697–1713. 4Anderson PJ, Wood SJ, Francis DE et al. Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Develop Neuropsych. 2007;32(2):645–668.

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

12 Comparison of NIH consensus recommended blood Phe for diet-managed PKU patients with the general population 62 ± 181 120–3602 60 ± 131 120–9002 General population* NIH recommended range for individuals with PKU *Values for patients ≤ 12 and ≥ 13 years of age based on a mean age of 8 and 16, respectively1 Conversion: 60 µmol/L = 1 mg/dL Comparison of NIH consensus recommended blood Phe for diet-managed PKU patients with the general population Average blood Phe levels for individuals in the general population are1 Adults: 58 ± 15 μmol/L Adolescents (mean age 16 years): 60 ± 13 μmol/L Children (mean age 8 years): 62 ± 18 μmol/L There is no national or international agreement on optimal blood Phe levels for individuals with PKU2 Britain: blood Phe in infants and children should be 120–360 μmol/L France and Germany: blood Phe levels should be maintained at 40–240 μmol/L until age 10 and 40–900 μmol/L between ages 10 and 15, and 40–1200 μmol/L after age 15 In the NIH consensus statement, recommended blood Phe levels for classic PKU are2 120–360 μmol/L for individuals ≤ 12 years old 120–900 μmol/L for individuals ≥ 13 years old Based on the lack of information on Phe levels and brain function after 12 years of age, even lower Phe levels (120–600 μmol/L) are strongly encouraged during this period2 Discussion Point: Given the difference between the average Phe level in the general population and recommended Phe ranges, should PKU patients be encouraged to reduce blood Phe levels even lower than the recommended lower limit? 1. Scriver 2001: P1670 col2 ¶1 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, Pediatrics. 2000;108:972–982. 2. NIH Consensus Statement, 2000: P975 col 1 ¶3 NIH Consensus Statement, 2000: P975 col 1 ¶3 2. NIH Consensus Statement, 2000: P977 col 1 ¶2 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, Pediatrics. 2000;108:972–982.

13 Significant correlation exists between Phe 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 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 Significant correlation exists between Phe and IQ in patients with PKU This study used meta-analysis to assess the relationship between blood Phe levels and IQ1 During the critical period, a 100 μmol/L increase in Phe predicts an average 1.3–3.1 point reduction in IQ for a Phe range of 423–750 μmol/L1 In addition, a 100 μmol/L increase in lifetime Phe predicts an average 1.9–4.1 point reduction in IQ over a Phe range of 394–666 μmol/L1 Results apply to both early-treated patients with classic PKU and all early-treated patients1 Background Results based on studies published between January 1980 and February 2004 that assessed Phe levels and neurological outcomes in PKU patients1 “Critical period” is the time considered essential for structural development of the brain (varied from 0–6 to 0–12 years of age)1 “Lifetime” Phe defined as the mean of 6- or 12-month median assessments for each patient from birth to the last measurement in each study1 A total of 3,361 patients were included and most had a diagnosis of classic PKU (34%) or unspecified PKU (46%)1 Results were obtained by combining the correlation between Phe level and IQ across studies. Statistical significance was assumed where 95% confidence intervals did not cross zero1 1. Waisbren, 2007: P64 col 2 ¶4 1. Waisbren, 2007: P65 col 2 ¶2 1. Waisbren, 2007: P66 col 2 ¶1 Waisbren SE, et al. Mol Genet Metab. 2007;92:63–70. 1. Waisbren, 2007: P66 col 1 ¶2 1. Waisbren, 2007: P64 col 1 ¶3 1. Waisbren, 2007: P64 col 2 ¶5 1. Waisbren, 2007: P64 col 2 ¶5 1. Waisbren, 2007: P65 col 1 ¶2 1. Waisbren, 2007: P65 col 1 ¶1 1Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007;92:63–70.

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 0–4 5–9 10–14 15–19 (n = 178) (n = 137) (n = 98) (n = 77) Dietary compliance in PKU: a serious issue In this retrospective study of blood Phe levels collected over a 7-year period at 4 regional PKU clinics, the goal was to determine the extent to which recommended Phe level targets were being met1 For patients in the 0–4 and 5–9 year age-groups, about 25% of the samples had Phe levels above the maximum recommended limit1 That proportion increased to 50% for 10–14 year olds and over 75% for 15–19 year olds1 In the same study, compliance (defined as adherence to recommended sampling frequency) decreased from 81% and 86% in 0–4 and 5–9 year olds, respectively, to 71% in 10–15 year olds, and 46% in 15–19 year olds1 Background Data were obtained from all individuals with PKU < 20 years old reviewed at one of four regional PKU clinics (3 in the UK, 1 in Australia)1 Each center had its own age-defined recommendations for sampling frequency and maximum blood Phe level (similar to those published by the National Society for PKU, UK)1 Data were available from 330 patients, and 160 patients crossed age-groups during the study, thus contributing to more than one set of data1 Results based on blood Phe levels and number of clinic visits for each patient from 1994–2000 were compared within each age band with a non-parametric analysis of variance1 1. Walter, 2002: P55 col 2 ¶1,¶2,¶3 1. Walter, 2002: P56 col 1 ¶2 1. Walter, 2002: P56 col 1 ¶2 Adapted from Table 2 of Walter JH, et al. Lancet. 2002;360:55–57. 1. Walter, 2002: P56 col 1 ¶2 1. Walter, 2002: P55 col 2 ¶2 1. Walter, 2002: P55 col 2 ¶2 1. Walter, 2002: P56 col 1 ¶1 1. Walter, 2002: P55 col 2 ¶3 1Walter JH, White FJ, Hall SK, et al. How practical are recommendations for dietary control in phenylketonuria? Lancet. 2002;360:55–57.

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* Even patients who claim to be on diet are not achieving blood Phe targets One component of this study on bone mineral density and PKU compared self-reported adherence and actual blood Phe levels1 Although 17 patients reported diet adherence, only 7 (41%) in the adherent group met the recommended blood Phe of < 726 μmol/L1,2 Thus, 59% of patients claiming to be diet-adherent had Phe levels above the recommended range1,2 Background The study included 31 adult PKU patients, mean age 25 ± 5.3 years (range 19–41)1 All patients had classic PKU (Phe > 1200 μmol/L at diagnosis) identified through the newborn screening program in Israel and started on a Phe-restricted diet within the first month of life1 Patients were classified as diet-adherent (n = 17) or non-adherent (n = 14) based on their own report (non-adherent patients were off diet for 7.4 ± 4.9 years)1 Mean Phe levels were 823 ± 411 μmol/L for the diet-adherent group and ± 762 μmol/L for the non-adherent group (not significantly different)1 1. Modan-Moses, 2007: P204 col 2 ¶1 1. Modan-Moses, 2007: P204 col 2 ¶1 2. Modan-Moses, Personal Communication, 2008 *Recommended target range for this study was < 726 µmol/L 1Modan-Moses D, et al. J Inherit Metab Dis. 2007;300:202–208. 2Modan-Moses D. communication. September 18, 2007 1. Modan-Moses, 2007: P204 col 2 ¶1 2. Modan-Moses, Personal Communication, 2008 1. Modan-Moses, 2007: P203 col 1 ¶5 1. Modan-Moses, 2007: P203 col 1 ¶5, top of col 2 1. Modan-Moses, 2007: P203 col 2 ¶3 1. Modan-Moses, 2007: P204 col 2 ¶1 1Modan-Moses D, Vered I, Schwartz G, et al. Peak bone mass in patients with phenylketonuria. J Inherit Metab Dis. 2007;300:202–208. 2Modan-Moses D. communication. September 18, 2007.

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

17 PKU Diet Potential health consequences associated with PKU diets
Bone mass reduction1,4 Weight gain/obesity3 Growth retardation2 Neuropathy/ Myelopathy6 Neurocognitive deficits5 Nutritional Problems2 PKU Diet Potential health consequences associated with PKU diets Bone mineral content and bone mineral density are decreased in PKU children1 and adults4, both on and off diet In adults, reduced bone density leads to osteopenia and osteoporosis4 Bone mineral density is lower in adults on diet than off diet4 Studies have shown that transient growth retardation is common in children treated for PKU during the first years of life2 Despite linear growth that is within the range of unaffected children, obesity is present in a significant number of children with PKU3 Reviews of cognitive functioning in PKU show that early-treated children with PKU perform below control levels in the domains of abstract reasoning, executive function and attention5 Individuals with PKU may be at risk from vitamin B12 (cobalamin) deficiency, resulting in neurological problems including peripheral neuropathy and spinal myelopathy6 1. Przyrembel 2000: PS133 col 1 ¶1 4. Modan-Moses 2007: P205 col 1¶3 4. Modan-Moses 2007: P205 Table 3 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. 2. Giovannini 2007: P148 col 2 ¶1 3. Acosta 2003: P1172 col 2 ¶1 5. Moyle 2007: P93 col 2 ¶4 6. Robinson 2000: P545 col 3 ¶1 1Przyrembel H, Bremer H. Nutrition, physical growth, and bone density in treated phenylketonuria. Eur J Pediatr. 2000;159(suppl 2):S129–S135. 2Giovannini M, Verduci E, Salvatici E, et al. Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis. 2007;30:145–152. 3Acosta PB, Yannicelli S, Singh R, et al. Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy. J Am Diet Assoc. 2003;103:1167–1173. 4Modan-Moses D, Vered I, Schwartz G, et al. Peak bone mass in patients with phenylketonuria. J Inherit Metab Dis. 2007;300:202–208. 5Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev. 2007;17(2):91–101. 6Robinson M, White FJ, Cleary MA, et al. Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J Pediatrics. 2000;136(4):545–547.

18 There is a strong correlation between plasma protein levels and growth
1. Arnold, 2002: P245 col 2 Figure There is a strong correlation between plasma protein levels and growth This study by Arnold and colleagues in children with PKU evaluated the role of protein sufficiency, measured by plasma prealbumin concentration, in attaining height percentiles appropriate for age1 There was a strong correlation between height and plasma prealbumin concentration, such that children with the lowest albumin levels were the shortest, whereas children with higher plasma albumin levels were correspondingly taller1 Background To meet the study criteria, subjects had to be 2–18 years of age with classic PKU (an untreated Phe level of > 1200 μmol/L) who were diet adherent and maintained a mean Phe level < 960 μmol/L1 The relationship between mean height percentile and prealbumin levels was determined by a multiple regression analysis that controlled for the affect of other factors such as age and BMI1 Actual plasma prealbumin values represented by the quartiles were not provided in study 1. Arnold, 2002: P244 col 2 ¶1 ¶2 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. 1. Arnold, 2002: P244 col 3 ¶1 1. Arnold, 2002: P244 col 1 ¶1 1. Arnold, 2002: P244 col 2 ¶2 1Arnold GL, Vladutiu CJ, Kirby RS, Blakely EM, Deluca J. Protein insufficiency and linear growth restriction in phenylketonuria. J Pediatrics. 2002;141(2):243–246.

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 13–29%3 Following a diet regimen with protein intake exceeding RDAs, most studies of growth and protein intake show no impairment1 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 13–29%3 Following a diet regimen with protein intake exceeding RDAs, most studies of growth and protein intake show no impairment1 1. Huemer 2007: P694 col 2 ¶1 2. McBurnie 1991: P366 ¶1 and ¶2 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. 3. Acosta 2003: P1167, abstract 1. Huemer 2007: P694 col 2 ¶1 and P695, top of col 1 1Huemer M, Huemer C, Mostinger D, Huter D, Stockler–Ipsiroglu S. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J Inherit Metab Dis. 2007;30(5):694–699. 2McBurnie MA, Kronmall RA, Schuette VE, Koch R, Azeng CG. Physical growth of children treated for phenylketonuria. Ann Hum Biol. 1991;18:357–368. 3Acosta PB, Yannicelli S, Singh R, et al. Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy. J Am Diet Assoc. 2003;103:1167–1173.

20 Summary of protein intake and growth studies in control and PKU populations
Group, Year N Results Age (years) Shäffer, et al Verkerk, et al Allen, et al Acosta, et al Arnold, et al Dobbelaere, et al Hoeksma, et al Huemer, et al 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 than reference population Significant correlation between head circumference growth and natural protein intake Significant correlation between fat 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 Summary of protein intake and growth studies in control and PKU populations This table summarizes studies that evaluated protein intake above RDA levels and physical growth in PKU patients1 Of the eight studies, four found evidence of impaired growth despite intake of protein that was above RDA levels1 1. Huemer 2007: P698 Table 3 Refer to slide above Adapted from Table 3 of Huemer M, et al. J Inherit Metab Dis. 2007:30(5):694–699. 1Huemer M, Huemer C, Mostinger D, Huter D, Stockler-Ipsiroglu S. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J Inherit Metab Dis. 2007:30(5):694–699.

21 Increase of natural protein in diet may be of value to PKU patients
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 Typical PKU diets, with up to 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 rather than further enhancement of total protein intake”2 1. McBurnie 1991: P357 ¶2 2. Huemer 2007: P697 col 2 ¶1 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. 3. Hoeksma 2005: P850 ¶1 2. Huemer 2007: P698 col 2 1McBurnie MA, Kronmall RA, Schuette VE, Koch R, Azeng CG. Physical growth of children treated for phenylketonuria. Ann Hum Biol. 1991;18:357–368. 2Huemer M, Huemer C, Mostinger D, Huter D, Stockler-Ipsiroglu S. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J Inherit Metab Dis. 2007;30(5):694–699. 3Hoeksma M, Van Run M, Verkerk P, et al. The intake of total protein, natural protein and protein substitute and growth of height and head circumference in Dutch infants with phenylketonuria. J Inherit Metab Dis. 2005;28:845–854.

22 Trace element status in PKU
Group, Year N Element Results 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 in PKU group compared to sibling controls Serum ferritin concentrations lower than normal in 28 subjects (53%) Plasma zinc significantly lower in PKU children ≥ 7 years old compared to control Plasma selenium significantly lower in in 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 PKU subjects Zinc, Copper Zinc Selenium, Iron, Zinc, Copper Iron Selenium Trace element status in PKU This slide provides a brief summary of studies that have reported on trace element status in PKU patients, the majority of whom were on Phe-restricted diets1-8 Some studies support deficiencies, while other studies failed to find deficiencies of the same trace elements (Reilly, 1990 and Artuch, 2004). These studies are fewer in number and tend to be supported by medical food companies. Taken together, these studies suggest that Phe-restricted diets may be deficient in some trace elements, in particular selenium, zinc, and iron1-8 Refer to table 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): Bodley JL, et al. Eur J Pediatr. 1993;152:140–143. Acosta PB, et al. Genet Med. 2004;6(2):96–101. Refer to table 1Acosta PB, Fernhoff PM, Warshaw HS, et al. Zinc and copper status of treated children with phenylketonuria. J Parenter Enteral Nutr. 1981;5(5):406–409. 2Taylor CJ, Moore G, Davidson DC, et al. The effect of treatment on zinc, copper and calcium status in children with phenylketonuria. J Inherit Metab Dis. 1984;7(4):160–164. 3Reilly C, Barrett JE, Patterson CM, et al. Trace element nutrition status and dietary intake of children with phenylketonuria. Am J Clin Nutr. 1990;52:159–165. 4Bodley JL, Austin VJ, Hanley WB, et al. Low iron stores in infants and children with treated phenylketonuria: a population at risk for iron-deficiency anaemia and associated deficits. Eur J Pediatr. 1993;152:140–143. 5Fisberg RM, Silva-Femandes ME, Fisberg M, et al. Plasma zinc, copper and erythrocyte superoxide dismutase in children with phenylketonuria. Nutrition. 1999;15(6):449–452. 6van Bakel MM, Printzen G, Wermuth B, et al. Antioxidant and thyroid status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Am J Clin Nutr. 2000;72(4):976–981. 7Artuch R, Colome C, Sierra C, Brandi N, et al. A longitudinal study of antioxidant status in phenylketonuric patients. Clin Biochem. 2004;37(3): 8Acosta PB, Yannicelli S, Singh RH, et al. Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors. Genet Med. 2004;6(2):96–101.

23 Decreases in bone mass can occur at early age in patients with PKU
Skeletal Site BMD Z-score Lumbar (L1–L4) -0.75 ± 1.04 Femoral Neck -0.73* ± 0.66 Total Body -0.47* ± 0.72 1. Modan-Moses, 2007: P205 col 1 ¶3 and Table 3 Decreases in bone mass can occur at early age in patients with PKU The main objective of this study was to evaluate peak bone mass in adult PKU patients and relate BMD to nutritional parameters1 Osteopenia was detected in 39% and osteoporosis was detected in 7% of the PKU patients1 BMD scores for the femoral neck and total body were significantly lower than expected for the normal population1 Background The study population included 31 adult PKU patients with a mean age of 25 ± 5.3 years (range 19–41); 17 were diet-adherent and 14 were non-adherent1 All patients had classic PKU (Phe > 1200 μmol/L at diagnosis) identified through the newborn screening program in Israel and started on a Phe-restricted diet within the first month of life1 Total bone density and bone density at the lumbar spine (L1 through L4) and femoral neck were evaluated by dual-energy x-ray absorptiometry (DXA)1 BMD was not correlated with age, blood minerals, Phe, vitamin D and alkaline phosphatase levels, calcium and protein intake, BMI and percent body fat, suggesting that these factors do not account for the results1 *Significantly lower than expected in the normal population (P < 0.005) BMD = Bone Mineral Density 1. Modan-Moses, 2007: P202 col 1 ¶1 1. Modan-Moses, 2007: P205 col 1 ¶3 1. Modan-Moses, 2007: P205 col 1 ¶3 Mean age of patients: 25 ± 5.3 years, N = 31 Modan-Moses D, et al. J Inherit Metab Dis. 2007;30:202–208. 1. Modan-Moses, 2007: P203 col 1 ¶5 1. Modan-Moses, 2007: P203 col 1 ¶5 1. Modan-Moses, 2007: P203 col 2 ¶4 1. Modan-Moses, 2007: P205 col 2 ¶1 1Modan-Moses D, Vered I, Schwartz G, et al. Peak bone mass in patients with phenylketonuria. J Inherit Metab Dis. 2007;300:202–208.

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
PKU patients Observable Deficits Verbal/IQ scales Memory Attention Cognitive Social Behavior/Mood disorders Diet-managed; Blood Phe not consistently in range Subtle Changes Executive function Processing speed Attention Inhibition Motor control Diet-managed; Blood Phe in currently recommended range Inadequate blood Phe control associated with suboptimal outcomes Studies have detected mild dysfunction in continuously treated adults on some but not all measures of cognitive function, with no evidence of psychosocial dysfunction. Taken together, the findings imply that any deficits in adulthood associated with well-treated PKU are relatively subtle.1 Neuropsychological studies clearly show that early and continuously treated children with PKU are at increased risk for subtle cognitive and behavioral impairments. Despite considerable research, debate persists with regard to the nature and etiology of these impairments.2 In early-treated PKU children, neuropsychological studies have reported executive function deficits in working memory, inhibitory control, conceptual reasoning, selective and sustained attention, mental flexibility and organizational strategy2 In a recent neuropsychological study of 33 early-treated PKU children ages 7–18 years and 34 age- matched controls, children in the PKU group exhibited global cognitive impairment including lower IQ, attentional problems, slow processing speed, reduced learning capacity, mild executive impairments and educational difficulties2 Metabolic control correlated weakly to moderately with attention, executive and memory/learning factors2 A recent meta-analysis of neuropsychological studies found that early-treated PKU patients differed significantly from controls on tests of IQ, processing speed, attention, inhibition and motor control3 1. Channon 2005: P684 col 1 ¶1 2. Anderson 2007: P646 ¶1 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. 2. Anderson 2007: P648 ¶1 2. Anderson 2007: P646 abstract 2. Anderson 2007: P646 abstract 3. Moyle 2007: P91 abstract 1Channon S, Mockler C, Lee P. Executive functioning and speed of processing in phenylketonuria. Neuropsychology. 2005;19:679–686. 2Anderson PJ, Wood SJ, Francis DE et al. Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Develop Neuropsych. 2007;32(2):645–668. 3Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev. 2007;17(2):91–101.

26 Paired comparisons on the Wechsler Intelligence Scale (IQ) for children with PKU and matched sibling controls at 8 years of age (n = 55) Koch, 1984: P87 Table 1 Paired comparisons on the Wechsler Intelligence Scale (IQ) for children with PKU and matched sibling controls at 8 years of age As part of the ongoing US PKU Collaborative Study, 55 pairs of 8 year old children and their siblings were tested for IQ1 Children with PKU scored 7 points lower than their siblings on the Wechsler Intelligence Scale for Children (WISC)1 The PKU subjects also scored lower than siblings on the Wide Range Achievement Test (WRAT) Reading and Arithmatic subtests, but not lower on the Spelling subtest1 When grouped by diet status, the scores of children following the PKU diet were at or above sibling scores, whereas the scores of children off-diet were 7-13 points below siblings1 The authors conclude that these results support the suggestion that children with PKU should restrict dietary Phe at least through the school-age years1 1. Koch, 1984: P86 col 2 ¶1 1. Koch, 1984: P87 Table 1 Koch R, et al. J Inherit Metab Dis. 1984;7(2):86-90. Koch, 1984: P89 Table 3 1. Koch, 1984: P89 col 1 ¶2 1. Koch, 1984: P90 col 1 ¶1 1Koch R, Azen C, Friedman EG, and Williamson ML. Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inherit Metab Dis. 1984;7(2):86-90.

27 Children on early and continuously Phe-restricted diet have reduced executive function compared to unaffected peers (n = 14) 1. Leuzzi, 2004: P116 ¶2 1. Leuzzi, 2004: P116 ¶2 Children on early and continuously Phe-restricted diet have reduced executive function compared to unaffected peers The goal of this study was to determine if early and continuously treated children with PKU have deficits in executive function compared to matched controls1 In both sets of tests of executive function, analysis of cumulative scores demonstrated that subjects in the PKU group under-performed subjects in the control group1 Background For this study, the PKU group was composed of 14 children (mean age 10.9 years, range 8–13) who were diagnosed as having classic PKU at birth, were started on diet early (mean age 33.1 days) and remained on diet during the study1 The mean full-scale IQ (as determined by the Wechsler Intelligence Scale for Children Revised) for the PKU group was ± 10.21 The control group consisted of individuals matched to the PKU group on the basis of age, sex, socioeconomic status, and full-scale IQ. All controls had normal intelligence (mean IQ ± 12.7), mental development, and scholastic achievement1 Executive function test scores were the sum of scores from a battery of individual tests1 Battery 1: sum of scores on 7 individual tests (Elithorn’s Perceptual Maze Test, Visual Search Test, Rey-Osterreith Complex Figure Tests (2), Motor Motor Learning Test, Weigl’s Sorting Test, and Tower of London) Battery 2: algebraic sum of differential scores on 11 subtests of the Wisconsin Card Sorting Test 1. Leuzzi, 2004: P116 ¶2 1. Leuzzi, 2004: P118 ¶5 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. 1. Leuzzi, 2004: P116 ¶2 1. Leuzzi, 2004: P116 ¶3 1. Leuzzi, 2004: P116 ¶3 1. Leuzzi, 2004: P117 ¶2 1Leuzzi V, Pansini M, Sechi E. Executive function impairment in early-treated PKU subjects with normal mental development. J Inherit Metab Dis. 2004;27:115–125.

28 Children with PKU demonstrate developmental deficit in working memory despite Phe-restricted diet
8 2 3 4 5 6 7 9 10 11 12 13 14 15 16 17 18 Age (years) Summary Memory Score Control (n = 20)** slope = 0.29† slope = 0.08† PKU (n = 20)* 1. White, 2002: P5 Figure 1 Children with PKU demonstrate developmental deficit in working memory despite Phe-restricted diet To analyze the developmental trajectory of working memory, test scores were averaged across categories (letters, objects and locations) and plotted as a function of age1 The slopes of the resulting functions for the control group and the PKU group were significantly different, indicating lower memory scores for PKU participants with increasing age1 Background Participants in the PKU group in this study were 20 children aged 6–17 years (mean 11.4 ± 3.5 years) with early-treated PKU who were started on dietary treatment before 6 weeks of age and remained on diet throughout the study1 Phe levels of PKU participants during the study ranged from 120 to 960 μmol/L (mean 498 ± 240 μmol/L)1 The control group consisted of 20 typically developing children aged 6–17 years (mean 10.5 ± 3.6 years)1 Education ranged from 0.6 to 11.3 years for the control group (mean 4.9 ± 3.4 years) and 0.9 to 11.9 for the PKU group (mean 6.0 ± 3.6 years)1 There were no significant differences between PKU and control participants for basic verbal and nonverbal abilities1 Working memory was assessed in 3 categories (letters, objects, and locations) by presenting a series of 2–9 stimuli on a computer monitor followed by an array of stimuli from which participants recalled the order of presentation1 1. White, 2002: P4 col 2 ¶4 1. White, 2002: P4 col 2 ¶4 *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. 1. White, 2002: P3 col 1 ¶2 1. White, 2002: P3 col 1 ¶2 1. White, 2002: P3 col 1 ¶3 1. White, 2002: P3 ¶3 1. White, 2002: P3 col 1 ¶4 1. White, 2002: P4 col 2 ¶4 1White DA, Nortz MJ, Mandernach T, Huntington K, Steiner R. Age-related working memory impairments in children with prefrontal dysfunction associated with phenylketonuria. J Int Neuropsychol Soc. 2002;8:1–11

29 Meta-analysis of PKU studies reveals cognitive deficits despite Phe-restricted diet
small medium large 1. Moyle 2007: P96 Figure 1. Meta-analysis of PKU studies reveals cognitive deficits despite Phe-restricted diet The results from this study are based on a meta-analysis of existing studies that have addressed the differences between PKU and control groups on measures of intellectual function1 Results are presented as overall effect sizes and 95% confidence intervals. With the exception of working memory, all domains revealed significant positive effect sizes, with the greatest effect in the domain of processing speed1 Background To be included, studies had to1 Be written in English Include data from psychometric tests Limit patient groups to adolescents (13–18 years old) and adults (18 and older) Limit treatment groups to classic PKU who followed strict treatment diets in childhood Provide a non-PKU control group Present data from which effect size could be calculated A total of 11 studies were included in the analysis. Variability in adherence was common, with the majority of papers (9 of 11) including patients who had followed a relaxed diet from adolescence1 Effect size represents the magnitude of a treatment effect in a way that is independent of sample size (eg, the difference between group means divided by a combined measure of standard deviation). A medium effect size (0.5 for a comparison of means) is “likely to be visible to the naked eye of a careful observer”, and a small effect size (0.2) is intended to be “noticeably smaller than medium, but not so small as to be trivial”2 1. Moyle, 2007: P94 col 1 ¶2 Control n: NP PKU n: NP 1. Moyle, 2007; P96 col 2 ¶1 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. 1. Moyle, 2007: P94 col 1 ¶5 1. Moyle, 2007: P94 col 2 ¶2 2. Cohen, 1992: P156 col 2 ¶6 1Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev. 2007;17(2):91–101. 2Cohen J. A Power Primer. Psych Bull. 1992;112:155–159.

30 Children with PKU present more school problems than unaffected peers
1. Gassio, 2005: P269 col 1 ¶2 Children with PKU present more school problems than unaffected peers These data were included in the study on PKU and IQ presented earlier. In addition to IQ, the authors also compared school-related problems for the control group and the PKU group1 Subjects in the PKU group experienced significantly more school problems than subjects in the control group. This included more students needing special tutoring and needing to repeat classes due to poor performance.1 Background As previously mentioned, the PKU group consisted of 26 children and adolescents 7–19 years old with a Phe tolerance of 250–600 mg/day1 PKU participants were diagnosed at birth and were treated early and continuously with a Phe-restricted diet1 The control group was composed of 21 age- and sex-matched individuals1 To obtain information about school-related problems, parents were asked to answer a questionnaire relating to type of school, academic degree achieved, need for special tutoring or repeating classes, and type of special tutoring1 1. Gassio, 2005: P268 col 1 ¶1 1. Gassio, 2005: P269 col 1 ¶3 *P = vs controls Gassio R, et al. Pediatr Neurol. 2005;33:267–271. 1. Gassio, 2005: P268 col 1 ¶2 1. Gassio, 2005: P268 col 1 ¶2 1. Gassio, 2005: P268 col 1 ¶3 1. Gassio, 2005: P268 col 2 ¶4 1Gassio R, Fusté E, López-Sale A, et al. School performance in early and continuously treated phenylketonuria. Pediatr Neurol. 2005;33:267–271.

31 Significant increase in treatment with stimulants for attentional dysfunction in children with PKU
1. Arnold, 2004: P139 ¶2, ¶3 Significant increase in treatment with stimulants for attentional dysfunction in children with PKU This study examined the prevalence of stimulant use to treat attentional dysfunction in children with PKU compared to children with diabetes and children in the general population1 26% of the children in the PKU group were treated for attentional dysfunction with a stimulant medication which was significantly higher than in the diabetes group and higher than the expected prevalence of ADHD in the general population1 There was also a significant relationship between stimulant use and Phe levels: blood Phe was 486 ± 336 μmol/L in the non-stimulant PKU group and 792 ± 396 μmol/L in the stimulant-treated PKU group (P < 0.02)1 The prevalence of ADHD in the general population is expected to be about 5%1 Background The 38 children in the PKU group met the following criteria1 5–20 years of age Continuously treated classic PKU (Phe > 1200 μmol/L untreated) Continuous enrollment in school on a full-time basis The diabetes group was composed of two sex- and age-matched children with type I diabetes mellitus per PKU patient (total of 76). The mean age of children in both the PKU group and the diabetes group was 10.81 1. Arnold, 2004: P137 Summary *P < as compared to children with diabetes mellitus 1. Arnold, 2004: P137 Summary Arnold GL, et al. J Inherit Metab Dis. 2004;27:137–143. 1. Arnold, 2004: P139 ¶5 1. Arnold, 2004: P140 ¶1 1. Arnold, 2004: P138 ¶2 1. Arnold, 2004: P138 ¶2 1Arnold GL, Vladutiu CJ, Orlowski CC, Blakely EM, DeLuca J. Prevalence of stimulant use of attentional dysfunction in children with phenylketonuria. J Inherit Metab Dis. 2004;27:137–143.

32 Increase in psychiatric symptoms in adults with PKU on Phe-restricted diets
1. Pietz, 1997: P348 Table 3 Increase in psychiatric symptoms in adults with PKU on Phe- restricted diets One of the objectives of this study was to compare the prevalence of psychiatric disorders in PKU patients with a group of non-PKU controls1 The overall rate of clearly observable psychiatric disorders was greater for the PKU group (25.7%) than for the control group (16.1%), but the difference was not significant1 There were significant differences observed between the two groups for symptoms of depressed mood, phobias, generalized anxiety, hypochondriac worries, and anxiety involving the workplace1 Background For this study, 35 patients were randomly drawn from a sample of 67 early-treated classic PKU patients, 17 years or older who had been followed since birth by the University of Heidelberg1 During the study, the diet status of the participants was mixed: 5 patients followed a strict diet, 16 patients followed a relaxed protein-restricted diet, and 14 were off diet1 Patients in the PKU group were compared with the results of a control sample of 181 non-PKU 18 year olds who were part of an epidemiological study at ages 8, 13, and 181 1. Pietz, 1997: P345 Abstract 1. Pietz, 1997: P346 col 2 ¶5 *P < 0.05 as compared to 18-year old controls Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:345–350. 1. Pietz, 1997: P346 col 2 ¶5 1. Pietz, 1997: P346 col 1 ¶1 1. Pietz, 1997: P346 col 1 ¶5 1. Pietz, 1997: P346 col 2 ¶3 1Pietz J, Fatkenheuer B, Burgard P, et al. Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics. 1997;99:345–350.

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 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


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