Abstract
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, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 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.
Highlights
Dopa-responsive dystonia (DRD) is a group of disorders that typically present with childhood onset diurnally fluctuating limb dystonia, referred to as hereditary progressive dystonia with marked diurnal fluctuation [1,2]
[12], some patients respond poorly or not at all. As this is often the situation for severe synthesis [12], some patients respond poorly or not at all. As this is often the situation cases of tyrosine hydroxylase (TH) deficiency (THD; OMIM *191290), a rare neurometabolic disorder inherited for severe cases of TH deficiency (THD; OMIM *191290), a rare neurometabolic disorder in an autosomal recessive manner, we focused more intensively on this patient group
In the human central nervous system (CNS), TH is mainly expressed in dopaminergic neurons in the ventral tegmental area (VTA), which projects to the nucleus accumbens and the prefrontal cortex and is involved in motivation, addiction, and reward, and in dopaminergic neurons in the pars compacta compartment of the neighboring substantia nigra which projects to the striatum and plays a central role in motor control
Summary
Dopa-responsive dystonia (DRD) is a group of disorders that typically present with childhood onset diurnally fluctuating limb dystonia, referred to as hereditary progressive dystonia with marked diurnal fluctuation [1,2]. DRD is rare, with an estimated prevalence of 0.5–1 per million worldwide [4,5], and it is mainly caused by abnormalities affecting the biosynthesis of catecholamines (CAs) Monoamine neurotransmitters, such as serotonin, dopamine, and other CAs, are synthesized in reaction pathways involving the tetrahydrobiopterin (BH4)-dependent aromatic amino acid hydroxylases (AAAHs). DRD results from deficient 3,4-dihydroxyphenylalanine (L-DOPA) synthesis, either through insufficient BH4 production or from defective tyrosine hydroxylase (TH; EC reaction pathways involving the tetrahydrobiopterin (BH4)-dependent aromatic amino acid hydroxylases (AAAHs) (Figure 1). Most DRD patients have a sustained beneficial response to levodopa which is used to restore dopamine levels in disorders with deficient dopamine synthesis (L-DOPA), which is used to restore dopamine levels in disorders with deficient dopamine [12], some patients respond poorly or not at all. 3-methoxy-4-hydroxyphenylethylene glycol; NMN, normetanephrine; PAH, phenylalanine hydroxglycol; NMN, normetanephrine; PAH, phenylalanine hydroxylase; PLP, pyridoxal phosphate; ylase; PLP, pyridoxal phosphate; PNMT, phenylethanolamine N-methyltransferase; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase
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