Clinical and genetic characteristics of dopamine-responsive dystonia in 3 children / 临床儿科杂志

Objective To explore the clinical and genetic characteristics, treatment. and prognosis of dopamine responsive dystonia (DRD) in children. Method The clinical data of DRD in 3 children admitted to neurology clinic from January 2014 to August 2017 were retrospectively analyzed. Results Two male children, 20-month-old and 2-year-old respectively, and one 4-year-old female child suffered from hypotonia after birth or one year after birth. Genetic testing found that case 1 had heterozygous mutations in tyrosine hydroxylase (TH) gene, C. G943A (p. G315S) from his mother (PMID 20056467) and C. G739A (p. G247S) from his father (PMID 18554280, 24753243) . Case 2 had a heterozygous mutation, c.454-2A＞G, in GCH-1 gene, which was identified to be from his father (PMID 10732814) . Case 3 had two mutations in TH1 gene, c.580+2T>C from her mother (novel mutation) and c.698G>A (p.R233H) from her father (PMID 9703425) . The mother of case 1 was pregnant again. Prenatal examination revealed that the fetus only carried c.G943A (p.G315S) from the mother. Three patients were treated with a small dose of madopar after diagnosis, and gradually increased to obtain the best effect. After 6-month follow-up, cases 1 and 2 recovered to normal, and case 3 showed significant improvement in dystonia, but left foot deformity. Conclusion DRD can start in infants and young children with atypical early symptoms. Genetic testing can make a definite diagnosis. The family that has proband should undergo prenatal examination.

Study of GCH1 and TH genes in Chinese patients with Parkinson's disease.

Whole-exome sequencing of Parkinson's disease (PD) patients has revealed that the frequency of GTP-cyclohydrolase I (GCH1) variants was significantly higher in patients than in controls. GCH1 rs11158026 was also found to increase the risk of PD. To investigate genetic contribution of dopa-responsive dystonia-related genes to PD, GCH1, and tyrosine hydroxylase (TH) were tested in PD patients. A total of 859 study subjects comprising 421 patients with PD and 438 controls were recruited. For GCH1 gene, one known variant (c.239G > A, p.S80N) was detected in a patient who was diagnosed with PD clinically. In TH, 3 heterozygous variants, c.1495G > A (p. V499M, rs1800033), c.334 A > G (p.V112M, rs6356), and c.813 G > A (p. K271K, rs6357), were identified. After stratification by age, the frequency of rs6356G allele was significantly lower (p = 0.041) for the late-onset PD group than controls. Our results indicate that to analyze the relationship between dopa-responsive dystonia-related genes and PD, it is important to screen GCH1 and test rs6356 of TH in a larger sample.

A novel tyrosine hydroxylase variant in a group of Chinese patients with dopa-responsive dystonia.

Dopa-responsive dystonia (DRD) comprises a heterogeneous group of movement disorders. A limited number of studies of Chinese patients with DRD have been reported. In the present study, we investigated the clinical and genetic features of 12 Chinese DRD families. Point mutation analysis of the GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SPR) genes was conducted by direct sequencing. In addition, multiplex ligation-dependent probe amplification targeting GCH1 and TH was performed in "mutation-free" patients. Three reported mutations (IVS2-2A>G, c.293C>T, c.550C>T) were detected in GCH1, whereas two compound heterozygous variants were identified in TH, one of which was novel (c.1083C>A). Furthermore, this novel variant was not detected in any of the 250 ethnicity-matched, healthy controls. No exon deletions or duplicate mutations in the two genes were found in patients with DRD. No mutation in SPR was found. In addition, one patient with the IVS2-2A>G mutation in GCH1 showed signs of Parkinsonism. In conclusion, we here identified a novel heterozygous variant in TH (c.1083C>A). It is important to perform routine screening of GCH1 and TH for patients with DRD. While for patients with Parkinsonism, GCH1 mutation analysis should be performed after screening of genes like PARKIN, PARK7 (DJ-1) and PINK1.

Experimental study on expression of TH and GDNF bi-gene of lentivirus by improved Tet-On system for a rat model of Parkinson’ s disease / 中国药理学通报

Aim To investigate TH and GDNF genes expression and regulation of lentivirus ( Lv-TH-GDNF ) based on improved Tet-On system and the effect of the Lv-TH-GDNF intrastriatal transfer on a rat Parkinson’ s disease( PD) model. Methods 1. HeLa cells were infected by obtained Lv-TH-GDNF and rtTA2 s-M2 vi-rus. The expression of tyrosine hydroxylase ( TH ) and glial cell line-derived neurotrophic factor( GDNF) genes was induced by doxycycline( Dox) which was examined by Western blot. 2. The Lv-TH-GDNF together with rtTA2 s-M2 viruses were injected into lesion-side stria-tum of a rat PD model, and the expression of GDNF and TH genes was induced by Dox. Then, the effects of Lv-TH-GDNF were evaluated by the apomorphine-induced rotational behavior, the number of dopaminer-gic neurons in substantia nigra,DA and DOPAC levels in the lesion-side striatum. In addition, Western blot was performed to check the expression of TH and GD-NF genes in the transplanted striatum. Results 1. In vitro studies on HeLa cells, Western blot showed clear protein bands of TH and GDNF in the Dox-positive group, but not in the Dox-negative group. 2. In vivo experiments in animals, the results showed that, 4 weeks after transplantation, the apomorphine-induced turning effect was significantly improved ( P<0 . 01 ) , the number of TH-positive cells in the lesion-side sub-stantia nigra pars compacta as well as the content of DA and DOPAC, the protein level of GDNF and TH genes in the lesion-side striatum was significantly in-creased ( P<0 . 01 ) , each of which was only in Lv-TH-GDNF+rtTA2 s-M2+Dox-treated rats as compared with PBS-treated rats. Conclusion The expression of TH and GDNF genes in Lv-TH-GDNF based on im-proved Tet-On system is effectively regulated by tetra-cycline antibiotics without basal activity in vitro, and the intrastriatal transfer of which has certain therapeutic effect on PD rats.

Functional polymorphism (C-824T) of the tyrosine hydroxylase gene affects IQ in schizophrenia.

AIMS: Progressive cognitive decline has been an important issue in the treatment and care of patients with schizophrenia. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the biosynthesis of catecholamine, including dopamine and noradrenaline. In this report, we examined a possible association of a genetic variant in the TH promoter region. METHODS: Association of a genetic variant in the TH promoter region, C-824T (rs10770141), with intellectual ability in 132 patients with schizophrenia and 282 healthy subjects was examined. The transcriptional activity of the plasmids harboring the TH promoter region with either C or T nucleotide at -824 was assayed using a luciferase gene as a reporter. RESULTS: We found significant effects of the genotype on the full-scale IQ, verbal IQ, and performance IQ, in patients with schizophrenia. IQ was lower in individuals with the C/C genotype than those with T carriers. The plasmid with the T allele at -824 showed higher transcriptional activity than that with the C allele in a transient transfection experiment using a luciferase gene as a reporter, implying that the T carriers may have higher TH activities and retain higher levels of catecholamines in the brain. CONCLUSIONS: The present data suggest that the biosynthesis of catecholamine by the action of TH should be deeply involved in decreased intellectual ability in patients with schizophrenia. This is the first report, as far as we know, showing a correlation between TH expression and IQ in humans.