Abstract
Hyperphenylalaninemia (HPA) is a condition caused by tetrahydrobiopterin (BH4) and phenylalanine hydroxylase (PAH) deficiencies. It is essential that differential diagnosis be conducted to distinguish these two causes of HPA, because BH4 deficiency is a more severe disease involving progressive neurologic deterioration. Based on the biological findings, HPA is defined as a plasma phenylalanine level of >2.0 mg/dl (>120 μmol/l). The National Biochemistry Reference Laboratory at the Pasteur Institute of Iran initiated BH4 deficiency screening tests for the first time during the implementation of a nationwide phenylketonuria (PKU) screening program. Measurement of blood phenylalanine and urinary neopterin and biopterin was conducted by high-performance liquid chromatography in 617 patients with HPA. Dihydropteridine reductase (DHPR) activity was measured in all patients by kinetic spectrophotometry. Differential diagnosis was conducted for PKU, transient HPA, and BH4 deficiencies.
Our results indicated that out of 76 cases involving BH4 deficiencies, 37 had 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, 35 had DHPR deficiency, 1 case had pterin-4a-carbinolamine dehydratase (PCD) deficiency, and 3 cases had GTP cyclohydrolase I (GTPCH) deficiency. In this study, 1 novel deletion mutation and 18 novel missense mutations were reported in addition to mutations that had previously been identified and registered in BIOMDB. At present, the screening program for PKU in Iran includes tests that detect different forms of BH4 deficiency presenting with HPA. Newborns that are BH4-deficient benefit from the availability of the tests because they can receive necessary care before being clinically affected.
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Acknowledgement
We are grateful to the many colleagues in contributing medical centers, the patients’ families, and their physicians for sending specimens. We would also like to give special thanks to Prof. Dr. Nenad Blau, Prof. Dr. Jörn Oliver Sass, Corinne Britschgi, Alessio Cremonesi, and Anahita Rassi for their helpful recommendations and efforts.
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Communicated by: Francois Feillet, MD, PhD
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Consortium
Soghra Khani, Rogiyeh Mirzazadeh, Sedigheh Sadeghi, Somayeh Mahmoudi Baram, Elham Farhangara, Arezou Asgari, Rayhaneh Hasanzaeh, Mina Barzegari, Parastoo Bayat, Hamid Mohammadaliha, Parinaz Saeedi, Robabeh Ahadi, Ghazaleh Dadashizadeh, Saeedeh Saeedi, Sarah Azadmehr, Tina Shirzad, Leali Rejali, and Mahbobeh Masoodifar.
Conflict of Interest
Shohreh Khatami, Soghra Rouhi Dehnabeh, Sirous Zeinali, Beat Thöny, Mohammadreza Alaei, Shadab Salehpour, Aria Setoodeh, Farzaneh Rohani, Fatemeh Hajivalizadeh, and Ashraf Samavat declare that they have no conflict of interest.
Informed Consent
The project was supported financially with research grants for implemented programs by the Ministry of Health of Iran. Informed consent was obtained from all patients for inclusion in the study.
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This article does not reference any studies with animal subjects performed by any of the authors.
Details of the Contributions of Individual Authors
Shohreh Khatami, as member of the PKU national scientific committee, contributed to the planning, conducting, and reporting of the BH4 screening tests described in the article.
Soghra Rouhi contributed to the conception and design of the DHPR test and peterin analysis setup and to drafting the article.
Mohammadreza Alaei, Shadab Salehpour, Aria Sotoudeh, and Farzaneh Rohani contributed as members of the PKU national scientific committee and introduced patients for sample gathering.
Sirous Zeinali, Sarah Azadmeh, Tina Shirzad, Leyli Rejali, Mahbobeh Masoodifarand, and Beat Thöny contributed to the genetics study.
Soghra Khani, Rogiyeh Mirzazadeh, Sedigheh Sadeghi, Somayeh Mahmoudi Baram, Elham Farhangara, Arezu Asgari, Ghazaleh Dadashizadeh, Rayhaneh Hasanzaeh, Mina Barzegari, Parinaz Saeedi, Parastoo Bayat, Robabeh Ahadi, Hamid Mohammadaliha, and Saeedeh Saeedi contributed to the setup and performing of the tests.
Ashraf Samavat (Head of the Genetics Office, Ministry of Health of Iran) and Fatemeh Hajivalizadeh contributed to the design of the PKU screening program in Iran and to revising the article critically for important intellectual content.
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Dr. Shohreh Khatami
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Khatami, S. et al. (2016). Four Years of Diagnostic Challenges with Tetrahydrobiopterin Deficiencies in Iranian Patients. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 32. JIMD Reports, vol 32. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_572
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DOI: https://doi.org/10.1007/8904_2016_572
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