Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.
Female ; Humans ; Infant ; Male ; Benserazide/therapeutic use* ; Dystonia/genetics* ; Hypokinesia/drug therapy* ; Levodopa/pharmacology* ; Muscle Hypotonia ; Retrospective Studies ; Tyrosine 3-Monooxygenase/genetics*

BACKGROUNDParkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD.

METHODSThe rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis.

RESULTSL-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test ( P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 ( P < 0.01) and 24:00 ( P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01).

CONCLUSIONSIn the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.

Animals ; Blotting, Western ; Body Weight ; drug effects ; Circadian Rhythm ; drug effects ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Levodopa ; therapeutic use ; Male ; Oxidopamine ; toxicity ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction

OBJECTIVETo analyze the clinical characteristics of the patient with tyrosine hydroxylase deficiency, and investigate it's molecular mechanism.

METHODThe clinical characteristics of a patient with tyrosine hydroxylase deficiency were summarized and analyzed, his and his family's peripheral blood specimens were collected after informed consent was signed. All exons and the intron-exon boundaries of guanosine triphosphate hydroxylase I gene, tyrosine hydroxylase gene and sepiapterin reductase gene were examined by DNA-PCR, bi-directional sequencing.

RESULTThe patient was a 3-year-old boy, presented with unexplained dystonia for 3 years, without significant impairment of intelligence. Physical examination showed limb muscle strength grade V, rigidity of extremities, hypertonicity, brisk deep tendon reflexes in limbs, without obvious abnormalities in auxiliary examination, such as brain MRI, hepatic biochemical panel, creatine kinase, and ceruloplasmin. He dramatically responded to small doses of levodopa in the follow-up for half a year. A homozygous missense change in exon 5 of TH gene, c.605G > A (p.R202H), which was a known pathogenic mutation, was found in the patient. His parents were heterozygous for the R202H mutation.

CONCLUSIONThe age of onset in tyrosine hydroxylase deficiency patients is usually within the first year of life. Unexplained dystonia and hypokinesia were the main clinical features of tyrosine hydroxylase deficiency. The dopa-responsive effects for some patients are so obvious that we should strengthen awareness of the disease. TH gene c.605G > A (p.R202H) may be a common type of causative mutations for the mild form at home and abroad.

Brain ; metabolism ; pathology ; Catecholamines ; biosynthesis ; Child, Preschool ; DNA ; genetics ; DNA Mutational Analysis ; Dopamine Agents ; administration & dosage ; therapeutic use ; Dystonic Disorders ; drug therapy ; genetics ; metabolism ; Homozygote ; Humans ; Hypokinesia ; drug therapy ; genetics ; metabolism ; Levodopa ; administration & dosage ; therapeutic use ; Male ; Muscle Rigidity ; drug therapy ; genetics ; metabolism ; Mutation, Missense ; Polymerase Chain Reaction ; Tyrosine 3-Monooxygenase ; deficiency ; genetics ; metabolism

PURPOSE: Levodopa is the most effective anti-Parkinsonian agent. It has also been known to exhibit analgesic properties in laboratory and clinical settings. However, studies evaluating its effects on neuropathic pain are limited. The aim of the present study was to examine the anti-allodynic effects of levodopa in neuropathic rats. MATERIALS AND METHODS: Sprague-Dawley male rats underwent the surgical procedure for L5 and L6 spinal nerves ligation. Sixty neuropathic rats were randomly divided into 6 groups for the oral administration of distilled water and levodopa at 10, 30, 50, 70, and 100 mg/kg, respectively. We co-administered carbidopa with levodopa to prevent peripheral synthesis of dopamine from levodopa, and observed tactile, cold, and heat allodynia pre-administration, and at 15, 30, 60, 90, 120, 150, 180, and 240 min after drug administration. We also measured locomotor function of neuropathic rats using rotarod test to examine whether levodopa caused side effects or not. RESULTS: Distilled water group didn't show any difference in all allodynia. For the levodopa groups (10-100 mg/kg), tactile and heat withdrawal thresholds were increased, and cold withdrawal frequency was decreased dose-dependently (p<0.01). In addition, levodopa induced biphasic analgesia. Different dosage of levodopa did not impact on the rotarod time (p>0.05). CONCLUSION: Levodopa reversed tactile, cold and heat allodynia in neuropathic rat without any side effects.
Animals ; Carbidopa/administration & dosage/adverse effects/therapeutic use ; Dopamine Agents/administration & dosage/adverse effects/*therapeutic use ; Hyperalgesia/*drug therapy ; Levodopa/administration & dosage/adverse effects/*therapeutic use ; Male ; Neuralgia/*drug therapy ; Rats ; Rats, Sprague-Dawley ; Rotarod Performance Test

BACKGROUNDParkinson's disease (PD) is a complicated disease, commonly diagnosed among the elderly, which leads to degeneration of the central nervous system. It presently lacks an effective therapy for its complex pathogenesis. Adverse effects from Western drug-based medical intervention prevent long-term adherence to these therapies in many patients. Traditional Chinese medicine (TCM) has long been used to improve the treatment of PD by alleviating the toxic and adverse effects of Western drug-based intervention. Therefore, the aim of this study is to evaluate the efficacy and safety of Xifeng Dingchan Pill (XFDCP), a compound traditional Chinese herbal medicine, taken in conjunction with Western medicine in the treatment of PD patients at different stages in the progression of the disease.

METHODS AND DESIGNThis is a multicenter, randomized controlled trial. In total, 320 patients with early- (n = 160) and middle-stage PD (n = 160) will be enrolled and divided evenly into control and trial groups. Of the 160 patients with early-stage PD, the trial group (n = 80) will be given XFDCP, and the control group (n = 80) will be given Madopar. Of the 160 patients with middle-stage PD, the trial group (n = 80) will be given XFDCP combined with Madopar and Piribedil, and the control group (n = 80) will be given Madopar and Piribedil. The Unified Parkinson's Disease Rating Scale scores, TCM symptoms scores, quality of life, change of Madopar's dosage and the toxic and adverse effects of Madopar will be observed during a 3-month treatment period and through a further 6-month follow-up period.

DISCUSSIONIt is hypothesized that XFDCP, combined with Madopar and Piribedil, will have beneficial effects on patients with PD. The results of this study will provide evidence for developing a comprehensive therapy regimen, which can delay the progress of the disease and improve the quality of life for PD patients in different stages.

TRIAL REGISTRATIONThis trial has been registered in the Chinese Clinical Trial Registry with the identifer ChiCTR-TRC-12002150.

Benserazide ; therapeutic use ; Data Interpretation, Statistical ; Drug Combinations ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Humans ; Levodopa ; therapeutic use ; Medicine, Chinese Traditional ; Parkinson Disease ; drug therapy ; psychology ; Phytotherapy ; Piribedil ; therapeutic use ; Quality of Life

Acute Disease ; Adult ; Antidotes ; therapeutic use ; Antiparkinson Agents ; therapeutic use ; Benserazide ; Cholinesterase Inhibitors ; poisoning ; Humans ; Insecticides ; poisoning ; Levodopa ; therapeutic use ; Male ; Organophosphate Poisoning ; Parkinson Disease ; drug therapy ; pathology ; Pralidoxime Compounds ; therapeutic use ; Trihexyphenidyl ; therapeutic use

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.
Adult ; Cerebral Palsy/diagnosis ; Codon, Initiator ; Diagnosis, Differential ; Dystonic Disorders/*diagnosis/drug therapy/*genetics ; Female ; GTP Cyclohydrolase/*genetics ; Humans ; Levodopa/therapeutic use ; Mutation ; Sequence Analysis, DNA

We compared the surgical outcome with electrode positions after bilateral subthalamic nucleus (STN) stimulation surgery for Parkinson's disease. Fifty-seven patients treated with bilateral STN stimulations were included in this study. Electrode positions were determined in the fused images of preoperative MRI and postoperative CT taken at six months after surgery. The patients were divided into three groups: group I, both electrodes in the STN; group II, only one electrode in the STN; group III, neither electrode in the STN. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage, and activities of daily living scores significantly improved at 6 and 12 months after STN stimulation in both group I and II. The off-time UPDRS III speech subscore significantly improved (1.6 +/- 0.7 at baseline vs 1.3 +/- 0.8 at 6 and 12 months, P < 0.01) with least L-dopa equivalent daily dose (LEDD) (844.6 +/- 364.1 mg/day at baseline; 279.4 +/- 274.6 mg/day at 6 months; and 276.0 +/- 301.6 mg/day at 12 months, P < 0.001) at 6 and 12 months after STN deep brain stimulation (DBS) in the group I. Our findings suggest that the better symptom relief including speech with a reduced LEDD is expected in the patients whose electrodes are accurately positioned in both STN.
Adult ; Aged ; Antiparkinson Agents/adverse effects/*therapeutic use ; Combined Modality Therapy ; *Deep Brain Stimulation/adverse effects/instrumentation/methods ; *Electrodes, Implanted ; Female ; Humans ; Levodopa/adverse effects/therapeutic use ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Parkinson Disease/drug therapy/*therapy ; Severity of Illness Index ; Subthalamic Nucleus/*physiology ; Treatment Outcome

OBJECTIVETo objectively evaluate the clinical efficacy of Gulling Pa'an Capsule (GPC), a Chinese medicine, in treating Parkinson's disease (PD).

METHODSAccording to the good clinical practice (GCP) principle, a multi-centered, double-blinded, layered, randomized and grouping-controlled clinical trial was carried out from May 2002 to January 2005 on 242 PD patients. Among them, 53 patients who had never received levodopa were randomized into two groups, 28 in group A treated with GPC, and 25 in group B treated with placebo; patients who had received levodopa were assigned depending on the Hoehn & Yahr (H-Y) grade, to 4 groups, 75 and 19 of grade 1.5 -3 in group C and E, respectively, 79 and 16 of grade 4 in group D and F, respectively, patients in group C and E were treated with GPC and Levodopa, and those in group D and F treated with placebo and Levodopa for control. The treatment course was 12 weeks for all. Changes of unified Parkinson's disease rating scale (UPDRS) II/III scores in comparing with the baseline were assessed. For the groups C, D, E and F, the dosage of levodopa administered was also recorded. Meanwhile, the blood pressure, pulse rate, blood and urine routine, liver and renal functions, electrocardiogram (ECG) and adverse reactions were monitored as the indices for safety supervise.

RESULTS(1) After treatment, symptoms were markedly improved in 1 out of the 28 patients in group A and improved in 11, the markedly improving rate was 3.6% and the improving rate 39.3%; while in group B, the corresponding outcomes were 0 (0/25) and 28.0% (7/25) respectively, showing insignificant difference between the two groups. UPDRS scores, including the total, II and III scores were all significantly lowered in group A after treatment (P < 0.01, P < 0.05); while in group B, significant lowering only showed in terms of UPDRS III (P < 0.05); but the inter-group comparison of the changes in all the three items showed no significant difference. (2) The significant improving rate was 12.0% (9/75) and improving rate 48.0% (36/75) in group C, while those in group D, 12.7% (10/79) and 24.1% (19/79) respectively, the efficacy in group C was better (P < 0.05). The items of 3 UPDRS scores in groups C and D were all significantly lowered after treatment (P < 0.01), and the lowering in group C was more significant in terms of the total and II scores (P < 0.05). (3) The significant improving rate was 5.3% (1/19) and improving rate 36.8% (7/19) in group E, while in group F 0% (0/19) and 25.0% (4/16), respectively, showing insignificant difference between them; UPDRS scores lowered significantly in the two groups after treatment (P < 0.01), also showed no statistical significance in comparison (P > 0.05). (4) The dosage of Levodopa required in groups C and E was significantly reduced after treatment (P < 0.05), while in groups D and F, it was unchanged (P > 0.05); yet, the further analysis displayed that significant reduction only presented in group C (P < 0.05), not in the other three groups.

CONCLUSIONSThe overall efficacy of levodopa in combined with GPC for treating PD patients of H-Y grade 1.5 -3 is significantly higher than that of levodopa alone. GPC shows obvious effects in improving patients' motor syndrome and the quality of life; as used in combining with levodopa, the dosage of levodopa required could be reduced.

Aged ; Double-Blind Method ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Levodopa ; therapeutic use ; Male ; Middle Aged ; Parkinson Disease ; drug therapy ; Phytotherapy

The aim of this study is to elucidate the clinical spectrum and frequency of non-motor symptoms during off periods (NMOS) in Parkinson's disease (PD) patients with motor fluctuation. We compared clinical characteristics between PD patients with motor symptoms only (M-off) and those with both motor and non-motor symptoms (NM-off) during off periods. The association of NMOS with parkinsonian clinical characteristics was also investigated. Sixty-seven consecutive PD patients of both M-off and NM-off groups were included in this study. We reviewed medical records, interviewed the patients, and administered a structured questionnaire. NMOS is classified into three categories: autonomic, neuropsychiatric and sensory. The frequency of NMOS and their individual manifestations were assessed. Of 67 patients with off symptoms, 20 were M-off group and 47 NM-off group. Among NMOS, diffuse pain was the most common manifestation, followed by anxiety and sweating. There were no significant differences between M-off and NM-off groups with regard to age, duration of disease and treatment, interval between onset of parkinsonian symptoms and off symptoms and off periods. Patients taking higher dosage of levodopa had fewer NMOS. NMOS is frequent in PD. Comprehensive recognition of NMOS can avoid unnecessary tests and is important for optimal treatment in PD.
Aged ; Female ; Humans ; Interviews as Topic ; Levodopa/therapeutic use ; Male ; Middle Aged ; Parkinson Disease/*diagnosis/etiology ; Prospective Studies ; Questionnaires ; Sensation Disorders/diagnosis ; Severity of Illness Index