Research Overview

Dr. Levy directs a clinical research group that is studying the effect of innovative therapies for phenylketonuria (PKU). His group has examined the role of cofactor therapy for stimulating phenylalanine hydroxylase (PAH) and is currently a major site for a clinical trial of alternative enzyme therapy of PKU. Dr. Levy is also an investigator for the national study of the natural history and treatment of urea cycle disorders, a study examining brain imagining in PKU, and a study to determine the feasibility of next generation sequencing in newborn screening.

Laboratory Projects

  1. Cofactor Therapy for PKU: Dietary therapy has been enormously successful in PKU, converting a disease that produced intellectual disability into a disorder that can result in normal growth and development. However, the diet is extremely difficult and because of this most adults and many adolescents do not follow the diet as required, resulting in long-term problems. Some individuals with PKU respond to megadoses of sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), with increased activity of PAH, the defective enzyme in PKU. This results in a lower phenylalanine level and greater tolerance of natural foods, alleviating some of the difficulties of the diet. Our ongoing work is in examining the benefits and long-term results of cofactor treatment in PKU.
     
  2. Alternative Enzyme Therapy for PKU:Phenylalanine ammonia lyase (PAL) is an enzyme that has been found to metabolize phenylalanine in a different direction from the natural pathway that is blocked in PKU. Consequently, this enzyme reduces the blood phenylalanine level in those with PKU and may serve as therapy for PKU, perhaps substituting for the difficult diet. Ongoing studies are examining this therapy to determine if it is safe and offers long-term treatment for PKU.

Research Background

Dr. Levy obtained his M.D. degree from the Medical College of Georgia. Following residences in Pediatrics and Pediatric Pathology at Boston City Hospital, Columbia- Presbyterian Medical Center in New York, and Johns Hopkins Hospital in Baltimore, he served a fellowship in Metabolism under Drs. Mary Efron and Hugo Moser at the Massachusetts General Hospital. Subsequently, Dr. Levy was on the faculty at the Massachusetts General Hospital and also served as Consultant and then Director of the Massachusetts Metabolic Disorders Program. When the New England Newborn Screening Program was established, Dr. Levy became the Chief of Biochemical Genetics.

In 1978, Dr. Levy moved to Boston Children’s Hospital as Director of the Metabolic Program where he expanded the program from a PKU clinic to inborn errors of metabolism, and at the same time directed the New England Maternal PKU Program. Dr. Levy has served as Chair of the Workgroup on Newborn Screening and Follow-Up and Chair of the Newborn Screening Translational Research Network for the American College of Medical Genetics. He is a reviewer for many leading medical journals, is on the Editorial Board of the International Journal of Neonatal Screening, has served on several research advisory boards, is a consultant for several laboratories that are developing new metabolic treatments, has published over 450 peer-reviewed articles on metabolic disorders, and has received a number of national and international awards and honors for research in newborn screening and biochemical genetics.

Selected Publications

  1. S.E. Waisbren, F. Rohr, V. Anastasoaie, M. Brown, D. Harris, A. Ozonoff, S. Petrides, A. Wessel, H.L. Levy. Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics. JIMD Rep. 2015;21:23-33. doi: 10.1007/8904_2014_365. Epub 2015 Feb 25.
  2. Landau YE, Lichter-Konecki U, Levy HL. Genomics in newborn screening. J Pediatr, 2014;164:14-9.
  3. Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz F, Whitely C, Feillet F, Feigenbaum A, Bebchuk J, Christ-Schmidt H, Dorenbaum A, for the Sapropterin Research Group. A Phase-III randomized placebo-controlled study of the efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6-BH4) in reducing phenylalanine levels in subjects with phenylketonuria. Lancet, 2007; 370:504-10.
  4. Levy HL, Burton B, Cederbaum S, Scriver C. Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment. Molec Genet Metab, 2007;92:287-91.

Education

Medical School

Medical College of Georgia
1960 Augusta GA

Internship

Boston City Hospital
1961 Boston MA

Residency

Columbia-Presbyterian Medical Center
1962 New York NY

Residency

Johns Hopkins Hospital
1965 New York NY

Residency

Boston City Hospital
1966 Boston MA

Fellowship

Massachusetts General Hospital
1968 Boston MA

Publications

  1. Past as Prologue: Predicting Potential Psychosocial-Ethical Burdens of Positive Newborn Screens as Conditions Propagate. Int J Neonatal Screen. 2024 Feb 06; 10(1). View Abstract
  2. The treatment of biochemical genetic diseases: From substrate reduction to nucleic acid therapies. Mol Genet Metab. 2023 11; 140(3):107693. View Abstract
  3. Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman. JIMD Rep. 2023 Sep; 64(5):312-316. View Abstract
  4. In memoriam: Charles Robert Scriver, CM, CC, GOQ, FRS, FRSC (1930-2023). J Inherit Metab Dis. 2023 Jul; 46(4):756-757. View Abstract
  5. Is More Effective Newborn Screening for Homocystinuria on the Horizon? Clin Chem. 2023 04 28; 69(5):433-434. View Abstract
  6. The hypergonadotropic hypogonadism conundrum of classic galactosemia. Hum Reprod Update. 2023 03 01; 29(2):246-258. View Abstract
  7. Charles Scriver: Epitome of the physician scientist. Mol Genet Metab. 2022 Dec; 137(4):388-398. View Abstract
  8. Early Development of Newborn Screening for HCU and Current Challenges. Int J Neonatal Screen. 2021 Oct 25; 7(4). View Abstract
  9. Pancreatic involvement in patients with inborn errors of metabolism. Orphanet J Rare Dis. 2021 01 20; 16(1):37. View Abstract
  10. Robert Guthrie and the Trials and Tribulations of Newborn Screening. Int J Neonatal Screen. 2021 Jan 19; 7(1). View Abstract
  11. Ethical and Psychosocial Implications of Genomic Newborn Screening. Int J Neonatal Screen. 2021 Jan 09; 7(1). View Abstract
  12. The Genetic Landscape and Epidemiology of Phenylketonuria. Am J Hum Genet. 2020 08 06; 107(2):234-250. View Abstract
  13. Discontinuation of Pegvaliase therapy during maternal PKU pregnancy and postnatal breastfeeding: A case report. Mol Genet Metab Rep. 2020 Mar; 22:100555. View Abstract
  14. Can Newborn Screening for Vitamin B12 Deficiency be Incorporated into All Newborn Screening Programs? J Pediatr. 2020 01; 216:9-11.e1. View Abstract
  15. Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study. Mol Genet Metab. 2019 12; 128(4):415-421. View Abstract
  16. Phenotypic variability in deficiency of the a subunit of succinate-CoA ligase. JIMD Rep. 2019 Mar; 46(1):63-69. View Abstract
  17. The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency. Mol Genet Metab. 2019 04; 126(4):368-376. View Abstract
  18. Revising the Psychiatric Phenotype of Homocystinuria. Genet Med. 2019 08; 21(8):1827-1831. View Abstract
  19. Untargeted metabolomics identifies unique though benign biochemical changes in patients with pathogenic variants in UROC1. Mol Genet Metab Rep. 2019 Mar; 18:14-18. View Abstract
  20. The BabySeq project: implementing genomic sequencing in newborns. BMC Pediatr. 2018 07 09; 18(1):225. View Abstract
  21. Phenylalanine ammonia lyase (PAL): From discovery to enzyme substitution therapy for phenylketonuria. Mol Genet Metab. 2018 08; 124(4):223-229. View Abstract
  22. Acute Illness Protocol for Urea Cycle Disorders. Pediatr Emerg Care. 2018 Jun; 34(6):e115-e119. View Abstract
  23. Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria. J Nutr. 2018 02 01; 148(2):194-201. View Abstract
  24. Acute Illness Protocol for Maple Syrup Urine Disease. Pediatr Emerg Care. 2018 Jan; 34(1):64-67. View Abstract
  25. Metabolomic Insights into the Nutritional Status of Adults and Adolescents with Phenylketonuria Consuming a Low-Phenylalanine Diet in Combination with Amino Acid and Glycomacropeptide Medical Foods. J Nutr Metab. 2017; 2017:6859820. View Abstract
  26. Dietary amino acid intakes associated with a low-phenylalanine diet combined with amino acid medical foods and glycomacropeptide medical foods and neuropsychological outcomes in subjects with phenylketonuria. Data Brief. 2017 Aug; 13:377-384. View Abstract
  27. Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria. Mol Genet Metab. 2017 06; 121(2):96-103. View Abstract
  28. Acute Illness Protocol for Fatty Acid Oxidation and Carnitine Disorders. Pediatr Emerg Care. 2017 Apr; 33(4):296-301. View Abstract
  29. Acute Illness Protocol for Organic Acidemias: Methylmalonic Acidemia and Propionic Acidemia. Pediatr Emerg Care. 2017 Feb; 33(2):142-146. View Abstract
  30. Long-term outcome of expanded newborn screening at Boston children's hospital: benefits and challenges in defining true disease. J Inherit Metab Dis. 2017 03; 40(2):209-218. View Abstract
  31. Confounding factors in identification of disease-resilient individuals. Nat Biotechnol. 2016 11 08; 34(11):1103-1104. View Abstract
  32. Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial. Am J Clin Nutr. 2016 Aug; 104(2):334-45. View Abstract
  33. The remarkable S. Harvey Mudd - A reminiscence. Mol Genet Metab. 2016 07; 118(3):143-144. View Abstract
  34. Hyperphenylalaninemia and the genomic revolution. Mol Genet Metab. 2015 Mar; 114(3):380-1. View Abstract
  35. Adherence to tetrahydrobiopterin therapy in patients with phenylketonuria. Mol Genet Metab. 2015 Jan; 114(1):25-8. View Abstract
  36. The complexity of newborn screening follow-up in phenylketonuria. JIMD Rep. 2014; 17:37-9. View Abstract
  37. Management of a Woman With Maple Syrup Urine Disease During Pregnancy, Delivery, and Lactation. JPEN J Parenter Enteral Nutr. 2015 Sep; 39(7):875-9. View Abstract
  38. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014 Jun; 112(2):87-122. View Abstract
  39. Newborn screening: the genomic challenge. Mol Genet Genomic Med. 2014 Mar; 2(2):81-4. View Abstract
  40. Genomics in newborn screening. J Pediatr. 2014 Jan; 164(1):14-9. View Abstract
  41. Is melatonin synthesis a new biomarker for the pathogenesis and treatment of phenylketonuria? J Pediatr. 2013 May; 162(5):893-4. View Abstract
  42. Congenital heart disease in maternal PKU. Mol Genet Metab. 2012 Dec; 107(4):648-9. View Abstract
  43. A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders. Eur J Hum Genet. 2013 Jan; 21(1):115-7. View Abstract
  44. The adult galactosemic phenotype. J Inherit Metab Dis. 2012 Mar; 35(2):279-86. View Abstract
  45. Newborn screening conditions: What we know, what we do not know, and how we will know it. Genet Med. 2010 Dec; 12(12 Suppl):S213-4. View Abstract
  46. Phenylketonuria. Lancet. 2010 Oct 23; 376(9750):1417-27. View Abstract
  47. Sudden death in medium chain acyl-coenzyme a dehydrogenase deficiency (MCADD) despite newborn screening. Mol Genet Metab. 2010 Sep; 101(1):33-9. View Abstract
  48. Newborn screening of lysosomal storage disorders. Clin Chem. 2010 Jul; 56(7):1071-9. View Abstract
  49. Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Mol Genet Metab. 2007 Dec; 92(4):287-91. View Abstract
  50. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet. 2007 Aug 11; 370(9586):504-10. View Abstract
  51. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007 Sep-Oct; 92(1-2):63-70. View Abstract
  52. Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles. Mol Genet Metab. 2007 Jul; 91(3):218-27. View Abstract
  53. Pericardial effusion in primary systemic carnitine deficiency. J Inherit Metab Dis. 2006 Aug; 29(4):589. View Abstract
  54. Newborn screening for metabolic disorders. J Pediatr. 2006 May; 148(5):577-584. View Abstract
  55. Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab. 2006 Jun; 88(2):138-45. View Abstract
  56. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006 Jul; 88(3):201-7. View Abstract
  57. The clinical aspects of newborn screening: importance of newborn screening follow-up. Ment Retard Dev Disabil Res Rev. 2006; 12(4):246-54. View Abstract
  58. Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet Gynecol. 2006 Jan; 107(1):115-20. View Abstract
  59. Metabolic disorders in the center of genetic medicine. N Engl J Med. 2005 Nov 03; 353(18):1968-70. View Abstract
  60. Krabbe disease: severe neonatal presentation with a family history of multiple sclerosis. J Child Neurol. 2005 Oct; 20(10):826-8. View Abstract
  61. Brief report: Predictors of parenting stress among parents of children with biochemical genetic disorders. J Pediatr Psychol. 2004 Oct; 29(7):565-70. View Abstract
  62. Expanded screening of newborns for genetic disorders. JAMA. 2004 Feb 18; 291(7):820-1; author reply 821. View Abstract
  63. Historical background for the maternal PKU syndrome. Pediatrics. 2003 Dec; 112(6 Pt 2):1516-8. View Abstract
  64. Research design, organization, and sample characteristics of the Maternal PKU Collaborative Study. Pediatrics. 2003 Dec; 112(6 Pt 2):1519-22. View Abstract
  65. The Maternal Phenylketonuria International Study: 1984-2002. Pediatrics. 2003 Dec; 112(6 Pt 2):1523-9. View Abstract
  66. Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome. Pediatrics. 2003 Dec; 112(6 Pt 2):1530-3. View Abstract
  67. Pregnancy experiences in the woman with mild hyperphenylalaninemia. Pediatrics. 2003 Dec; 112(6 Pt 2):1548-52. View Abstract
  68. Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress. JAMA. 2003 Nov 19; 290(19):2564-72. View Abstract
  69. Lessons from the past--looking to the future. Newborn screening. Pediatr Ann. 2003 Aug; 32(8):505-8. View Abstract
  70. Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH). Mol Genet Metab. 2003 Aug; 79(4):272-80. View Abstract
  71. Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap. Mol Genet Metab. 2003 May; 79(1):6-16. View Abstract
  72. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr. 2003 Mar; 142(3):349-52. View Abstract
  73. Expanded newborn screening using tandem mass spectrometry. Adv Pediatr. 2003; 50:81-111. View Abstract
  74. Neonatal screening for medium--chain acyl-CoA dehydrogenase deficiency. Lancet. 2002 Feb 16; 359(9306):628. View Abstract

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