Chapter 17: Disorders of Amino Acid Metabolism, Organic Acidaemias and Urea Cycle Disorders

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1 Chapter 17: Disorders of Amino Acid Metabolism, Organic Acidaemias and Urea Cycle Disorders 1. Garrod AE The incidence of alkaptonuria: a study in chemical individuality. Lancet, 1902, Garrod AE The Croonian lectures on inborn errors of metabolism. Lancet, 1908, Johannsen WL The genotype conception of heredity. American Naturalist, 1911, Beadle GW, Tatum EL The genetic control of biochemical reactions in Neurospora. Proc Natl Acad Sci, 1941, Pauling L, Itano HA, Singer SJ et al. Sickle cell anemia, a molecular disease. Science, 1949, Ingram VM Gene mutations in human hemoglobin: the chemical difference between normal and sickle hemoglobin. Nature, 1957, Genetics Home Reference Accessed 21 July Donlon J, Levy H, Scriver CR Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Valle D, Beaudet AL, Vogelstein B et al. (eds) The Online Metabolic

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4 28. Hanley WB Non-PKU mild hyperphenylalaninemia (MHP) the dilemma. Mol Genet Metab, 2011, Blau N, Hennermann JB, Langenbeck U et al. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab, 2011, 104(Suppl) S Williams RA, Mamotte CD, Burnett JR Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev, 2008, Opladen T, Hoffmann GF, Blau N An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis, 2012, Kaufman S Studies on the mechanism of the enzymatic conversion of phenylalanine to tyrosine. J Biol Chem, 1959, Smith I The hyperphenylaninaemias. In: Lloyd JK and Scriver CR (eds) Genetic and Metabolic Disease in Paediatrics. London: Butterworths, 1985, pp Kwok SC, Ledley FD, DiLella AG et al. Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry, 1985, PAH mutation database: Accessed 1 April Heintz C, Cotton RG, Blau N Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat, 2013, Zschocke J, Haverkamp T, Møller LB Clinical utility gene card for phenylketonuria. Eur J Hum Genet, 2012, 20: doi: /ejhg Accessed 22 February 2013.

5 38. Mitchell JJ Phenylalanine hydroxylase deficiency. In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews (Internet). Seattle, WA: University of Washington, Latest review January PKU Expert Group Report Newborn Screening in the UK UK Newborn Screening Programme Centre van Spronsen FJ, Burgard P The truth of treating patients with phenylketonuria after childhood: the need for a new guideline. J Inherit Metab Dis, 2008, Abadie V, Berthelot J, Feillet F et al. Association française pour le dépistage et la prévention des handicaps de l'enfant (AFDPHE) [Management of phenylketonuria and hyperphenylalaninemia: the French guidelines]. Arch Pediatr, 2005, Burgard P, Bremer HJ, Bührdel P et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria Eur J Pediatr, 1999, Medical Research Council Working Party on Phenylketonuria. Recommendations on the dietary management of phenylketonuria. Arch Dis Child, 1993, Fonnesbeck CJ, McPheeters ML, Krishnaswami S et al. Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis. J Inherit Metab Dis, 2012, Epub AOP. 45. Albrecht J, Garbade SF, Burgard P Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria: a meta-analysis. Neurosci Biobehav Rev, 2009, Christ SE, Huijbregts SC, de Sonneville LM et al. Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol Genet Metab, 2010, 99(Suppl 1) S22 32.

6 47. Waisbren 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, Janzen D, Nguyen M Beyond executive function: non-executive cognitive abilities in individuals with PKU. Mol Genet Metab, 2010, 99(Suppl 1) S VanZutphen K, Packman W, Sporri L et al. Executive functioning in children and adolescents with phenylketonuria. Clin Genet, 2007, Leuzzi V, Pansini M, Sechi E et al. Executive function impairment in early-treated PKU subjects with normal mental development. J Inherit Metab Dis, 2004, Dawson C, Murphy E, Maritz C et al. Dietary treatment of phenylketonuria: the effect of phenylalanine on reaction time. J Inherit Metab Dis, 2011, Anjema K, van Rijn M, Verkerk PH et al. PKU: high plasma phenylalanine concentrations are associated with increased prevalence of mood swings. Mol Genet Metab, 2011, Huijbregts SC, de Sonneville LM, Licht R et al. Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations. Neuropsychologia, 2002, Moyle JJ, Fox AM, Arthur M et al. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev, 2007, Anastasoaie V, Kurzius L, Forbes P et al. Stability of blood phenylalanine levels and IQ in children with phenylketonuria. Mol Genet Metab, 2008, Pietz J, Dunckelmann R, Rupp A et al. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr, 1998,

7 57. Brunner RL, Berch DB, Berry H Phenylketonuria and complex spatial visualization: an analysis of information processing. Dev Med Child Neurol, 1987, Huijbregts SC, De Sonneville LM, Van Spronsen FJ et al. Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria. Neuropsychology, 2003, Waisbren SE, Brown MJ, de Sonneville LM et al. Review of neuropsychological functioning in treated phenylketonuria: an information processing approach. Acta Paediatr Suppl, 1994, White DA, Nortz MJ, Mandernach T et al. Age-related working memory impairments in children with prefrontal dysfunction associated with phenylketonuria. J Int Neuropsychol Soc, 2002, Channon S, Mockler C, Lee P Executive functioning and speed of processing in phenylketonuria. Neuropsychology, 2005, Huijbregts SC, de Sonneville LM, van Spronsen FJ et al. The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory. Neurosci Biobehav Rev, 2002, ten Hoedt AE, Maurice-Stam H, Boelen CC et al. Parenting a child with phenylketonuria or galactosemia: implications for health-related quality of life. J Inherit Metab Dis, 2011, Janos AL, Grange DK, Steiner RD et al. Processing speed and executive abilities in children with phenylketonuria. Neuropsychology, 2012, Channon S, German E, Cassina C et al. Executive functioning, memory, and learning in phenylketonuria. Neuropsychology, 2004, Anderson PJ, Wood SJ, Francis DE et al Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter

8 abnormalities or elevated phenylalanine levels? Dev Neuropsychol, 2007, Smith I, Knowles J Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr, 2000, 159(Suppl 2) S Antshel KM, Waisbren SE Developmental timing of exposure to elevated levels of phenylalanine is associated with ADHD symptom expression. J Abnorm Child Psychol, 2003, Brumm VL, Grant ML The role of intelligence in phenylketonuria: a review of research and management. Mol Genet Metab, 2010, 99(Suppl 1) S Koch R, Burton B, Hoganson G et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis, 2002, Waisbren SE, Levy HL Agoraphobia in phenylketonuria. J Inherit Metab Dis, 1991, Weglage J, Grenzebach M, Pietsch M et al. Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls. J Inherit Metab Dis, 2000, Simon E, Schwarz M, Roos J et al. Evaluation of quality of life and description of the sociodemographic state in adolescent and young adult patients with phenylketonuria (PKU). Health Qual Life Outcomes, 2008, Bosch AM, Maurice-Stam H, Wijburg FA et al. Remarkable differences: the course of life of young adults with galactosaemia and PKU. J Inherit Metab Dis, 2009, Landolt MA, Nuoffer JM, Steinmann B et al. Quality of life and psychologic adjustment in children and adolescents with early treated phenylketonuria can be normal. J Pediatr, 2002,

9 76. Bhat M, Haase C, Lee PJ Social outcome in treated individuals with inherited metabolic disorders: UK study. J Inherit Metab Dis, 2005, Cotugno G, Nicolò R, Cappelletti S et al. Adherence to diet and quality of life in patients with phenylketonuria. Acta Paediatr, 2011, Thimm E, Schmidt LE, Heldt K et al. Health-related quality of life in children and adolescents with phenylketonuria: unimpaired HRQoL in patients but feared school failure in parents. J Inherit Metab Dis, 2013, Jan 8. Accessed 22 February Bik-Multanowski M, Didycz B, Mozrzymas R et al. Quality of life in noncompliant adults with phenylketonuria after resumption of the diet. J Inherit Metab Dis, 2008, 31(Suppl 2) S Gassió R, Campistol J, Vilaseca MA et al. Do adult patients with phenylketonuria improve their quality of life after introduction/resumption of a phenylalaninerestricted diet? Acta Paediatr, 2003, Belanger-Quintana A, Martinez-Pardo M Physical development in patients with phenylketonuria on dietary treatment: a retrospective study. Mol Genet Metab, 2011, Dokoupil K, Gokmen-Ozel H, Lammardo AM et al. Optimising growth in phenylketonuria: current state of the clinical evidence base. Clin Nutr, 2012, Huemer M, Huemer C, Möslinger D et al. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J Inherit Metab Dis, 2007, Verkerk PH, van Spronsen FJ, Smit GP et al. Impaired prenatal and postnatal growth in Dutch patients with phenylketonuria. The National PKU Steering Committee. Arch Dis Child, 1994,

10 85. Dhondt JL, Largillière C, Moreno L et al. Physical growth in patients with phenylketonuria. J Inherit Metab Dis, 1995, Schaefer F, Burgard P, Batzler U et al. Growth and skeletal maturation in children with phenylketonuria. Acta Paediatr, 1994, Holm VA, Kronmal RA, Williamson M et al. Physical growth in phenylketonuria: II. Growth of treated children in the PKU collaborative study from birth to 4 years of age. Pediatrics, 1979, White JE, Kronmal RA, Acosta PB Excess weight among children with phenylketonuria. J Am Coll Nutr, 1982, McBurnie MA, Kronmal RA, Schuett VE et al. Physical growth of children treated for phenylketonuria. Ann Hum Biol, 1991, Burrage LC, McConnell J, Haesler R et al. High prevalence of overweight and obesity in females with phenylketonuria. Mol Genet Metab, 2012, Albersen M, Bonthuis M, de Roos NM et al. Whole body composition analysis by the BodPod air-displacement plethysmography method in children with phenylketonuria shows a higher body fat percentage. J Inherit Metab Dis, 2010, Jun 24. [Epub ahead of print] 92. Scaglioni S, Verduci E, Fiori L et al. Body mass index rebound and overweight at 8 years of age in hyperphenylalaninaemic children. Acta Paediatr, 2004, Robertson LV, McStravick N, Ripley S et al. Body mass index in adult patients with diet-treated phenylketonuria. J Hum Nutr Diet, 2013, Apr 3. [Epub ahead of print] 94. Rocha JC, van Spronsen FJ, Almeida MF et al. Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab, 2012,

11 95. de Groot MJ, Hoeksma M, van Rijn M et al. Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients. Mol Genet Metab, 2012, Modan-Moses D, Vered I, Schwartz G et al. Peak bone mass in patients with phenylketonuria. J Inherit Metab Dis, 2007, Pérez-Dueñas B, Cambra FJ, Vilaseca MA et al. New approach to osteopenia in phenylketonuric patients. Acta Paediatr, 2002, Porta, F, Roato I, Mussa A et al. Increased spontaneous osteoclastogenesis from peripheral blood mononuclear cells in phenylketonuria. J Inherit Metab Dis, 2008, online publication. 99. McMurry MP, Chan GM, Leonard CO et al. Bone mineral status in children with phenylketonuria relationship to nutritional intake and phenylalanine control. Am J Clin Nutr, 1992, Lage S, Bueno M, Andrade F et al. Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density. J Inherit Metab Dis, 2010, Sep 10. [Epub ahead of print] 101. Porta F, Mussa A, Zanin A et al. Impact of metabolic control on bone quality in phenylketonuria and mild hyperphenylalaninemia. J Pediatr Gastroenterol Nutr, 2011, Al-Qadreh A, Schulpis KH, Athanasopoulou H et al. Bone mineral status in children with phenylketonuria under treatment. Acta Paediatr, 1998, Yannicelli S, Medeiros DM Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice. J Inherit Metab Dis, 2002, Hanley WB, Feigenbaum A, Clarke JT et al. Vitamin B12 deficiency in adolescents

12 and young adults with phenylketonuria. Lancet, 1993, Aung TT, Klied A, McGinn J et al. Vitamin B12 deficiency in an adult phenylketonuric patient. J Inherit Metab Dis, 1997, Lee P, Smith I, Piesowicz A et al. Spastic paraparesis after anaesthesia. Lancet, 1999, Robinson M, White FJ, Cleary MA et al. Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J Pediat, 2000, Lombeck I, Kasperek K, Feinendegen LE et al. Serum-selenium concentrations in patients with maple-syrup-urine disease and phenylketonuria under diet therapy. Clin Chim Acta, 1975, Longhi R, Rottoli A, Vittorelli A et al. Trace elements nutriture in hyperphenylalaninemic patients. Long-term follow up study. Eur J Pediatr, 1987, 146(Suppl 1) A Reilly C, Barrett JE, Patterson CM et al. Trace element nutrition status and dietary intake of children with phenylketonuria. Am J Clin Nutr, 1990, Alves, MR, Starling AL, Kanufre VC et al. Selenium intake and nutritional status of children with phenylketonuria in Minas Gerais, Brazil. Jornal Pediatria, 2012, MacDonald A, Gum A, Daly A et al. The micronutrient status of patients with PKU on dietary treatment: an ongoing audit. SSIEM, Geneva. J Inherit Metab Dis, 2011, Abstract Barretto JR, Silva LR, Leite ME et al. Poor zinc and selenium status in phenylketonuric children and adolescents in Brazil. Nutr Res, 2008,

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14 124. Moats RA, Moseley KD, Koch R et al. Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics, 2003, 112 (6 Pt 2) van Spronsen FJ, de Groot MJ, Hoeksma M et al. Large neutral amino acids in the treatment of PKU: from theory to practice. J Inherit Metab Dis, 2010, van Spronsen FJ, Enns GM Future treatment strategies in phenylketonuria. Mol Genet Metab, 2010, 99(Suppl 1) S Matalon R, Surendran S, Matalon KM et al. Future role of large neutral amino acids in transport of phenylalanine into the brain. Pediatrics, 2003, 112(6 Pt 2) Koch R, Moseley KD, Yano S et al. Large neutral amino acid therapy and phenylketonuria: a promising approach to treatment. Mol Genet Metab, 2003, Kalkanoglu HS, Ahring KK, Sertkaya D et al. Behavioural effects of phenylalaninefree amino acid tablet supplementation in intellectually disabled adults with untreated phenylketonuria. Acta Paediatr, 2005, Matalon R, Michals-Matalon K, Bhatia G et al. Large neutral amino acids in the treatment of phenylketonuria (PKU). J Inherit Metab Dis, 2006, Matalon R, Michals-Matalon K, Bhatia G et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis, 2007, Schindeler S, Ghosh-Jerath S, Thompson S et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab, 2007, Lim K, van Calcar SC, Nelson KL et al. Acceptable low-phenylalanine foods and beverages can be made with glycomacropeptide from cheese whey for individuals with PKU. Mol Genet Metab, 2007,

15 134. Ney DM, Gleason ST, van Calcar SC et al. Nutritional management of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis, 2009, Ney DM, Hull AK, van Calcar SC et al. Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria. J Nutr, 2008, van Calcar SC, MacLeod EL, Gleason ST et al. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. Am J Clin Nutr, 2009, MacLeod EL, Clayton MK, van Calcar SC et al. Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. Mol Genet Metab, 2010, Cunningham A, Bausell H, Brown M et al. Recommendations for the use of sapropterin in phenylketonuria. Mol Genet Metab, 2012, Blau N, Erlandsen H The metabolic and molecular bases of tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency. Mol Genet Metab, 2004, Hennermann JB, Roloff S, Gebauer C et al. Long-term treatment with tetrahydrobiopterin in phenylketonuria: treatment strategies and prediction of longterm responders. Mol Genet Metab, 2012, Levy HL, Milanowski A, Chakrapani A et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebocontrolled study. Lancet, 2007, Trefz FK, Burton BK, Longo N et al. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr, 2009,

16 143. Keil S, Anjema K, van Spronsen FJ et al. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics, 2013, 131 e Ziesch B, Weigel J, Thiele A et al. Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life. J Inherit Metab Dis, 2012, Zurflüh MR, Zschocke J, Lindner M et al. Molecular genetics of tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency. Hum Mutat, 2008, Blau N, Bélanger-Quintana A, Demirkol M et al. Optimizing the use of sapropterin (BH4) in the management of phenylketonuria. Mol Genet Metab, 2009, Trefz FK, Scheible D, Frauendienst-Egger G Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment. J Inherit Metab Dis, 2010, March 9. Accessed 22 February Sarkissian CN, Gámez A, Wang L et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci USA, 2008, Sarkissian CN, Shao Z, Blain F et al. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc Natl Acad Sci USA, 1999, Sarkissian CN, Boulais DM, McDonald JD et al. A heteroallelic mutant mouse model: a new orthologue for human hyperphenylalaninemia. Mol Genet Metab, 2000, Gámez A, Sarkissian CN, Wang L et al. Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria. Mol Ther, 2005,

17 152. Biomarin Press Release, 26 September Harding CO, Gillingham MB, Hamman K et al. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vectormediated gene therapy in murine phenylketonuria. Gene Ther, 2006, Ding Z, Harding CO, Rebuffat A et al. Correction of murine PKU following AAVmediated intramuscular expression of a complete phenylalanine hydroxylating system. Mol Ther, 2008, Leandro J, Saraste J, Leandro P et al. The G46S-hPAH mutant protein: a model to study the rescue of aggregation-prone PKU mutations by chaperones. Mol Genet Metab, 2011, 104(Suppl) S Santos-Sierra S, Kirchmair J, Perna AM et al. Novel pharmacological chaperones that correct phenylketonuria in mice. Hum Mol Genet, 2012, Marriage B Nutrition management of patients with inherited disorders of branchedchain amino acid metabolism. In: Acosta PB (ed.) Nutrition Management of Patients with Inherited Metabolic Disorders. Massachusetts: Jones and Bartlett, 2010, pp Chuang DT, Wynn RM, Shih VE Maple syrup urine disease (branched-chain ketoaciduria). In: Valle D, Beaudet AL, Vogelstein B et al. (eds) The Online Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2008, Ch. 87, pp Accessed 1 February Treacy E, Clow CL, Reade TR et al. Maple syrup urine disease: interrelations between branched-chain amino-, oxo- and hydroxyacids: implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis, 1992, de Baulny HO, Dionisi-Vici C, Wendel U Branched-chain organic acidurias/acidaemias. In: Saudubray JM, van den Berghe G, Walter JH (eds) Inborn Metabolic Diseases Diagnosis and Treatment, 5th edn. Berlin: Springer-Verlag, 2012, pp

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