Biopterin responsive phenylalanine hydroxylase deficiency

Reuben Matalon, Richard Koch, Kimberlee Michals-Matalon, Kathryn Moseley, Sankar Surendran, Stephen Tyring, Heidi Erlandsen, Alejandra Gamez, Raymond C. Stevens, Anne Romstad, Lisbeth B. Møller, Flemming Guttler

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Purpose: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. There have been more than 400 mutations identified in the PAH gene leading to variable degrees of deficiency in PAH activity, and consequently a wide spectrum of clinical severity. A pilot study was undertaken to examine the response to 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in patients with atypical and classical PKU. Methods: PAH gene mutation analysis was performed using denaturing gradient gel electrophoresis and gene sequencing. Patients with classical, atypical, or mild PKU were orally given BH4 10 mg/kg. Blood phenylalanine and tyrosine levels were determined using tandem MS/MS at 0 hours, 4 hours, 8 hours, and 24 hours intervals. Results: Thirty-six patients were given a single oral dose of 10 mg/kg of BH4. Twenty one patients (58.33%) responded with a decrease in blood phenylalanine level. Of the patients that responded, 12 were classical, 7 atypical, and 2 mild. The mean decline in blood phenylalanine at 24 hours was > 30% of baseline. There were 15 patients who did not respond to the BH4 challenge, 14 of those had classical and one had atypical PKU. Mapping the mutations that responded to BH4 on the PAH enzyme showed that mutations were in the catalytic, regulatory, oligomerization, and BH4 binding domains. Five patients responding to BH4 had mutations not previously identified. Conclusion: The data presented suggest higher than anticipated number of PKU mutations respond to BH4, and such mutations are on all the domains of PAH.

Original languageEnglish
Pages (from-to)27-32
Number of pages6
JournalGenetics in Medicine
Volume6
Issue number1
DOIs
StatePublished - Jan 2004

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Biopterin
Phenylketonurias
Phenylalanine Hydroxylase
Mutation
Phenylalanine
Genes
Denaturing Gradient Gel Electrophoresis
Tyrosine

Keywords

  • BH
  • Phenylalanine
  • Phenylketonuria
  • PKU
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Matalon, R., Koch, R., Michals-Matalon, K., Moseley, K., Surendran, S., Tyring, S., ... Guttler, F. (2004). Biopterin responsive phenylalanine hydroxylase deficiency. Genetics in Medicine, 6(1), 27-32. https://doi.org/10.1097/01.GIM.0000108840.17922.A7

Biopterin responsive phenylalanine hydroxylase deficiency. / Matalon, Reuben; Koch, Richard; Michals-Matalon, Kimberlee; Moseley, Kathryn; Surendran, Sankar; Tyring, Stephen; Erlandsen, Heidi; Gamez, Alejandra; Stevens, Raymond C.; Romstad, Anne; Møller, Lisbeth B.; Guttler, Flemming.

In: Genetics in Medicine, Vol. 6, No. 1, 01.2004, p. 27-32.

Research output: Contribution to journalArticle

Matalon, R, Koch, R, Michals-Matalon, K, Moseley, K, Surendran, S, Tyring, S, Erlandsen, H, Gamez, A, Stevens, RC, Romstad, A, Møller, LB & Guttler, F 2004, 'Biopterin responsive phenylalanine hydroxylase deficiency', Genetics in Medicine, vol. 6, no. 1, pp. 27-32. https://doi.org/10.1097/01.GIM.0000108840.17922.A7
Matalon R, Koch R, Michals-Matalon K, Moseley K, Surendran S, Tyring S et al. Biopterin responsive phenylalanine hydroxylase deficiency. Genetics in Medicine. 2004 Jan;6(1):27-32. https://doi.org/10.1097/01.GIM.0000108840.17922.A7
Matalon, Reuben ; Koch, Richard ; Michals-Matalon, Kimberlee ; Moseley, Kathryn ; Surendran, Sankar ; Tyring, Stephen ; Erlandsen, Heidi ; Gamez, Alejandra ; Stevens, Raymond C. ; Romstad, Anne ; Møller, Lisbeth B. ; Guttler, Flemming. / Biopterin responsive phenylalanine hydroxylase deficiency. In: Genetics in Medicine. 2004 ; Vol. 6, No. 1. pp. 27-32.
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abstract = "Purpose: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. There have been more than 400 mutations identified in the PAH gene leading to variable degrees of deficiency in PAH activity, and consequently a wide spectrum of clinical severity. A pilot study was undertaken to examine the response to 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in patients with atypical and classical PKU. Methods: PAH gene mutation analysis was performed using denaturing gradient gel electrophoresis and gene sequencing. Patients with classical, atypical, or mild PKU were orally given BH4 10 mg/kg. Blood phenylalanine and tyrosine levels were determined using tandem MS/MS at 0 hours, 4 hours, 8 hours, and 24 hours intervals. Results: Thirty-six patients were given a single oral dose of 10 mg/kg of BH4. Twenty one patients (58.33{\%}) responded with a decrease in blood phenylalanine level. Of the patients that responded, 12 were classical, 7 atypical, and 2 mild. The mean decline in blood phenylalanine at 24 hours was > 30{\%} of baseline. There were 15 patients who did not respond to the BH4 challenge, 14 of those had classical and one had atypical PKU. Mapping the mutations that responded to BH4 on the PAH enzyme showed that mutations were in the catalytic, regulatory, oligomerization, and BH4 binding domains. Five patients responding to BH4 had mutations not previously identified. Conclusion: The data presented suggest higher than anticipated number of PKU mutations respond to BH4, and such mutations are on all the domains of PAH.",
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AU - Tyring, Stephen

AU - Erlandsen, Heidi

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N2 - Purpose: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. There have been more than 400 mutations identified in the PAH gene leading to variable degrees of deficiency in PAH activity, and consequently a wide spectrum of clinical severity. A pilot study was undertaken to examine the response to 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in patients with atypical and classical PKU. Methods: PAH gene mutation analysis was performed using denaturing gradient gel electrophoresis and gene sequencing. Patients with classical, atypical, or mild PKU were orally given BH4 10 mg/kg. Blood phenylalanine and tyrosine levels were determined using tandem MS/MS at 0 hours, 4 hours, 8 hours, and 24 hours intervals. Results: Thirty-six patients were given a single oral dose of 10 mg/kg of BH4. Twenty one patients (58.33%) responded with a decrease in blood phenylalanine level. Of the patients that responded, 12 were classical, 7 atypical, and 2 mild. The mean decline in blood phenylalanine at 24 hours was > 30% of baseline. There were 15 patients who did not respond to the BH4 challenge, 14 of those had classical and one had atypical PKU. Mapping the mutations that responded to BH4 on the PAH enzyme showed that mutations were in the catalytic, regulatory, oligomerization, and BH4 binding domains. Five patients responding to BH4 had mutations not previously identified. Conclusion: The data presented suggest higher than anticipated number of PKU mutations respond to BH4, and such mutations are on all the domains of PAH.

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