6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects
Almannai M1, Felemban R1, Saleh MA1, Faqeih EA1, Alasmari A1, AlHashem A2, Mohamed S3, Sunbul R4, Al-Murshedi F5, AlThihli K5, Eyaid W6, Ali R7, Ben-Omran T7, Blau N8, El-Hattab AW9, Alfadhel M10.
1 Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
2 Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
3 Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia.
4 Pediatrics Medical Genetic Unit (PMGU), Pediatrics Department, Qatif Central Hospital, Qatif, Saudi Arabia.
5 Department of Genetics, College of Medicine, Sultan Qaboos University, Muscat, Sultanate of Oman.
6 Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
7 Clinical and Metabolic Genetics Section, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
8 Dietmar-Hopp-Metabolic Center, University Children’s Hospital, Heidelberg, Germany; Division of Metabolism, University Children’s Hospital Zurich, Switzerland.
9 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Genetics Clinics, KidsHeart Medical Center, Dubai, United Arab Emirates.
10 Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Electronic address: firstname.lastname@example.org.
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Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders.
We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency.
Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?).
The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.