Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, <i>GCH1</i> gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahy...

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Autores principales:	Gyrid Nygaard, Peter D. Szigetvari, Ann Kari Grindheim, Peter Ruoff, Aurora Martinez, Jan Haavik, Rune Kleppe, Marte I. Flydal
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tyrosine hydroxylase dopamine dopa-responsive dystonia dystonia neurometabolic disorders personalized medicine Medicine R
Acceso en línea:	https://doaj.org/article/be20b1861c08418c9e12d4f3db470b2f
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spelling	oai:doaj.org-article:be20b1861c08418c9e12d4f3db470b2f2021-11-25T18:07:52ZPersonalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency10.3390/jpm111111862075-4426https://doaj.org/article/be20b1861c08418c9e12d4f3db470b2f2021-11-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1186https://doaj.org/toc/2075-4426Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, <i>GCH1</i> gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in <i>GCH1</i> are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.Gyrid NygaardPeter D. SzigetvariAnn Kari GrindheimPeter RuoffAurora MartinezJan HaavikRune KleppeMarte I. FlydalMDPI AGarticletyrosine hydroxylasedopaminedopa-responsive dystoniadystonianeurometabolic disorderspersonalized medicineMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1186, p 1186 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tyrosine hydroxylase dopamine dopa-responsive dystonia dystonia neurometabolic disorders personalized medicine Medicine R
spellingShingle	tyrosine hydroxylase dopamine dopa-responsive dystonia dystonia neurometabolic disorders personalized medicine Medicine R Gyrid Nygaard Peter D. Szigetvari Ann Kari Grindheim Peter Ruoff Aurora Martinez Jan Haavik Rune Kleppe Marte I. Flydal Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
description	Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, <i>GCH1</i> gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in <i>GCH1</i> are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.
format	article
author	Gyrid Nygaard Peter D. Szigetvari Ann Kari Grindheim Peter Ruoff Aurora Martinez Jan Haavik Rune Kleppe Marte I. Flydal
author_facet	Gyrid Nygaard Peter D. Szigetvari Ann Kari Grindheim Peter Ruoff Aurora Martinez Jan Haavik Rune Kleppe Marte I. Flydal
author_sort	Gyrid Nygaard
title	Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
title_short	Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
title_full	Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
title_fullStr	Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
title_full_unstemmed	Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency
title_sort	personalized medicine to improve treatment of dopa-responsive dystonia—a focus on tyrosine hydroxylase deficiency
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/be20b1861c08418c9e12d4f3db470b2f
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Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

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