Phenylketonuria and Mental Retardation An urgent need for availability of therapeutic diet at National Level
Abstract
PKU is an autosomal recessive inborn error of amino acid metabolism (IEM) and the classic PKU disorder is characterised by a deficiency in phenylalanine hydroxylase (PAH) enzyme which is responsible for intellectual disability in this condition. In PKU patients, severe neurological and functional deficits can be prevented by early detection at neonatal level and strict nutritional treatment aimed at reducing blood Phenylalanine to non-toxic levels through a PKU diet. The outcome for patients with PKU treated from the first weeks of life is generally excellent with normal developmental milestones and good performance in schools. Significant clinical, psychological and neurocognitive abnormalities are observed in untreated patients and in those non-compliant with PKU.
New advances and challenges are constantly being explored in the nutritional management of PKU. Long term dietary guidance and monitoring of the nutritional status of patients with PKU should be a part of follow-up programme that continues for life. Paediatricians, geneticists and dieticians should prescribe and carefully monitor macronutrient and micronutrient intake, growth and physical activity in PKU patients. Despite the new advances and strategies, dietary treatment remains the main stay of PKU therapy. Issues and challenges for PKU screening, diagnosis and management are discussed with emphasis on hurdles in availability of special PKU medical food and urgency for local special diet in India. A need of national programme to cover rural & urban Indian population to tackle the diet issues and to maintain ‘Registry for PKU’ patients is the need of today.
This review article on therapeutic aspects and diet in Phenylketonuria (PKU) covers the information on the PKU disorder, clinical manifestations, pathophysiology, genetics of PKU, therapy concept and various modalities used so far in the development of therapies as well as the global and Indian scenario with regard to PKU diet and its management.
References
1. Guthrie R: Blood screening for phenylketonuria. JAMA 1961; 178(8):863.
2. Valle D, Beaudet AL, Voglstein B, Kinzler KW, Antonarakis SE, et al. (2012). The Online Metabolic & Molecular Basis of Inherited Disease.
3. Devi AR, Naushad SM. Newborn screening in India. Indian J Pediatr. 2004; 71: 157-160.
4. Blau N, Hennermann JB, Langenbeck U, et al. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104 Suppl:S2-9.
5. Centerwall SA and Centerwall WR:The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist, Pediatrics. 2000;105:89-103.
6. Folling A: Phenylpyruvic acid as a metabolic anomaly in connection with imbecility. Nord Med Tudskr.1934;8:1054-1059.
7. Bickel H, Gerrad J, Hickmans EM: Influence of phenylalanine intake on phenylketonuria. Lancet.1953; 265(6790):812- 813.
8. Guthrie R and Susi A: A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963; 32:338-343.
9. François R, Yves G, Thérèse M, Guérette D, Girard J and Déry M: Newborn Screening By Tandem Mass Spectrometry: Impacts, Implications and Perspectives, Tandem Mass
Spectrometry - Applications and Principles; Dr Jeevan Prasain (Ed.). 2012; ISBN: 978-953-51-0141-3.
10. Williams RA: Phenylketonuria: An Inborn Error of Phenylalanine Metabolism.Clin Biochem Rev. 2008;29(1): 31–41.
11. Scriver CR, Hurtubise M, Konecki D, Phommarinh M, Prevost L, Erlandsen H, Stevens R et al.PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat. 2003;21(4):333-44.
12. Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly SW, et al. editors. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill, 2001:1667-724.
13. Levy HL and Ghavama M: Maternal phenylketonuria: A metabolic teratogen. Teratology. 1996; 53:176–184.
14. Hanley WB, Azen C, Koch R, Michals-Matalon K, Matalon R et al. Maternal PKU Collaborative Study – The “Outliers”. J Inherit Metab Dis.2004; 27: 711-723.
15. Weglage J, Pietsch R, Feldman R, Koch H-G, Zschocke J et al. Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res. 2001; 49: 532-546.
16. Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest.
1999; 103(8): 1169–1178.
17. Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG, Brenton DP. Brain MRI changes in phenylketonuria. Association with dietary status. Brain. 1993;116: 811-21.
18. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP. Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 1995;127:251-5.
19. Bashyam MD et al: Phenylalanine hydroxylase gene mutations in phenylketonuria patients from India: Identification of novel mutations that affect PAH RNA, Molecular Genetics and Metabolism. 2010: 100 96–99.
20. PAH:Phenylalanine hydroxylase locus knowledgebase. Available From–http://www.pahdb.mcgill.ca/ (Accessed 12 April 2007).
21. AAP Newborn Screening Task Force.Newborn screening: a blueprint for the future. A call for a national agenda on state newborn screening programs:Pediatrics 2000;106(Suppl):389-422.
22.Trahms CM. Program for phenylketonuria, Seattle: Washington State newborn Screening Program 2008.
23.Phenylketonuria (PKU): screening and management. NIH Consensus statement 2000; 17:1-33.
24.Management of PKU: A consensus document for the diagnosis and management of children, adolescents and adults with phenylketonuria, The National Society for Phenylketonuria (United Kingdom) Ltd; 2004.
25. Indian Council of Medical Research (ICMR). Newborn Screening -Pilot Project for CH & CAH: 2007.
26. Kapoor S, Kabra M: Newborn Screening in India: Current Perspective. Indian J Pediatrics 2010; 47:219-224.
27. Wilson JMG, Jungner F. Principles and Practice of Screening for Disease. Public Health Papers, No. 34. Geneva, Switzerland: World Health Organization; 1968.
28. Rao NA, Devi AR, Savithri HS et al: Neonatal screening for amino acid disorders in Karnataka, South India. Clin Genet. 1988; 34:60-63.
29. Dave UP, Das BR. Newborn Screening-From Guthrie age to Genomic age. J Obstet Gynecol India. 2010; 60(3);210-220.
30. Blaskovics ME, Nelson TL. Phenylketonuria and its variations. A review of recent developments. Calif Med.1971;115:42-57.
31. Williamson M, Dobson JC, Koch R. Collaborative study of children treated for phenylketonuria: study design. Pediatrics 1977;60:815-21.
32. Acosta PB, Matalon KM. Nutrition management of patients with inherited disorders of aromatic amino acid metabolism. In: Acosta PB, editors. Nutrition Management of Patients with Inherited Metabolic Disorders. Boston: Jones and Bartlett Publishers, 2010:119-74.
33. Matalon R, Michals-Matalon K, Bhatia G, et al. Large neutral amino acids in the treatment of phenylketonuria (PKU). J Inherit Metab. Dis 2006;29:732-8.
34. Van Spronsen FJ, Enns GM. Future treatment strategies in phenylketonuria. Mol Genet Metab 2010;99 Suppl 1:S90-5.
35. Beblo S, Reinhardt H, Muntau A et al : Fish oil supplementation improve visual evoked potentials in children with Phenylkeonuria. Neurology, 2001; 57(8): 1488-1491.
36. Hanley WB. Phenylketonuria (PKU)-What Next? Mini- Review. J Genetic Disorder Rep. J Genet Disor Genet Rep 2013; 2(2)
37. Hafid NA, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015;4(4):304- 317
38. Kaufman S, Berlow S, Summer GK et al. Hyperphenylalaninemia Due to a Deficiency of Biopterin. N Engl J Med. 1978;299:673-9.
39. Danks DM, Schlesinger P, Firgaira F, Cotton RGH, Watson BM, Rembold H, Hennings G.Malignant Hyperphenylalaninemia-Clinical Features, Biochemical Findings, and
Experience with Administration of Biopterins.Pediat. Res. 1979; 13:1150-115.5.
40. Hennermann JB, Bührer C, Blau N, Vetter B and Mönch E. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab. 2005; 86(Suppl):S86-90.
41. Schaub J, Däumling S, Curtius HC et al. Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child. 1978;53:674-6.
42. Kure S, Hou DC, Ohura Tet al. Tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency. J Pediatr. 1999;135:375-8.
43. Hoskins JA, Jack G, Wade HE et al. Enzymatic control of phenylalanine intake in phenylketonuria. Lancet. 1980;1:392-4.
44. Rocha JC, Martel F. Large neutral amino acids supplementation in phenylketonuric patients. J InheritMetab Dis. 2009;32:472-80.
45. 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;92 :176-8.
46. Ney DM, Gleason ST, van Calcar SC, et al. Nutritional management of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis. 2009;32:32-9.
47. USA & WHO, 2001 report :Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Food and Agriculture Organization of the United Nations
and World Health Organization expert consultation report, FAO, Rome, Italy, 2001. Available online.
48. Vajro P, Strisciuglio P, Houssin D, Huault G, Laurent J et al. Correction of phenylketonuria after liver transplantation in a child with cirrhosis. N Engl J Med. 1993;329:363.
49. Fang B, Eisensmith RC, Li XH et al. Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Gene Ther. 1994;1:247-54.
50. Ding Z, Harding CO, Thöny B. State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab. 2004; 81:3-8.
51. Oh HJ, Park ES, Kang S, Jo I, Jung SC. Longterm enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vector-mediated gene transfer. Pediatr Res. 2004;56: 278-84.
52. Wappner R, Cho S, Kronmal RA et al. Management of phenylketonuria for optimal outcome: a review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors. Pediatrics. 1999;104:e68.
53. Moyle JJ, Fox AM, Arthur M et al. Meta-Analysis of Neuropsychological Symptoms of Adolescents and Adults with PKU. Neuropsychol Rev. 2007;17:91-101.
54. Rampini S, Vollmin JA, Bosshard HR, M. Muller, and Curtius HC: Aromatic Acids inUrine of Healthy Infants, Persistent Hyperphenylalaninemia, and Phenylketonuria, before and after Phenylalanine Load.Pediat Res. 1974; 8:704- 709.
55. Marholin D, Pohl RE, Stewart RM, Touchette PE, Townsend NM, and Kolodny EH. Effects of Diet and Behavior Therapy on Social and Motor Behavior of Retarded Phenylketonuric Adults: An Experimental Analysis. Pediat. Res. 1978, 2:179- 187.
56. Rao P: Prenatal Diagnosis of Phenylketonuria.Indian J Med Res. 2005; 122:400-403.
57. Kurpad AV, Meredith RM, Tony DS Raj, Rao VN, Gnanou J, and Vernon RY: The daily phenylalanine requirement of healthy Indian adults.Am J Clin Nutr. 2006; 83:1331–1336.
58. Koch R, Hanley W, Levy H, Matalon K, Matalon R,Rouse B, Trefz F, Flemming G et al.The Maternal Phenylketonuria International Study: 1984–2002Pediatrics.2003; 112:1523.
59. Lee PJ, Ridout D, Walter JH and Cockburn F:Maternal phenylketonuria: report from the United Kingdom Registry 1978-97. Arch Dis Child. 2005; 90:143-146.
60. Shaw-Smith C, Hogg SL, Reading R, Calvin J, Trump D.Learning and behavioural difficulties but not microcephaly in three brothers resulting from undiagnosed maternal phenylketonuria. Child Care Health Dev. 2004;30:551-555.
61. American Academy of Pediatrics: Committee on Genetics. Maternal phenylketonuria. Pediatrics 2001;107:427-428.
62. Kumar KR. Newborn Screening in India: What are the Challenges and Pitfalls? Pediatric Oncall. [serial online] 2014[cited 2014 October-December 1]; 11. Art #69. Available From – http://www.pediatriconcall.com/Journal/Article/ FullText.aspx?artid=903&type=J&tid=&imgid=&reportid=4 73&tbltype=.
2. Valle D, Beaudet AL, Voglstein B, Kinzler KW, Antonarakis SE, et al. (2012). The Online Metabolic & Molecular Basis of Inherited Disease.
3. Devi AR, Naushad SM. Newborn screening in India. Indian J Pediatr. 2004; 71: 157-160.
4. Blau N, Hennermann JB, Langenbeck U, et al. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104 Suppl:S2-9.
5. Centerwall SA and Centerwall WR:The discovery of phenylketonuria: the story of a young couple, two retarded children, and a scientist, Pediatrics. 2000;105:89-103.
6. Folling A: Phenylpyruvic acid as a metabolic anomaly in connection with imbecility. Nord Med Tudskr.1934;8:1054-1059.
7. Bickel H, Gerrad J, Hickmans EM: Influence of phenylalanine intake on phenylketonuria. Lancet.1953; 265(6790):812- 813.
8. Guthrie R and Susi A: A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963; 32:338-343.
9. François R, Yves G, Thérèse M, Guérette D, Girard J and Déry M: Newborn Screening By Tandem Mass Spectrometry: Impacts, Implications and Perspectives, Tandem Mass
Spectrometry - Applications and Principles; Dr Jeevan Prasain (Ed.). 2012; ISBN: 978-953-51-0141-3.
10. Williams RA: Phenylketonuria: An Inborn Error of Phenylalanine Metabolism.Clin Biochem Rev. 2008;29(1): 31–41.
11. Scriver CR, Hurtubise M, Konecki D, Phommarinh M, Prevost L, Erlandsen H, Stevens R et al.PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat. 2003;21(4):333-44.
12. Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly SW, et al. editors. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill, 2001:1667-724.
13. Levy HL and Ghavama M: Maternal phenylketonuria: A metabolic teratogen. Teratology. 1996; 53:176–184.
14. Hanley WB, Azen C, Koch R, Michals-Matalon K, Matalon R et al. Maternal PKU Collaborative Study – The “Outliers”. J Inherit Metab Dis.2004; 27: 711-723.
15. Weglage J, Pietsch R, Feldman R, Koch H-G, Zschocke J et al. Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res. 2001; 49: 532-546.
16. Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest.
1999; 103(8): 1169–1178.
17. Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG, Brenton DP. Brain MRI changes in phenylketonuria. Association with dietary status. Brain. 1993;116: 811-21.
18. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP. Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 1995;127:251-5.
19. Bashyam MD et al: Phenylalanine hydroxylase gene mutations in phenylketonuria patients from India: Identification of novel mutations that affect PAH RNA, Molecular Genetics and Metabolism. 2010: 100 96–99.
20. PAH:Phenylalanine hydroxylase locus knowledgebase. Available From–http://www.pahdb.mcgill.ca/ (Accessed 12 April 2007).
21. AAP Newborn Screening Task Force.Newborn screening: a blueprint for the future. A call for a national agenda on state newborn screening programs:Pediatrics 2000;106(Suppl):389-422.
22.Trahms CM. Program for phenylketonuria, Seattle: Washington State newborn Screening Program 2008.
23.Phenylketonuria (PKU): screening and management. NIH Consensus statement 2000; 17:1-33.
24.Management of PKU: A consensus document for the diagnosis and management of children, adolescents and adults with phenylketonuria, The National Society for Phenylketonuria (United Kingdom) Ltd; 2004.
25. Indian Council of Medical Research (ICMR). Newborn Screening -Pilot Project for CH & CAH: 2007.
26. Kapoor S, Kabra M: Newborn Screening in India: Current Perspective. Indian J Pediatrics 2010; 47:219-224.
27. Wilson JMG, Jungner F. Principles and Practice of Screening for Disease. Public Health Papers, No. 34. Geneva, Switzerland: World Health Organization; 1968.
28. Rao NA, Devi AR, Savithri HS et al: Neonatal screening for amino acid disorders in Karnataka, South India. Clin Genet. 1988; 34:60-63.
29. Dave UP, Das BR. Newborn Screening-From Guthrie age to Genomic age. J Obstet Gynecol India. 2010; 60(3);210-220.
30. Blaskovics ME, Nelson TL. Phenylketonuria and its variations. A review of recent developments. Calif Med.1971;115:42-57.
31. Williamson M, Dobson JC, Koch R. Collaborative study of children treated for phenylketonuria: study design. Pediatrics 1977;60:815-21.
32. Acosta PB, Matalon KM. Nutrition management of patients with inherited disorders of aromatic amino acid metabolism. In: Acosta PB, editors. Nutrition Management of Patients with Inherited Metabolic Disorders. Boston: Jones and Bartlett Publishers, 2010:119-74.
33. Matalon R, Michals-Matalon K, Bhatia G, et al. Large neutral amino acids in the treatment of phenylketonuria (PKU). J Inherit Metab. Dis 2006;29:732-8.
34. Van Spronsen FJ, Enns GM. Future treatment strategies in phenylketonuria. Mol Genet Metab 2010;99 Suppl 1:S90-5.
35. Beblo S, Reinhardt H, Muntau A et al : Fish oil supplementation improve visual evoked potentials in children with Phenylkeonuria. Neurology, 2001; 57(8): 1488-1491.
36. Hanley WB. Phenylketonuria (PKU)-What Next? Mini- Review. J Genetic Disorder Rep. J Genet Disor Genet Rep 2013; 2(2)
37. Hafid NA, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015;4(4):304- 317
38. Kaufman S, Berlow S, Summer GK et al. Hyperphenylalaninemia Due to a Deficiency of Biopterin. N Engl J Med. 1978;299:673-9.
39. Danks DM, Schlesinger P, Firgaira F, Cotton RGH, Watson BM, Rembold H, Hennings G.Malignant Hyperphenylalaninemia-Clinical Features, Biochemical Findings, and
Experience with Administration of Biopterins.Pediat. Res. 1979; 13:1150-115.5.
40. Hennermann JB, Bührer C, Blau N, Vetter B and Mönch E. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab. 2005; 86(Suppl):S86-90.
41. Schaub J, Däumling S, Curtius HC et al. Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child. 1978;53:674-6.
42. Kure S, Hou DC, Ohura Tet al. Tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency. J Pediatr. 1999;135:375-8.
43. Hoskins JA, Jack G, Wade HE et al. Enzymatic control of phenylalanine intake in phenylketonuria. Lancet. 1980;1:392-4.
44. Rocha JC, Martel F. Large neutral amino acids supplementation in phenylketonuric patients. J InheritMetab Dis. 2009;32:472-80.
45. 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;92 :176-8.
46. Ney DM, Gleason ST, van Calcar SC, et al. Nutritional management of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis. 2009;32:32-9.
47. USA & WHO, 2001 report :Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Food and Agriculture Organization of the United Nations
and World Health Organization expert consultation report, FAO, Rome, Italy, 2001. Available online.
48. Vajro P, Strisciuglio P, Houssin D, Huault G, Laurent J et al. Correction of phenylketonuria after liver transplantation in a child with cirrhosis. N Engl J Med. 1993;329:363.
49. Fang B, Eisensmith RC, Li XH et al. Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Gene Ther. 1994;1:247-54.
50. Ding Z, Harding CO, Thöny B. State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab. 2004; 81:3-8.
51. Oh HJ, Park ES, Kang S, Jo I, Jung SC. Longterm enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vector-mediated gene transfer. Pediatr Res. 2004;56: 278-84.
52. Wappner R, Cho S, Kronmal RA et al. Management of phenylketonuria for optimal outcome: a review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors. Pediatrics. 1999;104:e68.
53. Moyle JJ, Fox AM, Arthur M et al. Meta-Analysis of Neuropsychological Symptoms of Adolescents and Adults with PKU. Neuropsychol Rev. 2007;17:91-101.
54. Rampini S, Vollmin JA, Bosshard HR, M. Muller, and Curtius HC: Aromatic Acids inUrine of Healthy Infants, Persistent Hyperphenylalaninemia, and Phenylketonuria, before and after Phenylalanine Load.Pediat Res. 1974; 8:704- 709.
55. Marholin D, Pohl RE, Stewart RM, Touchette PE, Townsend NM, and Kolodny EH. Effects of Diet and Behavior Therapy on Social and Motor Behavior of Retarded Phenylketonuric Adults: An Experimental Analysis. Pediat. Res. 1978, 2:179- 187.
56. Rao P: Prenatal Diagnosis of Phenylketonuria.Indian J Med Res. 2005; 122:400-403.
57. Kurpad AV, Meredith RM, Tony DS Raj, Rao VN, Gnanou J, and Vernon RY: The daily phenylalanine requirement of healthy Indian adults.Am J Clin Nutr. 2006; 83:1331–1336.
58. Koch R, Hanley W, Levy H, Matalon K, Matalon R,Rouse B, Trefz F, Flemming G et al.The Maternal Phenylketonuria International Study: 1984–2002Pediatrics.2003; 112:1523.
59. Lee PJ, Ridout D, Walter JH and Cockburn F:Maternal phenylketonuria: report from the United Kingdom Registry 1978-97. Arch Dis Child. 2005; 90:143-146.
60. Shaw-Smith C, Hogg SL, Reading R, Calvin J, Trump D.Learning and behavioural difficulties but not microcephaly in three brothers resulting from undiagnosed maternal phenylketonuria. Child Care Health Dev. 2004;30:551-555.
61. American Academy of Pediatrics: Committee on Genetics. Maternal phenylketonuria. Pediatrics 2001;107:427-428.
62. Kumar KR. Newborn Screening in India: What are the Challenges and Pitfalls? Pediatric Oncall. [serial online] 2014[cited 2014 October-December 1]; 11. Art #69. Available From – http://www.pediatriconcall.com/Journal/Article/ FullText.aspx?artid=903&type=J&tid=&imgid=&reportid=4 73&tbltype=.
Published
2019-07-31
How to Cite
U P Dave. (2019). Phenylketonuria and Mental Retardation An urgent need for availability of therapeutic diet at National Level. The Indian Practitioner, 69(1), 52-61. Retrieved from https://articles.theindianpractitioner.com/index.php/tip/article/view/506
Section
Review article
