Changes in methylation status of the whole genome and GCH1 gene in patients with herpes zoster neuralgia / 中华皮肤科杂志

Objective To analyze the correlation between herpes zoster neuralgia and the methylation status of the whole genome and GCH1 gene.Methods From June to October in 2017,patients with confirmed herpes zoster and obvious neuralgia were selected in Department of Dermatology,The Affiliated Hospital of Xuzhou Medical University,who achieved complete remission (no effect was observed on normal sleep) of neuralgia after antiviral and neurotrophic treatment.Finally,36 patients and 36 healthy controls were enrolled into this study.Peripheral blood samples were obtained from the healthy controls and patients before and after the treatment.Dot-blot hybridization assay was performed to determine the methylation status of the whole genome,methylated-DNA IP kit was used to enrich the methylation sites of the GCH1 gene,and real-time quantitative PCR was conducted to detect changes in methylation status of the GCH1 gene.Statistical analysis was carried out with GraphPad Prism v7.00 software by using paired t test for the comparison of methylation status before and after the treatment,and two-sample t test for the comparison between the patient group and control group.Results The relative methylation level of the whole genome was 135.94 ± 2.52 in the patients before treatment,significantly lower than that in the patients after treatment (144.76 ± 3.48,t =2.056,P ＜ 0.05) and healthy control group (146.84 ± 3.39,t =2.580,P ＜ 0.05).However,there was no significant difference in the methylation status of the whole genome between the patients after treatment and healthy controls (t =0.429,P ＞ 0.05).Compared with the patients after treatment (0.89 ± 0.13) and healthy control group (0.97 ± 0.07),the methylation status of the GCH1 gene significantly decreased in the patients before treatment (0.65 ± 0.17;t =3.977,4.648 respectively,P ＜ 0.05,＜ 0.01 respectively),while no significant difference between the patients after treatment and the healthy controls (t =0.506,P ＞ 0.05).Conclusion The methylation status of the whole genome and GCH 1 gene markedly decreased in the patients with herpes zoster neuralgia.

Analysis of GCH1 gene mutation of close relatives marriage caused dopa reactive dystonia ( report of one family) / 临床神经病学杂志

Objective To analyze the characteristics of GCH1 gene mutation of close relatives marriage caused dopa reactive dystonia (DRD).Methods The data of 3 patients with DRD from the same family in our hospital and their families were analyzed.Genes related to hereditary dyskinesia in their families were detected and validated. Results In this family, the proband’s parents (Ⅲ3 and Ⅲ4) were close relatives.The proband (Ⅳ2) and her eldest daughter (Ⅴ2) and niece (Ⅴ7) were all DRD patients.All of them were young onset , mainly manifested as Parkinsonina-like symptoms and dystonia , and all responded well to dopamine therapy.Gene detection showed that the GCH1 gene had c.245T＞C (p.Leu82Pro) mutation.The second daughter (Ⅴ3), son (Ⅴ5), granddaughter (Ⅵ3) and brother (Ⅳ3) of the proband were carriers of abnormal genes.Conclusions Close relatives marriage increases the incidence of DRD.DRD may be considered in patients with a positive family history of dystonia.Gene detection is an effective diagnosis method.

A Case of Dopa-responsive Dystonia with a Mutation in the GCH1 Gene Misdiagnosed as Cerebral Palsy for 2 Years / 대한소아신경학회지

Dopa-responsive dystonia (DRD) is characterized by lower limb-onset, diurnally fluctuating dystonia and dramatic and sustained response to levodopa treatment. Segawa disease, an autosomal dominant deficiency of guanosine triphosphate cyclohydrolase 1 (encoded by GCH1) is the most common and well-known condition manifesting as DRD. However, similar clinical manifestations can be seen in individuals with deficiencies of other enzymes that are involved in the biosynthesis of dopamine. We describe the case of an 11-year-old girl who presented with abnormal gait, which had initially begun 2 years back. The patient showed diurnally fluctuating dystonia in both legs. She was able to walk without support in the morning, but was unable to stand without support in the evening. She had been diagnosed as having spastic cerebral palsy and had been managed with physical therapy at a local rehabilitation clinic. The patient had been healthy until the development of dystonia, and did not have a history of perinatal problems or developmental delay. Routine hematologic and biochemical test results were normal. Brain magnetic resonance imaging and electroencephalography showed no abnormalities. When levodopa was administered, the patient's abnormal gait dramatically improved 1 hour after receiving the medication. Genetic testing for the GCH1 gene revealed a missense mutation (c.293C>T [p.A98V]) that has previously been reported in patients with DRD. This case demonstrated that a levodopa trial is vital for accurate and early diagnosis of DRD in patients with dystonia resulting from an unknown cause.

Dopa-responsive Dystonia with a Novel Initiation Codon Mutation in the GCH1 Gene Misdiagnosed as Cerebral Palsy

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic response to relatively low doses of levodopa. However, patients with DRD can be misdiagnosed as cerebral palsy or spastic diplegia due to phenotypic variation. Here we report a young woman with DRD who were severely disabled and misdiagnosed as cerebral palsy for over 10 yr. A small dose of levodopa restored wheelchair-bound state to normality. However, thoracolumbar scoliosis has remained as a sequel due to late detection of DRD. Genetic analysis by using PCR-direct sequencing revealed a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GTP cyclohydrolase 1 (GCH1) gene. Although it is known that DRD can be misdiagnosed as cerebral palsy, this case reinforces the importance of differential diagnosis of DRD from cerebral palsy.

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

Dopa-responsive dystonia (DRD) is an inherited metabolic disorder now classified as DYT5 with two different biochemical defects: autosomal dominant GTP cyclohydrolase 1 (GCH1) deficiency or autosomal recessive tyrosine hydroxylase deficiency. We report the case of a 10-years-old girl with progressive generalized dystonia and gait disorder who presented dramatic response to levodopa. The phenylalanine to tyrosine ratio was significantly higher after phenylalanine loading test. This condition had two different heterozygous mutations in the GCH1 gene: the previously reported P23L mutation and a new Q182E mutation. The characteristics of the DRD and the molecular genetic findings are discussed.

Distonia dopa-responsiva (DRD), classificada como DYT5, é um erro inato do metabolismo que pode ser causado por dois diferentes tipos de defeito bioquímico: deficiência de GTP ciclo-hidrolase 1 (GCH1) (autossômica dominante) ou de tirosina hidroxilase (autossômica recessiva). Descrevemos o caso de menina de 10 anos com distonia generalizada progressiva e alteração da marcha com importante melhora após uso de levodopa. A relação fenilalanina/tirosina estava aumentada após teste de sobrecarga com fenilalanina. O estudo molecular mostrou que o paciente apresenta uma combinação hererozigótica de mutação no gene GCH1: a já conhecida mutação P23L e uma nova mutação Q182E. Discutem-se as características da DRD e as alterações genéticas possíveis.