Distonías primarias respondedoras a levodopa (DRD): búsqueda sistemática en Latinoamérica / Dopa-responsive dystonia (DRD): systematic search in Latin America

RESUMEN Las distonías que responden a levodopa (DRD, siglas en inglés) abarcan un grupo de distonías primarias, causadas por deficiencias enzimáticas en la vía metabólica de las aminas y, por definición, comparten como característica principal su respuesta favorable y sostenida a levodopa. Existen hasta seis genes asociados a DRD, siendo el gen GCH1 el más frecuentemente involucrado. La presentación típica de esta entidad se caracteriza por su aparición en la niñez, distonía de inicio en miembros inferiores con fluctuación diurna, leve parkinsonismo y respuesta clara a dosis bajas de levodopa. Se incluye una búsqueda sistemática de la literatura con casos de DRD publicados en Latinoamérica.

SUMMARY Dopa-responsive dystonia (DRD) encompasses a heterogenous group of primary dystonias, caused by enzymatic deficiencies across the amines pathway and, by definition, show as their main characteristic a favorable and sustained response to levodopa. There are up to 6 genes associated with DRD, including pathogenic variants of the GCH1 gene as the most frequently involved. The typical presentation of DRD is characterized by start in childhood, lower limb-onset dystonia with daytime fluctuation, mild parkinsonism, and a sustained response to low doses of levodopa. A systematic literature search on DRD reported cases in Latin America is presented.

Hipoglucemia hiperinsulinémica congénita persistente, reporte de un caso / Persistent congenital hyperinsulinemic hypoglucemia, case report

Resumen La placenta y el hígado son los encargados del metabolismo de los carbohidratos. La glucosa es fundamental para el metabolismo cerebral. La hipoglucemia se define con valores < 47 mg/dl. La hipoglicemia que persiste más de 7 días se atribuye a problemas metabólicos o endocrinológicos y requiere un flujo de glucosa > 12 mg/kg/min para alcanzar normo-glicemia. La hipoglicemia hiperinsulinémica congénita persistente (HHCP) es poco común (1:50,000 nacidos vivos), es la causa más común de hipoglicemia persistente secundaria a una secreción inadecuada de insulina, que puede afectar el neurodesarrollo. Hay una forma difusa y una focal, con manifestaciones clínicas idénticas, pero con mecanismos patológicos diferentes. El tratamiento médico es a base de diazóxido y ocreótide. En el 95% de los casos no hay respuesta al tratamiento médico, requiriendo pancreatectomía subtotal. Se utilizó ocreótide y nifedipino. La tomografía computada con emisión de positrones (PET/TC 18F-DOPA) encontró incremento en la capación pancreática de insulina, se realizó pancreactectomía. Se egresó sin complicaciones y en seguimiento pediátrico sin alteraciones neurológicas.

Abstract The placenta and liver are responsible for the metabolism of carbohydrates. The glucose is fundamental for brain metabolism. Hypoglycaemia is defined as values < 47 mg/dl. Hypoglycaemia that persists for more than 7 days is attributed to metabolic or endocrine problems and requires glucose flow > 12 GKM to reach normoglycemia. Persistent congenital hyperinsulinemic hypoglycemia (PCHH) is uncommon (1:50,000 live births) is the most common cause of persistent hypoglycemia secondary to inadequate insulin secretion, can significantly affect neurodevelopment. There is a diffuse and a focal form, with identical clinical manifestations, but with different pathological mechanisms. The medical treatment is diazoxide and ocreotide. In 95% of cases there is no response to medical treatment, requiring subtotal pancreatectomy. Ocreotide and nifedipine were used. Positron emission computed tomography (PET/CT 18F-DOPA) found an increase in pancreatic insulin capacity, a pancreactectomy was performed. He was discharged without complications and in pediatric follow-up without neurological alterations.

Clinical analysis of nine infants with tyrosine hydroxylase deficiency / 中华神经科杂志

Objective:To explore the clinical characteristics of children with tyrosine hydroxylase deficiency (THD) in order to recognize this disease early as to optimize the treatment to improve the prognosis.Methods:A retrospective analysis was done on the clinical data of nine children with THD who were diagnosed at the Children′s Hospital of Fudan University from May 2018 to May 2020, including name, gender, age, age of onset, age of presentation, age of diagnosis, clinical manifestations, head imaging, tyrosine hydroxylase gene mutation, treatment, follow-up, and other results, which were classified according to Willemsen′s method, and the clinical characteristics were summarized and a literature review was carried out.Results:There were five males and four females with the age at onset ranged from newborn to two years and six months (median three months). The duration of diagnosis ranged from four months to five years and seven months (median nine months). The presenting symptom was motor retardation in seven cases. Clinical symptoms included hypokinesia in eight cases, limb dystonia in five cases, truncal hypotonia in four cases, dysphagia/dysarthria in four cases, oculogyric crises in four cases, tremor in three cases, rigidity in three cases, mask faces in three cases, bilateral ptosis in two cases, hypersalivation/sweating in two cases, diurnal fluctuation in two cases, myoclonic jerks in one case, and status dystonicus in one case. Cranial magnetic resonance imaging was normal in seven cases and non-specific in two cases (backward myelination in one case and bilateral ventricle enlargement and decreased white matter in another one). Eight tyrosine hydroxylase gene variants were found, including four missense variants, two frameshift variants, one shear variants and one nonsense variant, as well as three novel variants [c.1505_1518dup (p.R507Afs *23), c.1128_1138del (p.Q377Gfs *12), c.1058A>G(p.H353R)]. All patients were treated with levodopa and benserazide hydrochloride tables. The initial and maintenance doses of type A were 1.7-8.3 mg·kg -1·d -1 and 4.5-20.0 mg·kg -1·d -1, respectively. The initial and maintenance doses of type B were 1.7-12.5 mg·kg -1·d -1 and 4.6-12.0 mg·kg -1·d -1, respectively. In type A, four patients had dyskinesis which was relieved by decreasing the dose or maintaining the same dose of levodopa. One case of type B had dyskinesis which was self-resolving. Conclusions:Although the clinical manifestations of this disease are varied, the initial symptoms in children with onset within the first year of life are mostly hypokinesia, truncal hypotonia, and dystonia in limbs. It is recommended that children with THD, regardless of clinical type, should start at the minimum dose for easy segmentation in the range of 1.0-5.0 mg·kg -1·d -1, and the maintenance dose can be adjusted according to the individual response of the child. The incidence of dyskinesia of this disease is not low, but most can be treated by decreasing the initial dose and delaying the dosage rate.

Association of excessive daytime sleepiness and freezing of gait in Parkinson′s disease / 中华神经科杂志

Objective:To investigate the relationship between excessive daytime sleepiness and freezing of gait in Parkinson′s disease (PD).Methods:A total of 136 participants with PD were consecutively recruited between August 2017 and January 2018 at the Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The patients were divided into freezers with 50 patients and nonfreezers with 86 patients. The clinical characteristics of freezers and nonfreezers in PD patients were assessed. In the longitudinal study, a cohort of nonfreezers with 86 patients at baseline clinical visit for a maximum of 18 months were prospectively followed. The patients were divided into the excessive daytime sleepiness group ( n=14) and the non-excessive daytime sleepiness group ( n=72). Then a Cox regression analysis was performed to further investigate the relationship between excessive daytime sleepiness and freezing of gait in PD, and explore risk factors for freezing of gait. Results:The freezers had significantly worse sleep compared with the nonfreezers. The proportion of patients with excessive daytime sleepiness in freezers was higher than nonfreezers [40% (20/50) vs 16% (14/86), χ2=9.49, P=0.002]. The proportion of freezers in the patients with excessive daytime sleepiness was significantly higher than that in the patients without excessive daytime sleepiness [59% (20/34) vs 29% (30/102), χ2 =9.49, P=0.002]. During a maximum of 18-month follow-up, freezing of gait incidence (6/7) in the excessive daytime sleepiness group was significantly higher than that in the non-excessive daytime sleepiness group [21% (8/39) , χ2 =9.04, P=0.003]. Excessive daytime sleepiness ( HR=8.03, 95% CI 2.58-24.99, P<0.01) and high L-dopa equivalent daily dose ( HR=5.92, 95% CI 1.95-17.93, P=0.002) were significantly associated with an increased hazard of freezing of gait. Conclusion:Excessive daytime sleepiness and high L-dopa equivalent daily dose may be risk factors for the development of freezing of gait in PD in the future.

Heterogeneous expression of DOPA decarboxylase to improve the production of dopamine in Escherichia coli / 生物工程学报

Dopamine is the precursor of a variety of natural antioxidant compounds. In the body, dopamine acts as a neurotransmitter that regulates a variety of physiological functions of the central nervous system. Thus, dopamine is used for the clinical treatment of various types of shock. Dopamine could be produced by engineered microbes, but with low efficiency. In this study, DOPA decarboxylase gene from Sus scrofa (Ssddc) was cloned into plasmids with different copy numbers, and transformed into a previously developed L-DOPA producing strain Escherichia coli T004. The resulted strain was capable of producing dopamine from glucose directly. To further improve the production of dopamine, a sequence-based homology alignment mining (SHAM) strategy was applied to screen more efficient DOPA decarboxylases, and five DOPA decarboxylase genes were selected from 100 candidates. In shake-flask fermentation, the DOPA decarboxylase gene from Homo sapiens (Hsddc) showed the highest dopamine production (3.33 g/L), while the DOPA decarboxylase gene from Drosophila Melanogaster (Dmddc) showed the least residual L-DOPA concentration (0.02 g/L). In 5 L fed-batch fermentations, production of dopamine by the two engineered strains reached 13.3 g/L and 16.2 g/L, respectively. The residual concentrations of L-DOPA were 0.45 g/L and 0.23 g/L, respectively. Finally, the Ssddc and Dmddc genes were integrated into the genome of E. coli T004 to obtain genetically stable dopamine-producing strains. In 5 L fed-batch fermentation, 17.7 g/L of dopamine was produced, which records the highest titer reported to date.

Gallbladder Paraganglioma Associated with SDHD Mutation: a Potential Pitfall on ¹⁸F-FDOPA PET Imaging / 대한핵의학회잡지

A 36-year-old male patient initially presented with hypertension, tinnitus, bilateral carotid masses, a right jugular foramen, and a periaortic arch mass with an elevated plasma dopamine level but an otherwise normal biochemical profile. On surveillance MRI 4 years after initial presentation, he was found to have a 2.2-cm T2 hyperintense lesion with arterial enhancement adjacent to the gallbladder, which demonstrated avidity on ⁶⁸Ga-DOTATATE PET/CTand retrospectively on ¹⁸F-FDOPA PET/CT but was nonavid on ¹⁸F-FDG PET/CT. Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels were found to be within normal limits. This lesion was surgically resected and was confirmed to be a paraganglioma (PGL) originating from the gallbladder wall on histopathology. Pheochromocytoma (PHEO) and PGL are rare tumors of the autonomic nervous system. Succinate dehydrogenase subunit D (SDHD) pathogenic variants of the succinate dehydrogenase complex are usually involved in parasympathetic, extra-adrenal, multifocal head, and neck PGLs. We report an unusual location of PGL in the gallbladder associated with SDHD mutation which could present as a potential pitfall on ¹⁸F-FDOPA PET/CT as its normal excretion occurs through biliary system and gallbladder. This case highlights the superiority of ⁶⁸Ga-DOTATATE in comparison to ¹⁸F-FDOPA and ¹⁸F-FDG in the detection of SDHD-related parasympathetic PGL.ClinicalTrials.gov Identifier: NCT00004847.

Tracer Accumulation in Relation to Venous Thrombus on ¹⁸F-DOPA PET/CT in a Case of Persistent Hyperinsulinemic Hypoglycemia of Infancy / 대한핵의학회잡지

¹⁸F-DOPA PET/CT is commonly done in patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) to look for any focal lesion in the pancreas.We present the findings in a 20-day-old neonate with PHHI who underwent ¹⁸F-DOPA PET/CT. The scan showed diffuse uptake in the pancreas with no focal lesion, physiologic excretion into the genito-urinary system, and interestingly tracer accumulation was seen in the inferior vena cava and ilio-femoral veins which is a non-physiological site for tracer accumulation. The uptake corresponded to a large venous thrombus which was confirmed by a venous Doppler.

Progress on study of guanosine triphosphate cyclohydrolase 1 / 中国医师杂志

Guanosine triphosphate cyclohydrolase 1 (GTPCH1) is a protein encoded by the GCH1 gene,which catalyze GTP to tetrahydrofolinine (BH4) under physiological condition.BH4 is a coenzyme of aromatic amino acid hydroxylase and a cofactor of nitric oxide synthases.BH4 involves in the synthesis of various hormones and neurotransmitters and plays an important role in a series of pathophysiological processes in vivo.Recent studies showed that GTPCH1 is involved in the pathogenesis of neuropathic pain,doparesponsive dystonia,cancer and cardiovascular diseases.In this review,we will discuss the role of GTPCH1 in those diseases mentioned above.

Analysis of a Pedigree with Dopa-responsive Dystonia Caused by Novel Mutation of TH Gene / 中山大学学报(医学科学版)

@#【Objective】 To study the mutation characteristics of Tyrosine hydroxyls（TH） gene in a pedigree with dopa-responsive dystonia（DRD）. 【Methods】 Extraction of genomic DNA from peripheral blood of a proband and his parents and two sisters using high- throughput sequencing （NGS） method were detected on 256 known pathogenicity genes associated with dystonia and dyskinesia.【Results】Mutations on tyrosine hydroxylase（TH）gene in the exon 14 and exon 9 were detected in the proband and his eldest sister in this pedigree. They had a complex heterozygosity of c.1481C > T（p.Thr494Met）and c.943G >A（p.Gly315Ser），and one heterozygous mutation was carried by parents respectively. The mutation was not detected in his second sister and 50 people with normal phenotype controls. 【Conclusion】 The mutations of TH gene c. 1481C > T（p.Thr494Met）and c. 943G > A（p.Gly315Ser）led to the gene abnormality in DRD family，and a new mutation of TH gene was found，which expanded the relationship between DRD genotype and clinical phenotype. It is vital that early accurate diagnosis and treatment of DRD is the key to improve prognosis.

Diagnosis and treatment of parkinsonism with freezing of gait: A prospective study / 第二军医大学学报

[Abstract] Objective To study the clinical diagnosis and treatment of parkinsonism (PDS) with freezing of gait (FoG), so as to provide clues to delay the progress of the symptom. Methods A prospective study was designed. The outpatients of PDS with the main complaint of FoG were included and followed up for 2-6 years in the Department of Neurology, Changzheng Hospital, Naval Medical University (Second Military Medical University) from Nov. 2010 to Jan. 2016. The patients were given L-dopa first, and then antidepressants and other therapies (including other medication and surgery) were given if the previous treatments were not effective. The motor function of patients was evaluated by Hoehn-Yahr staging scale and the second and third part of the unified Parkinson disease rating scale (UPDRS); the general mental, behavior and emotional state were evaluated by the first part of UPDRS; the cognition was evaluated by minimum mental state examination (MMSE); depression and anxiety were evaluated by 17-item Hamilton depression scale (HAMD-17) and Hamilton anxiety scale (HAMA); and the severity of FoG was evaluated by the timed up and go test (TUGT). Results Six of the 15 cases with FoG were diagnosed as Parkinson disease (PD), and 9 had other disorders (2 with progressive supranuclear palsy, 3 with primary progressive FoG, 1 with frontotemporal dementia, 1 with vascular PDS, 1 with drug-induced PDS, and 1 with unknown-cause PDS). There were no significant differences in age, gender, severity of symptom or mental state (Hoehn-Yahr stage, UPDRS- score, UPDRS-Ⅱ score, UPDRS-III score, MMSE score, HAMD-17 score, HAMA score and TUGT time) between PD group and non-PD group (all P0.05). At the baseline, the FoG duration of PD patients ([7.50±2.66] years) was longer than that of non-PD patients ([2.56±0.88] years, P0.01). After treatment with increasing dose of L-dopa, 4 PD patients were improved while non-PD patients had no responses (4/6 vs 0/9, P＝0.01). Conclusion The causes of PDS with FoG are heterogeneous. The duration of FoG is helpful for diagnosis of idiopathic PD, while the severity of FoG has little value for etiological analysis. Increasing the dose of L-dopa is effective for FoG in advanced PD, while it has uncertain effect for FoG of other reasons.

Clinical characteristics and genetic analysis of patients with autosomal recessive dopa-responsive dystonia / 中华实用儿科临床杂志

Objective@#To analyze the clinical characteristics and gene mutation of autosomal recessive dopa-responsive dystonia(AR-DRD), and to explore its therapeutic effect, follow-up findings and molecular genetic me-chanism.@*Methods@#The whole exome sequencing, which based on next-generation sequencing, was performed in 6 movement-disordered patients who denied family history at the outpatient clinic of Children′s Hospital Affiliated to Capital Institute of Pediatrics from April 2016 to September 2017.The mutations identified in probands were then confirmed in probands and their parents by Sanger sequencing in order to analyze the cause of mutations.@*Results@#(1)Clinical features: the onset of 6 patients was around infancy, complicated with muscle weakness and abnormal muscle tone.(2)Gene mutation analysis: All 6 patients carried TH gene mutations.Five patients were of complex heterozygosis mutations, 1 patient was of homozygosis mutation.Five mutations were detected: c.605 G>A, c.601 C>T, c.364C>T, c.1412_1413insCCCCCAGGCCGTGC and c. 646G>A.(3)Therapeutic effect: all 6 patients achieved improvement of motor function after dopamine treatment, and they presented the different degrees of improvement in muscle tone and muscle strength.@*Conclusions@#The AR-DRD patients who carried c. 605 G>A mutation have a good therapeutic effect treated with L-Dopamine.This mutation may be a common mutation site of mild to moderate defective AR-DRD at home and abroad.The frameshift mutation c. 1412_1413insCCCCCAGGCCGTGC is a new TH gene pathogenicity mutation site discovered by this study.

Progress in diagnosis and treatment of restless legs syndrome / 中华全科医师杂志

Restless legs syndrome (RLS) is defined as a sleep-wake disorder, with the key feature being an urge to move, which can be classified as two types as primary RLS and secondary RLS. Iron deficiency is a key role of RLS, low levels of serum ferritin is noted in RLS lab tests. Pathophysiology of RLS is complex, genetic variants, anatomical network vulnerability, neurotransmission abnormalities and abnormal dopaminergic neurotransmission may all contribute to its pathogenesis. The mild RLS can choose non-drug therapy, but most of the patients need drug therapy especially the severe cases. The aboved aspects are discussed in this review based on recent literatures.

Clinical characteristics and genetic analysis of patients with autosomal recessive dopa-responsive dystonia / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics and gene mutation of autosomal recessive doparesponsive dystonia(AR-DRD),and to explore its therapeutic effect,follow-up findings and molecular genetic mechanism.Methods The whole exome sequencing,which based on next-generation sequencing,was performed in 6 movement-disordered patients who denied family history at the outpatient clinic of Children's Hospital Affiliated to Capital Institute of Pediatrics from April 2016 to September 2017.The mutations identified in probands were then confirmed in probands and their parents by Sanger sequencing in order to analyze the cause of mutations.Results (1) Clinical features:the onset of 6 patients was around infancy,complicated with muscle weakness and abnormal muscle tone.(2) Gene mutation analysis:All 6 patients carried TH gene mutations.Five patients were of complex heterozygosis mutations,1 patient was of homozygosis mutation.Five mutations were detected:c.605 G ＞ A,c.601 C ＞ T,c.364C ＞T,c.1412_1413insCCCCCAGGCCGTGC and c.646G ＞ A.(3) Therapeutic effect:all 6 patients achieved improvement of motor function after dopamine treatment,and they presented the different degrees of improvement in muscle tone and muscle strength.Conclusions The AR-DRD patients who carried c.605 G ＞ A mutation have a good therapeutic effect treated with L-Dopamine.This mutation may be a common mutation site of mild to moderate defective AR-DRD at home and abroad.The frameshift mutation c.1412_1413insCCCCCAGGCCGTGC is a new TH gene pathogenicity mutation site discovered by this study.

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.

In vitro dissolution and anti-vitiligo activity of isopsoralen nanostructured lipid carriers / 中草药

Objective To evaluate the in vitro dissolution characteristic of IPRN-NLC and to study its effects on B16F10 cells proliferation, melanin synthesis, and tyrosinase activity. Methods The dynamic dialysis was employed to compare the in vitro dissolution of IPRN and IPRN-NLC; MTT assay was used to detect the proliferation of B16F10; The tyrosinase activity was determined by L-DOPA-oxidation; The melain content was determined by GENMED Cell Melanin Quantitative Assay Kit. Results The accumulation dissolution of IPRN-NLC was 67.31% within 72 h, which showed sustained release; While the dissolution of IPRN-suspension, IPRN-physical mixture, and IPRN-DMSO were 53.34%, 90.30%, and 98.67%, respectively. The IPRN-NLC could significantly promote the proliferation, tyrosinase activity and melanin content compared with IPRN DMSO groups (P < 0.05) at the same concentration. Conclusion IPRN-NLC could increase the solubility of the drug with sustained release, and showed good cell biology intermiscibility, which could significantly increase the effects on B16F10 cells.

Clinical and genetic study on 5 children with dopa-responsive dystonia due to tyrosine hydroxylase deficiency / 中华实用儿科临床杂志

Objective To explore the clinical characteristics,gene mutations,diagnosis and treatment of chil-dren with dopa-responsive dystonia due to tyrosine hydroxylase(TH)deficiency.Methods Five patients(3 boys and 2 girls)with dopa-responsive dystonia due to TH deficiency were diagnosed and followed up from January 2002 to October 2017.The clinical manifestations,laboratory findings,treatment and TH gene mutations associated with TH defi-ciency were analyzed.Results Five patients came from different families.They had the onset at the age of 8 months to 20 months with dystonia,paroxysmal muscular hypertonia and normal intelligence or mild mental retardation.All of them had been misdiagnosed as cerebral palsy.Two cases with floppy limbs presented with fatigue and tremor.One case with floppy limbs presented with seizures. Complex heterozygous mutations were found in TH gene of all patients,which helped to confirm the diagnosis.Eight mutations were identified in TH gene.Six of them were reported.Two novel muta-tions,c.1077C>A(p.C359X)and c.1228C>T(p.R410C)were detected.After the treatment by levodopa[2.2-5.4 mg/(kg·d)],significant improvement was observed.Three patients recovered their intellectual and motor activi-ties.Two patients were dramatically improved but with slightly uncoordinated movements.Conclusion The patients of dopa-responsive dystonia due to TH deficiency usually have the onset around one year of age with almost normal inte-lligence,motor retardation and dystonia.The patients are likely misdiagnosed as cerebral palsy.The treatment with levo-dopa can dramatically improve the symptoms.The etiological diagnosis is very important.

A novel pathological mutation of tyrosine hydroxylase gene in dopa-responsive dystonia / 中华神经科杂志

Objective To explore the clinical characteristics and gene mutation in a patient clinically diagnosed as dopa-responsive dystonia (DRD) without family history.Methods The clinical characteristics of a patient clinically diagnosed as DRD without family history were collected and molecular and bioinformatic analyses were performed.Results The patient demonstrated as type A tyrosine hydroxylase deficiency and a compound heterozygous mutation of tyrosine hydroxylase (TH) gene was found,including a known nonsense mutation,c.457C＞T and a novel missense mutation,c.734G＞T that was probably pathologically predicted by bioinformatic analysis.Conclusion c.734G＞T may be a novel pathological mutation of TH gene.

Study on the 3,4-Dihydroxyphenylalanine Redox State Characterization Method of Mussel Adhesive Protein / 中国医疗器械杂志

<p><b>OBJECTIVE</b>To investigate the feasibility of using liquid chromatography (HPLC) to characterize the 3, 4-Dihydroxyphenylalanine (DOPA) redox state of mussel adhesive protein (MAP).</p><p><b>METHODS</b>The DOPA and protein contents of MAP were determined by HPLC, Arnow and Bradford methods respectively.</p><p><b>RESULTS</b>With extended oxidation time, the protein contents of MAP samples remained unchanged whereas the DOPA contents declined. The retention times of main peaks in HPLC for both the accelerated oxidation and retained samples shifted as the storage time extended, which could be related to the changes of sample redox state.</p><p><b>CONCLUSIONS</b>The redox state of MAP can be characterized by the change of HPLC peak retention time. HPLC can be used in the research on the MAP redox state, which is beneficial to the product development and quality control.</p>

Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike

Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency); SOX6 mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy.