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Impact and Outcomes of Dietary Management of Phenylketonuria (PKU)

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Presentation on theme: "Impact and Outcomes of Dietary Management of Phenylketonuria (PKU)"— Presentation transcript:

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

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

3 Persistent elevated blood phenylalanine (Phe) caused by a deficiency of the phenylalanine hydroxylase (PAH) enzyme 1 The term PKU is reserved for primary dysfunction of the PAH enzyme due to mutations in the PAH gene 2 The degree of impairment varies greatly among patients resulting in a broad continuum of phenotypes 1 Categories based on blood Phe at diagnosis 3 –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? 1 NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16– 18, Pediatrics. 2000;108:972 – Scriver S. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management. October 16–18, 2000;19–23. 3 Mitchell J, et al. Mol Genet Metab. 2005;86:S81–S85.

4 Most frequent disorder of amino acid metabolism Incidence of PKU in the USA 1 –1 per 13,500 to 1 per 19,000 newborns –Higher in Whites and Native Americans –Lower in Blacks, Hispanics, and Asians 1 NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, Pediatrics. 2000;108:972–982. PKU is a relatively common metabolic disorder

5 PAH = phenylalanine hydroxylase BH 4 = cofactor tetrahydrobiopterin Simplified biochemistry of phenylalanine metabolism Phenylalanine Tyrosine PAH Enzyme BH 4 Cofactor D E F E C T I V E

6 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; : 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 1950s1960s1970s1980s1990s2000s

7 Earliest reports of dietary treatment Bickel, Gerrard, and Hickmans, –Treated 2-year old PKU child with low-Phe diet –Cognitive and behavioral deficits improved Armstrong and Tyler, –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, –Treated three PKU children (ages 2 to 5) with low Phe diet –All three showed marked intellectual improvement 1 Bickel H, Gerrard J, Hickmans EM. Lancet.1953;265(6790): Armstrong MD, Tyler FH. J Clin Invest.1955;34(4): Woolf LI, Griffiths R, Moncrieff A. 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 test 2 –Detected ketones in urine –Limited use in newborns because appearance of ketones can be delayed The Guthrie test 3 –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 1 Bickel H, et al. Acta Pediatr.1954;43: Dhondt J-L. Laboratory Diagnostics in Phenylketoneuria. In: Blau N. PKU and BH4–Advances in Phenylketonuria and Tetrahydrobiopterin. 1st ed. SPS Publications; Guthrie R, Susi A. 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 population 1 –At age 6: IQ was significantly related to the age of starting dietary treatment 2 –At age 8: Subjects on-diet performed better on IQ and school achievement tests than subjects off-diet 2 –As adults: Subjects on-diet had fewer medical and mental disorders and higher cognitive test scores than subjects off-diet 3 As a whole, these findings have led to the philosophy of a Diet for Life at most clinics in the United States 3 1 Dobson JC, et al. Pediatrics. 1977;60: Koch R, et al. J Inher Metab Dis. 1984;7: Koch R, et al. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management. October 16–18, 2000;59-65.

10 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 Consequences of elevated blood phenylalanine levels vary by age

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

12 1 Scriver 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; NIH Consensus Development Panel. National Institutes of Health consensus development conference statement: Phenylketonuria: screening and management, October 16–18, Pediatrics. 2000;108:972–982. Comparison of NIH consensus recommended blood Phe for diet-managed PKU patients with the general population 62 ± – ± –900 2 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, respectively 1 Conversion: 60 µmol/L = 1 mg/dL

13 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 between Phe 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) 423–7501.3–3.1 Lifetime (all ages) 394–6661.9–4.1

14 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 0–4 5–910–14 15–19 (n = 178) (n = 137) (n = 98) (n = 77)

15 * Recommended target range for this study was < 726 µmol/L 1 Modan-Moses D, et al. J Inherit Metab Dis. 2007;300:202– Modan-Moses D. communication. September 18, % 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

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

17 Potential health consequences associated with PKU diets 1 Pryzrembel H, et al. Eur J Pediatr. 2000;159(suppl 2):S129–S Giovannini M, et al. J Inherit Metab Dis. 2007;30:145– Acosta PB, et al. J Am Diet Assoc. 2003;103:1167– Modan-Moses D, et al. J Inherit Metab Dis. 2007;30:202– Moyle JJ, et al. Neuropsychol Rev. 2007;17(2):91– Robinson M, et al. J Pediatrics. 2000;136(4):545–547. PKU Diet Bone mass reduction 1,4 Weight gain/obesity 3 Growth retardation 2 Neuropathy/ Myelopathy 6 Neurocognitive deficits 5 Nutritional Problems 2

18 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

19 Growth retardation has been observed in PKU patients on diet meeting age-specific RDAs for protein 1 In studies in which height is not different, PKU patients often have significantly higher weight than controls 2 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 impairment 1 1 Huemer M, et al. J Inherit Metab Dis. 2007;30(5):694– McBurnie MA, et al. Ann Hum Biol. 1991;18:357– Acosta PB, et al. J Pediatr Gastroenterol Nutr. 1998;276:287–291. Nutrition and growth in PKU patients

20 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– 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 Results Age (years)

21 Typical PKU diets, with 75–90% of total protein intake from synthetic amino acids in medical foods, shift away from natural protein sources 1 Natural protein intake, rather than total protein, is most closely correlated with fat-free muscle mass 2 There is significant correlation between natural protein (not synthetic protein) and head circumference growth in the first three years of life 3 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 1 McBurnie MA, et al. Ann Hum Biol. 1991;18:357– Huemer M, et al. J Inherit Metab Dis. 2007;30(5):694– Hoeksma M, et al. J Inherit Metab Dis. 2005;28:845–854.

22 Acosta, et al Taylor, et al Reilly, et al Bodley, et al Fisberg, et al van Bakel, et al Artuch, et al Acosta, et al 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 Zinc Selenium Iron Group, YearN 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): 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

23 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 occur at early age in patients with PKU Skeletal Site BMD Z-score Lumbar (L1 – L4) ± 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 (n = 11)(n = 2)

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

25 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 range PKU patients

26 Koch R, et al. J Inherit Metab Dis. 1984;7(2): Paired comparisons on the Wechsler Intelligence Scale (IQ) for children with PKU and matched sibling controls at 8 years of age (n = 55)

27 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. (n = 14) Children on early and continuously Phe-restricted diet have reduced executive function compared to unaffected peers

28 * 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 diet Age (years) Summary Memory Score Control (n = 20) ** slope = 0.29 slope = 0.08 PKU (n = 20) *

29 NP = not provided * Hedges 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: NP PKU n: NP small medium large Meta-analysis of PKU studies reveals cognitive deficits despite Phe-restricted diet

30 * P = vs controls Gassio R, et al. Pediatr Neurol. 2005;33:267–271. Children with PKU present more school problems than unaffected peers

31 Arnold GL, et al. J Inherit Metab Dis. 2004;27:137–143. (n = 38) (n = 76) Significant increase in treatment with stimulants for attentional dysfunction in children with PKU *P < as compared to children with diabetes mellitus

32 *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 in adults with PKU on Phe-restricted diets

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

34 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


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