View source for 6-Pyruvoyltetrahydropterin synthase deficiency

{{Infobox medical condition (new)
| name            = 6-Pyruvoyltetrahydropterin synthase deficiency
| synonyms        = Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency<ref>{{Cite web |title=Orphanet: 6 pyruvoyl tetrahydropterin synthase deficiency |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=13 |access-date=16 June 2019 |website=www.orpha.net |language=en}}</ref>
| image           = Autosomal recessive - en.svg
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| caption         = This condition is inherited in an autosomal recessive manner
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'''6-Pyruvoyltetrahydropterin synthase deficiency''' is an autosomal recessive disorder that causes malignant [[hyperphenylalaninemia]] due to [[tetrahydrobiopterin deficiency]].<ref name="pmid9222755">{{Cite journal |last=Thöny B |last2=Blau N |year=1997 |title=Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes |journal=Hum. Mutat. |volume=10 |issue=1 |pages=11–20 |doi=10.1002/(SICI)1098-1004(1997)10:1<11::AID-HUMU2>3.0.CO;2-P |pmid=9222755 |s2cid=9085242}}</ref> It is a recessive disorder that is accompanied by [[hyperphenylalaninemia]]. Commonly reported symptoms are initial truncal [[hypotonia]], subsequent appendicular [[hypertonia]], [[bradykinesia]], [[cogwheel]] [[rigidity (neurology)|rigidity]], generalized [[dystonia]], and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, [[oculogyric crises]], [[somnolence]], [[irritability]], [[hyperthermia]], and [[seizures]]. [[Chorea]], [[athetosis]], [[hypersalivation]], rash with [[eczema]], and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given [[folate antagonists]] such as [[methotrexate]], which can interfere with a salvage pathway through which [[dihydrobiopterin]] is converted into [[tetrahydrobiopterin]] via [[dihydrofolate reductase]]. Treatment options include substitution with neurotransmitter precursors ([[levodopa]], [[5-hydroxytryptophan]]), [[monoamine oxidase inhibitors]], and [[tetrahydrobiopterin]].<ref>{{Cite journal |last=Pearl PL |last2=Taylor JL |last3=Trzcinski S |last4=Sokohl A |date=May 2007 |title=The pediatric neurotransmitter disorders |journal=[[J Child Neurol]] |volume=22 |issue=5 |pages=606–616 |doi=10.1177/0883073807302619 |pmid=17690069 |s2cid=10689202}}</ref> Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial [[International Working Group on Neurotransmitter Related Disorders]] (iNTD).<ref>{{Cite web |title=Home |url=http://intd-online.org/}}</ref>

== Presentation ==
Movement disorders mentioned are caused by the inability to produce [[L-DOPA|L-Dopa]]. [[Dopamine]] is a neurotransmitter which is also involved in movement. The absence of enough of this molecule causes the movement disorders in an affected individual.<ref name="Ogawa Kanazawa Takayanagi Kitani 2008 pp. 82–85">{{Cite journal |last=Ogawa |first=Atsushi |last2=Kanazawa |first2=Masaki |last3=Takayanagi |first3=Masaki |last4=Kitani |first4=Yutaka |last5=Shintaku |first5=Haruo |last6=Kohno |first6=Yoichi |year=2008 |title=A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of l-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels |url=https://pubmed.ncbi.nlm.nih.gov/17590551/ |journal=Brain and Development |publisher=Elsevier BV |volume=30 |issue=1 |pages=82–85 |doi=10.1016/j.braindev.2007.05.011 |issn=0387-7604}}</ref>

== Mechanism ==
To understand how the absence of this enzyme affects the body, we must look at the BH<sub>4</sub> synthesis pathway. [[6-Pyruvoyltetrahydropterin synthase|PTPS]] is an intermediate in this cycle and is needed to convert 7,8 - dihydroneopterin triphosphate to 6-Pyruvoyltetrahydryobiopterin. 6-Pyruvoyltetrahydryobiopterin is converted into BH<sub>4</sub> (Tetrahydrobiopterin), but since it stops at 6-Pyruvoyltetrahydrobiopterin no BH<sub>4</sub> is made.<ref>{{Cite journal |last=Escalante-Acosta |first=Bruno Alfonso |last2=Ramos-Brizuela |first2=Luz Maria |last3=Vargas-Robles |first3=Hilda |last4=Rubio-Guerra |first4=Alberto Francisco |date=2010-09-29 |title=Is tetrahydrobiopterin a therapeutic option in diabetic hypertensive patients? |journal=Integrated Blood Pressure Control |language=en |volume=3 |pages=125–32 |doi=10.2147/ibpc.s7479 |pmc=3172060 |pmid=21949628 |doi-access=free}}</ref> The absence of BH<sub>4</sub> affects the metabolism of [[Phenylalanine]]. This is the reason that PKU and [[6-Pyruvoyltetrahydropterin synthase|PTPS]] deficiency share some similar symptoms. However, since BH<sub>4</sub> is needed for much more than just the metabolism of [[Phenylalanine]], there are other symptoms as well.<ref name="Regier Greene 2017 e284">{{Cite web |last=Regier |first=Debra S |last2=Greene |first2=Carol L |date=January 5, 2017 |title=Phenylalanine Hydroxylase Deficiency |url=https://www.ncbi.nlm.nih.gov/books/NBK1504/ |access-date=November 27, 2023 |publisher=University of Washington, Seattle |pmid=20301677}}</ref>
[[File:BH4 synthesis pathway.jpg|thumb|This image depicts the pathway for the synthesis if tetrahydrobiopterin, a very important cofactor in the human body.]]

=== Structure and function of 6-Pyruvoyltetrahydropterin Synthase ===
[[6-Pyruvoyltetrahydropterin synthase|PTPS]] is a hexamer of identical subunits. The [[6-Pyruvoyltetrahydropterin synthase|PTPS]] monomer folds into a sequential four-stranded, antiparallel 𝛃-sheet. Three [[6-Pyruvoyltetrahydropterin synthase|PTPS]] monomers form a 12-stranded antiparallel 𝛃-barrel by tight association between the N and C terminus of 2 adjacent subunits. The active enzyme complex is formed by two trimers in a head-to-head fashion. The active site is in between the trimer-trimer interface and has 3 monomers: A, A′, B.<ref name=":0">{{Cite journal |last=Nar |first=H. |last2=Huber |first2=R. |last3=Heizmann |first3=C.W. |last4=Thöny |first4=B. |last5=Bürgisser |first5=D. |date=March 1994 |title=Three-dimensional structure of 6-pyruvoyl tetrahydropterin synthase, an enzyme involved in tetrahydrobiopterin biosynthesis. |journal=The EMBO Journal |volume=13 |issue=6 |pages=1255–1262 |doi=10.1002/j.1460-2075.1994.tb06377.x |issn=0261-4189 |pmc=394939 |pmid=8137809}}</ref> There are three histidine residues that form the metal-binding site in the substrate binding pocket: His 23,48 and 50. Residues Cys42, Glu133, and His89 are in close proximity to the binding pocket but are not binding it. These are thought to serve as proton donors and acceptors during catalysis. The cofactor bound can be either Mg2+ or Ni2+ (Protein Database). As previously mentioned it is involved in the biosynthesis of BH4 and catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin synthase. The kinetic values for this enzyme are KM = 8.1 μM and Vmax = 120 nmol/min/mg.<ref>{{Cite journal |last=Scherer-Oppliger |first=Tanja |last2=Leimbacher |first2=Walter |last3=Blau |first3=Nenad |last4=Thöny |first4=Beat |date=1999-10-29 |title=Serine 19 of Human 6-Pyruvoyltetrahydropterin Synthase Is Phosphorylated by cGMP Protein Kinase II |journal=Journal of Biological Chemistry |volume=274 |issue=44 |pages=31341–31348 |doi=10.1074/jbc.274.44.31341 |issn=0021-9258 |pmid=10531334 |doi-access=free}}</ref> The structure of [[6-Pyruvoyltetrahydropterin synthase|PTPS]] is unique and is different than other examples of antiparallel 𝛃-barrels. It is described as being formed by "a three-fold symmetrical arrangement of subunits".<ref name=":0" /> A similar 𝛃-barrel formation has been discovered in [[CKS2]],<ref>{{Cite journal |last=Parge |first=H.E. |last2=Arvai |first2=A.S. |last3=Tainer |first3=J.A. |date=1995-02-07 |title=Human Ckshs2 Atomic Structure: A Role for ITS Hexameric Assembly in Cell Cycle Control |journal=Science |volume=262 |issue=5132 |pages=387–95 |doi=10.2210/pdb1cks/pdb |pmid=8211159}}</ref> the difference between [[6-Pyruvoyltetrahydropterin synthase|PTPS]] and [[CKS2]] is that the formation of the latter is metal induced and reversible. The PTPS trimer is similar to a [[Porin (protein)|porin]]<ref name=":0" /> and is hypothesized to serve as a tunnel for [[7,8-Dihydroneopterin triphosphate|dihydroneopterin triphosphate]].

== Diagnosis ==
PTPS deficiency can usually be detected by the same screening test used for PKU, because both disorders result in elevated levels of [[Phenylalanine]]. This test is known as the Guthrie test and is done on babies a few days after birth. Another diagnostic method is to measure [[Pteridine]] levels in urine and to measure neurotransmitters [[5-hydroxyindolacetic acid]] (5-HIAA) and [[homovanillic acid]] (HVA).<ref>{{Cite web |title=6-pyruvoyl-tetrahydropterin synthase deficiency {{!}} Genetic and Rare Diseases Information Center (GARD)&nbsp;– an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/5682/6-pyruvoyl-tetrahydropterin-synthase-deficiency |access-date=2018-12-09 |website=rarediseases.info.nih.gov}}</ref>

== Treatment ==
{{Empty section|date=May 2023}}

== Epidemiology ==
Taiwanese Chinese are more likely to get PTPS  deficiency as the prevalence in Taiwanese Chinese is about 1/132,000 compared to white individuals at about 1/1,000,000. PTPS deficiency occurs most commonly in Asian countries and this makes sense because of the incidence of this disease in Taiwanese Chinese being significantly higher than any other population.<ref>{{Cite journal |last=Liu |first=Tze-Tze |last2=Chiang |first2=Szu-Hui |last3=Wu |first3=Sheu-Jen |last4=Hsiao |first4=Kwang-Jen |date=November 2001 |title=Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese |journal=Clinica Chimica Acta |volume=313 |issue=1–2 |pages=157–169 |doi=10.1016/s0009-8981(01)00669-6 |issn=0009-8981 |pmid=11694255}}</ref>

== History ==
[[6-Pyruvoyltetrahydropterin synthase|PTPS]] deficiency is not necessarily its own disease. It shares history with PKU and [[hyperphenylalaninemia]] (HPA) . [[Ivar Asbjørn Følling|Asbjørn Følling]], a physician studying metabolic diseases, identified an excess of [[Phenylpyruvic acid|phenylpyruvate]] as the cause of a strange, musty odor from the urine of two Norwegian children.<ref>FollingIA. 1934. Uber Ausscheidung von Phenylbrenztraubensaure in den Harn als Stoffwechselanomalie in Verbindung mit Inbicillitat. Hoppe Seylers Z Physiol Chem 227:169.</ref> Further research by Penrose in 1935 lead to the coining of the term, "[[phenylketonuria]]". The foundations for dietary restrictions were laid down by George Jervis and Host Bickel which is still one of the best ways to treat PKU. However, this very practice of excluding [[phenylalanine]] from the diet was not working for other forms of HPA. This was attributed to a deficiency of tetrahydrobiopterin (BH4), a cofactor for PAH.<ref>Blau N, Thony B, Cotton RGH, Hyland K. 2001. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill. pp 1725–1776.</ref> The most common form of BH4 deficiency is due to [[6-Pyruvoyltetrahydropterin synthase|PTPS]]. Later on [[6-Pyruvoyltetrahydropterin synthase|PTPS]] was discovered and it was learned that PKU causes HPA but not all HPA is PKU.<ref>{{Cite journal |last=Blau |first=Nenad |date=February 2016 |title=Genetics of Phenylketonuria: Then and Now |journal=Human Mutation |volume=37 |issue=6 |pages=508–515 |doi=10.1002/humu.22980 |pmid=26919687 |doi-access=free}}</ref>

== See also ==
* [[6-pyruvoyltetrahydropterin synthase]]

== References ==
{{reflist}}

== External links ==
{{Medical resources
| ICD11           = {{ICD11|5C59.01}}
| ICD10           = {{ICD10|E70.1}}
| ICD10CM         = <!-- {{ICD10CM|Xxx.xxxx}} -->
| ICD9            = {{ICD9|270.1}}
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| OMIM            = 261640
| MeshID          = C535325
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| GARDNum         = 5682
| GARDName        = 6-pyruvoyl-tetrahydropterin synthase deficiency
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| Orphanet        = 13
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{{Amino acid metabolic pathology}}
{{Metabolic disorders of vitamins, coenzymes, and cofactors}}

[[Category:Amino acid metabolism disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Vitamin, coenzyme, and cofactor metabolism disorders]]