Objective To investigate the clinical features of dyskinesia and related risk factors in female patients with Parkinson disease （PD）. Methods A cross-sectional study was conducted among the female patients who met the diagnostic criteria for PD at the outpatient service of PD in Aerospace Center Hospital， and demographic data and clinical data were collected and compared between groups， including levodopa equivalent daily dose （LEDD）， Unified Parkinson’s Disease Rating Scale-Ⅲ（UPDRS-Ⅲ）， UPDRS-Ⅳ， scores of non-motor symptoms （cognition and depression）， presence or absence of dyskinesia， and single levodopa dose （LD） during the onset of dyskinesia. A binary logistic regression analysis was used to investigate the influencing factors for dyskinesia in female patients with PD. Results A total of 146 female PD patients were enrolled， among whom 30 patients had dyskinesia， with an incidence rate of 20.5%. Compared with the non-dyskinesia group in terms of clinical features， the dyskinesia group had a significantly younger age of onset [（54.3±12.5） years vs （62.7±10.0） years， P<0.001]， a significantly longer disease duration [（9.9±3.7） years vs （4.5±3.7） years， P<0.001]， a significantly higher severity of disease [H-Y stage： （2.65±0.58） vs （2.35±0.83）， P=0.03]， a significantly longer duration of LD administration [（7.5±3.2） years vs （3.2±2.6） years， P<0.001]， a significantly higher LEDD [（703.2±203.9） mg vs （442.1±226.3） mg， P<0.001]， and significantly lower body weight [（54.1±8.2） kg vs （60.0±8.7） kg， P=0.001] and BMI [（20.9±3.1） kg/m2 vs （23.4±3.1） kg/m2， P<0.001]. The multivariate logistic regression analysis showed that high BMI （OR=0.770， P=0.005） was a protective factor against dyskinesia in female PD patients， while long disease duration （OR=1.304， P=0.001） and high LEDD （OR=1.003， P=0.012） were risk factors for dyskinesia. Conclusion There is a relatively high incidence rate of dyskinesia in female PD patients， which should be taken seriously in clinical practice， and high BMI is a protective factor， while long disease duration and high LEDD are risk factors for dyskinesia in female PD patients.
Parkinson Disease ; Dyskinesias ; Levodopa

This study aims to observe the mind-tranquilizing effect of Fushen Decoction on mice and investigate its effects on the 5-hydroxytryptamine(5-HT) system and γ-aminobutyric acid(GABA) in the brain of the mouse model of 4-chloro-DL-phenylalanine(PCPA)-induced insomnia. ICR mice were administrated with coffee(1 g·kg~(-1)) for 3 days, and the effects of Fushen Decoction(10, 20, and 40 g·kg~(-1)) on the autonomic activities of normal mice and coffee-treated mice were observed. Furthermore, the effects of Fushen Decoction on the autonomic activity and sleep induced by a suprathreshold dose of pentobarbital sodium in the mouse model of PCPA(350 mg·kg~(-1) for 3 consecutive days)-induced insomnia were observed. The levels of tryptophan hydroxylase(TPH), 5-hydroxytryptophan(5-HTP), and 5-HT in the serum, as well as those of 5-HTP and 5-HT in the brain stem, hippocampus, and cortex, were measured by enzyme-linked immunosorbent assay(ELISA). The fluorescence intensity of 5-HT in the raphe nucleus, hippocampus, and cortex was measured by the immunofluorescence method. The protein levels of tryptophan hydroxylase-2(TPH2) and 5-HT_(1A) receptor(5-HT_(1A)R) in the brain stem, hippocampus, and cortex were measured by Western blot. The levels of GABA in the hypothalamus, hippocampus, and cortex were measured by ELISA and immunohistochemistry methods. The results showed that Fushen Decoction(20, 40 g·kg~(-1)) reduced the number of autonomous activities in normal mice, coffee-treated mice, and the mouse model of PCPA-induced insomnia, and prolonged the duration of sleep induced by a suprathreshold dose of pentobarbital sodium in the mouse model. Fushen Decoction(20, 40 g·kg~(-1)) elevated the levels of TPH, 5-HTP, and 5-HT in the serum, and TPH2, 5-HTP, 5-HT, and 5-HT_(1A)R in the brain stem, hippocampus, and cortex, and up-regulated GABA expression in the hypothalamus, cortex, and hippocampus of the mouse model of PCPA-induced insomnia. In conclusion, Fushen Decoction(20, 40 g·kg~(-1)) exerted a mind-tranquilizing effect on mice by up-regulating the expression of TPH2, enhancing the 5-HT system, and elevating the GABA level in the brain.
Animals ; Serotonin/genetics* ; Sleep Initiation and Maintenance Disorders/genetics* ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Mice, Inbred ICR ; gamma-Aminobutyric Acid/genetics* ; Disease Models, Animal ; Fenclonine/adverse effects* ; Tryptophan Hydroxylase/genetics* ; Brain/metabolism* ; Sleep/drug effects* ; Humans ; 5-Hydroxytryptophan/metabolism*

OBJECTIVES: To investigate the molecular epidemiology of children with phenylketonuria (PKU) in Gansu, China, providing foundational data for intervention strategies. METHODS: A retrospective analysis was conducted on 1 159 PKU families who attended Gansu Provincial Maternity and Child Care Hospital from January 2012 to December 2024. Sanger sequencing, multiplex ligation-dependent probe amplification, whole exome sequencing, and deep intronic variant analysis were used to analyze the PAH gene. RESULTS: For the 1 159 children with PKU, 2 295 variants were identified in 2 318 alleles, resulting in a detection rate of 99.01%. The detection rates were 100% (914/914) in 457 classic PKU families, 99.45% (907/912) in 456 mild PKU families, and 96.34% (474/492) in 246 mild hyperphenylalaninemia families. The 2 295 variants detected comprised 208 distinct mutation types, among which c.728G>A (14.95%, 343/2 295) had the highest frequency, followed by c.611A>G (4.88%, 112/2 295) and c.721C>T (4.79%, 110/2 295). The cumulative frequency of the top 23 hotspot variants reached 70.28% (1 613/2 295), and most variant alleles were detected in exon 7 (29.19%, 670/2 295). CONCLUSIONS Deep intronic variant analysis of the PAH gene can improve the genetic diagnostic rate of PKU. The development of targeted detection kits for PAH hotspot variants may enable precision screening programs and enhance preventive strategies for PKU.
Humans ; Phenylketonurias/epidemiology* ; Female ; Male ; Retrospective Studies ; Phenylalanine Hydroxylase/genetics* ; Mutation ; Child, Preschool ; China/epidemiology* ; Child ; Infant

OBJECTIVES: To investigate the growth parameters of children with phenylketonuria and assess the impact of a phenylalanine-restricted diet on their physical development. METHODS: The study involved 39 children diagnosed with phenylketonuria through newborn screening at the Central Child Teaching Hospital, Baghdad, Iraq. Data were collected during scheduled monthly check-ups, including phenylalanine levels, diet compliance, and anthropometric measurements. The children were divided into two groups based on their phenylalanine levels during the 3-year follow-up period: well-controlled group (average phenylalanine level of less than 360 μmol/L, with no single reading exceeding 600 μmol/L; n=14) and poorly-controlled group (one or more phenylalanine readings above 600 μmol/L during the follow-up period; n=25). RESULTS: The mean height readings for all time points (at birth and 3, 6, 9, 12, 15, 18, 21, 24 and 36 months of age) were higher in the well-controlled group than the poorly-controlled group, however, only at 3 months of age the difference was statistically significant. Height Z-scores revealed a clearer pattern: although the poorly-controlled group had higher height Z-scores at birth (P=0.001), the well-controlled group showed significantly higher height Z-scores at 3, 6, 12, 15, 18, 24, and 36 months (P<0.05). The well-controlled group exhibited significantly higher mean weight measurements compared to the poorly-controlled group at 3, 6, 9, 15, 18 months and 21 months (P<0.05). From 6 to 36 months, the well-controlled group consistently had significantly higher weight Z-scores than the poorly-controlled group (P<0.05). The well-controlled group showed more favorable height and weight Z-score distributions at 36 months of age compared to the poorly-controlled group, but the differences were not statistically significant (P>0.05). Both groups had height and weight Z-scores within the normal range at 36 months of age. CONCLUSIONS The children with phenylketonuria who receive good dietary control show better improvements in growth parameters compared to those with poor dietary control, however, both groups maintain height and weight Z-scores within the normal range, indicating generally adequate physical development across the cohort.
Humans ; Phenylketonurias/diet therapy* ; Male ; Female ; Child, Preschool ; Infant ; Body Height ; Infant, Newborn ; Child Development ; Phenylalanine/blood*

Anthoceros angustus Steph. is rich in phenolic acids such as rosmarinic acid (RA). Phenylalanine ammonia-lyase (PAL) is an entry enzyme in the phenylpropanoid pathway of plants, playing an important role in the biosynthesis of RA. To investigate the important role of PAL in rosmarinic acid synthesis, two PAL genes (designated as AanPAL1 and AanPAL2) were cloned from A. angustus, encoding 755 and 753 amino acid residues, respectively. The AanPAL deduced amino acid sequences contain the conserved domains of PAL and the core active amino acid residues Ala-Ser-Gly. The phylogenetic analysis indicated that AanPAL1 and AanPAL2 were clustered with PALs from bryophytes and ferns and had the shortest evolutionary distance with the PALs from Physcomitrella patens. Quantitative real-time PCR results showed that the expression of AanPAL1 and AanPAL2 was induced by exogenous methyl jasmonate (MeJA). HPLC results showed that the MeJA treatment significantly increased the accumulation of RA. AanPAL1 and AanPAL2 were expressed in Escherichia coli and purified by histidine-tag affinity chromatography. The recombinant proteins catalyzed the conversion of L-phenylalanine to generate trans-cinnamic acid with high efficiency, with the best performance at 50 ℃ and pH 8.0. The K_m and k_cat of AanPAL1 were 0.062 mmol/L and 4.35 s^-1, and those of AanPAL2 were 0.198 mmol/L and 14.48 s^-1, respectively. The specific activities of AanPAL1 and AanPAL2 were 2.61 U/mg and 8.76 U/mg, respectively. The two enzymes had relatively poor thermostability but good pH stability. The high activity of AanPAL2 was further confirmed via whole-cell catalysis with recombinant E. coli, which could convert 1 g/L L-phenylalanine into trans-cinnamic acid with a yield of 100% within 10 h. These results give insights into the regulatory role of AanPAL in the biosynthesis of RA in A. angustus and provide candidate enzymes for the biosynthesis of cinnamic acid.
Phenylalanine Ammonia-Lyase/metabolism* ; Cloning, Molecular ; Cinnamates/metabolism* ; Recombinant Proteins/metabolism* ; Rosmarinic Acid ; Depsides/metabolism* ; Escherichia coli/metabolism* ; Amino Acid Sequence ; Plant Proteins/metabolism* ; Phylogeny ; Acetates/pharmacology* ; Cyclopentanes ; Oxylipins

Patients with Parkinson disease （PD） can have hand and foot deformities called “striatal deformities”， which often occur in the middle and late stages of PD， but also in the early stage. The clinical manifestations of such deformity are similar to those of hand-foot deformity due to osteoarticular diseases， and some patients may have pain and discomfort； however， the low incidence rate and few reports of this disease may easily lead to misdiagnosis and mistreatment.
Parkinson Disease ; Levodopa

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*

OBJECTIVES: To retrospectively analyze the variation and characteristics of phenylalanine hydroxylase (PAH) gene, and to observe the long-term treatment effect and follow-up of newborns with PAH deficiency. METHODS: Clinical data, treatment and follow-up results of 198 patients with PAH deficiency diagnosed by newborn screening in Jinan from 1996 to 2021 were collected. The genetic analysis of 55 patients with PAH deficiency diagnosed by newborn screening in Jinan and 213 patients referred from the surrounding areas of Jinan were summarized. Gene variations were checked by a customized Panel gene detection method. Blood phenylalanine-concentration and physical development indicators including height and weight were regularly monitored. Intellectual development was assessed using a neuropsychological development scale for patients aged 0-6 years and academic performance, and brain injury in patients was assessed using brain magnetic resonance imaging. RESULTS: c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. The genotype of c.158G>A variation is compound heterozygous variation, with mainly a mild hyperpheny-lalaninemia. 168 patients with PAH deficiency who were followed-up regularly had normal physical development without dwarfism or malnutrition. Among the 33 preschool patients who underwent mental development assessment, 2 were mentally retarded and the initial treatment age was older than 6 months. Nine patients with an average age of (17.13±2.42) years completed brain magnetic resonance imaging, one case was normal, and 8 cases were abnormal. There were patchy or patchy hyperintense foci near the bilateral lateral ventricles on T₂WI, and the intellectual development was normal. Compared with the other eight patients, the blood phenylalanine concentration of the normal child was better and stably controlled within the ideal range. CONCLUSIONS c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. After standardized treatment, most patients with PAH deficiency diagnosed by screening can obtain normal growth and intellectual development in adolescence, but there are different degrees of organic lesions in the cerebral white matter.
Child ; Child, Preschool ; Adolescent ; Humans ; Infant, Newborn ; Young Adult ; Adult ; Neonatal Screening ; Follow-Up Studies ; Retrospective Studies ; Phenylketonurias/genetics* ; Phenylalanine Hydroxylase/genetics* ; Phenylalanine/therapeutic use* ; Mutation

L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D₂ receptor (D₂R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D₂R⁺ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D₂R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D₂-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D₂R⁺ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D₂R⁺ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D₂R⁺ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D₂R⁺ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Rats ; Animals ; Levodopa/toxicity* ; Dopamine ; Parkinsonian Disorders/drug therapy* ; Oxidopamine ; Dyskinesia, Drug-Induced ; Corpus Striatum/metabolism* ; Neurons/metabolism* ; Receptors, Dopamine D2/metabolism* ; Antiparkinson Agents/toxicity*

This study aims to reveal the endogenous metabolic characteristics of acteoside in the young rat model of purinomycin aminonucleoside nephropathy(PAN) by non-targeted urine metabolomics and decipher the potential mechanism of action. Biochemical indicators in the urine of rats from each group were determined by an automatic biochemical analyzer. The potential biomarkers and related core metabolic pathways were identified by ultra-high performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry(UHPLC-LTQ-Orbitrap MS) combined with principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA). MetaboAnalyst 5.0 was used to establish the receiver operating characteristic(ROC) curve for evaluating the clinical diagnostic performance of core metabolites. The results showed that acteoside significantly decreased urinary protein-to-creatinine ratio in PAN young rats. A total of 17 differential metabolites were screened out by non-targeted urine metabolomics in PAN young rats and they were involved in phenylalanine metabolism and phenylalanine, tyrosine and tryptophan biosynthesis. Thirtten differential metabolites were screened by acteoside intervention in PAN young rats, and they were involved in phenylalanine metabolism and arginine and proline metabolism. Among them, leucylproline and acetophenone were the differential metabolites that were significantly recovered after acteoside treatment. These pathways suggest that acteoside treats PAN in young rats by regulating amino acid metabolism. The area under the curve of two core biomarkers, leucylproline and acetophenone, were both greater than 0.9. In summary, acteoside may restore amino acid metabolism by regulating endogenous differential metabolites in PAN young rats, which will help to clarify the mechanism of acteoside in treating chronic glomerulonephritis in children. The characteristic biomarkers screened out have a high diagnostic value for evaluating the treatment of chronic glomerulonephritis in children with acteoside.
Humans ; Child ; Rats ; Animals ; Puromycin Aminonucleoside ; Metabolomics/methods* ; Biomarkers/urine* ; Chromatography, High Pressure Liquid/methods* ; Acetophenones ; Glomerulonephritis ; Phenylalanine ; Amino Acids