RARE DISEASE
Dopa-responsive dystonia
Dopa-responsive dystonia
Dopa-responsive dystonia
Synonyms: HPD with diurnal fluctuation, Hereditary progressive dystonia with diurnal fluctuation
Synonyms: HPD with diurnal fluctuation, Hereditary progressive dystonia with diurnal fluctuation
Synonyms: HPD with diurnal fluctuation, Hereditary progressive dystonia with diurnal fluctuation
Drug discovery
0
drugs
With orphan designations
Overview
Dopa-responsive dystonia (DRD) is a rare genetic disorder characterized by childhood-onset dystonia, parkinsonism, and marked diurnal fluctuations due to mutations in GCH1 or other genes impairing dopamine synthesis. It exhibits dramatic, sustained improvement with low-dose levodopa therapy, distinguishing it from neurodegenerative parkinsonism [1][6][9][12].
Burden
Diagnostic delays average 13–15 years, leading to unnecessary surgeries or contractures [6][12].
Nonmotor symptoms (depression, anxiety, migraine) affect 30%–40% of patients, impacting quality of life [2][6][12].
Lifelong treatment is required, though most achieve near-complete remission with early intervention [1][9][16].
Therapies
First-line: Low-dose levodopa (10–20 mg/kg/day) with long-term efficacy and minimal side effects [1][3][16].
Refractory cases: Consider deep brain stimulation (targeting subthalamic nuclei or globus pallidus internus) [1][13].
Avoid dopamine antagonists, aspartame, and SSRIs (risk of symptom exacerbation) [1][2][6].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
143 drug discovery papers about Dopa-responsive dystonia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
143 drug discovery papers about Dopa-responsive dystonia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-30 | Beyond the Diagnosis of Cerebral Palsy: A Decade of Misdiagnosis Before Clinical Reappraisal Revealed GCH1-Associated Dopa-Responsive Dystonia
Dopa-responsive dystonia (DRD) is an uncommon but highly treatable movement disorder that may closely mimic cerebral palsy (CP). We report a 16-year-old female who carried a diagnosis of spastic cerebral palsy for nearly ten years despite progressive symptoms, prolonged rehabilitation, and bilateral Achilles tendonlengthening procedures. During routine neurological reassessment at Iashvili Children's Central Hospital, careful history-taking identified marked diurnal fluctuation. Re-evaluation of previously performed genetic testing revealed a GCH1 variant of uncertain significance in the appropriate phenotypic context. Treatment with levodopa/benserazide resulted in remarkable functional recovery, including independent ambulation within three months. This case highlights the importance of longitudinal reassessment, avoidance of diagnostic anchoring, and phenotype-guided interpretation of genetic findings.
2026-05-31 | Segawa Syndrome (Dopa-Responsive Dystonia): Current Concepts in Pathogenesis, Clinical Spectrum, Diagnosis, and Contemporary Management
Segawa syndrome, also known as dopa-responsive dystonia (DRD), is a rare inherited neurometabolic movement disorder characterized by childhood-onset dystonia, gait abnormalities, marked diurnal fluctuation, and dramatic responsiveness to low-dose levodopa therapy. [1,2] Since its original description by Segawa and colleagues in 1976, substantial advances have occurred in the understanding of the molecular genetics, neurotransmitter biochemistry, clinical heterogeneity, and therapeutic responsiveness of this disorder. [1,3] Classical Segawa syndrome is most commonly associated with autosomal dominant mutations involving the guanosine triphosphate cyclohydrolase I (GCH1) gene, resulting in impaired tetrahydrobiopterin (BH4) synthesis and subsequent dopamine deficiency within the nigrostriatal pathway. [3,4] Additional pathogenic variants involving TH, SPR, and related neurotransmitter biosynthetic pathways have expanded the phenotypic spectrum to include atypical and complex forms associated with parkinsonism, developmental delay, autonomic dysfunction, psychiatric manifestations, and cognitive impairment. [5,11] The disorder frequently presents diagnostic challenges because of significant phenotypic overlap with cerebral palsy, hereditary spastic paraplegia, juvenile Parkinson disease, idiopathic dystonia, and neurodegenerative disorders. [6,10,21] Delayed diagnosis remains common despite the existence of highly effective treatment, resulting in avoidable disability, skeletal deformities, psychosocial impairment, and reduced quality of life. [18,21] The hallmark clinical feature remains a dramatic and sustained response to levodopa therapy, which distinguishes DRD from most progressive neurodegenerative movement disorders. [8] Recent advances in molecular diagnostics, next-generation sequencing, cerebrospinal fluid neurotransmitter analysis, and functional neuroimaging have improved disease recognition and expanded understanding of genotype–phenotype correlations. [5,10,11] Nevertheless, contemporary controversies persist regarding diagnostic classification, atypical phenotypes, long-term disease progression, neuropsychiatric involvement, and optimization of individualized therapeutic strategies. [17,22] This comprehensive descriptive review examines the epidemiology, molecular pathogenesis, neurochemical mechanisms, clinical presentation, diagnostic evaluation, differential diagnosis, treatment approaches, prognosis, contemporary controversies, limitations of current evidence, and future research directions related to Segawa syndrome.
2026-04-16 | Long-Term Outcomes in Tyrosine Hydroxylase Deficiency: A Case Series of Four Paediatric Patients.
This study aims to investigate the clinical characteristics and long-term outcomes of patients with TH gene-related dopa-responsive dystonia (DRD), which providing further insights into this disorder. In this study, we analysed the clinical data, genetic test results and 3-year follow-up information of four patients treated with levodopa. Detailed clinical information was collected on these patients, and the results of genetic testing were analysed. Among the four patients, there were two males and two females with the age of onset ranging from 5 months to 2 years. At the same time, we review relevant literature about the clinical spectrum, treatment and prognosis.
2026-04-12 | Genetic analysis reveals phenotypic variability in three Colombian families with dopa-responsive dystonia: novel genotype-phenotype correlations.
BACKGROUND: Dopa-responsive Dystonia (DRD) due to GTP cyclohydrolase 1 (GTPCH1) deficiency is a neurogenetic disorder caused by pathogenic GCH1 variants. Tetrahydrobiopterin (BH4) deficiency impairs dopamine synthesis in the basal ganglia, leading to childhood-onset dystonia with excellent response to levodopa. CASE PRESENTATION: We report eight patients from three unrelated families with GCH1 (NM_000161.3) variants: c.142 C > T; p.(Gln48*), c.241T > C; p.(Ser81Pro), and c.607G > A; p.(Gly203Arg). Two individuals homozygous for c.142 C > T showed phenotypic discordance. Mean age at onset was 7.3 years (range: 6–12), with an average diagnostic delay of 13.4 years. All symptomatic individuals responded well to low-dose levodopa. DISCUSSION: This is the first report to describe variable expressivity among individuals homozygous for p.(Gln48*). Previous literature has focused on heterozygous carriers with incomplete penetrance, and homozygous variability remains scarcely documented. CONCLUSIONS: Our findings expand the clinical and molecular spectrum of DRD and challenge the assumption that autosomal recessive GCH1 variants invariably cause a severe phenotype. This report underscores the importance of family-based genetic studies, detailed pedigrees, and careful clinical surveillance of asymptomatic carriers. A low threshold for levodopa trials is warranted, even when inheritance patterns or symptom severity deviate from classical expectations. These insights are critical to improving early recognition and timely treatment.
2026-03-24 | A novel heterozygous GCH1 gene variant in a family with dopa-responsive dystonia: a case report
Dopa-responsive dystonia (DRD), also known as Segawa disease, is a treatable childhood-onset movement disorder most commonly caused by heterozygous variants in the GCH1 gene. Reduced penetrance and sex-related differences in disease expression may obscure recognition of autosomal dominant inheritance in affected families. An 11-year-old girl developed a right-predominant in-toeing gait at age 10, followed by limitation of ankle dorsiflexion and diurnal worsening of dystonia. Brain and spinal magnetic resonance imaging and dopamine transporter imaging were normal. Cerebrospinal fluid (CSF) analysis revealed reduced neopterin and biopterin levels with decreased active tetrahydrobiopterin (BH 4 ), while CSF homovanillic acid and 5-hydroxyindoleacetic acid levels were normal. Oral levodopa/carbidopa administration completely resolved dystonia, confirming the diagnosis of DRD. Genetic testing identified a heterozygous GCH1 variant (c.704G>C, p.Arg235Pro). Her paternal cousin, a 12-year-old girl, showed early-childhood onset of progressive gait disturbance with lower-limb stiffness, equinus gait, and marked diurnal fluctuation. CSF pteridine analysis demonstrated markedly reduced neopterin levels with only mildly decreased biopterin levels, accompanied by profoundly decreased active BH 4 . Brain imaging was normal, and symptoms responded to levodopa therapy. Despite carrying the identical GCH1 variant, the two patients differed substantially in age at onset and clinical severity, whereas the proband's father and paternal uncle were asymptomatic. This family highlights marked intrafamilial variability in GCH1 -related DRD. Awareness of such variability, together with low penetrance and sex-related differences in disease expression, is important for accurate diagnosis and genetic counseling.
gene therapies
2025-04-30 | Spectrum of Inherited Childhood‐Onset Dystonia: Case Series of 19 Families With Genotype and Phenotype Characterization Highlighting the Treatable Causes
Childhood-onset dystonia, a clinically and genetically diverse group of disorders, can be challenging to diagnose. Information on the genotype and phenotype spectrum in the Indian population is limited. This study reports the clinical and molecular findings of monogenic childhood-onset dystonia in 22 individuals from 19 Indian families. Complex dystonia was the most frequent type, followed by combined and isolated forms. A total of 23 variants across 17 genes were identified, including nine novel ones. These disorders include four autosomal dominant, one X-linked recessive, one mitochondrial, and the remaining 11 autosomal recessive conditions. Five potentially treatable disorders were identified, and treatment was initiated in three families, showing satisfactory responses, particularly in dopa-responsive dystonias. Our study contributes four additional genes-CYP27A1, NDUFAF3, FUCA1, and FIG4-to the list of genes associated with complex dystonia. Exome sequencing proved crucial in diagnosing the etiology of dystonia, identifying treatable forms, and aiding genetic counseling. This study emphasizes the significance of using NGS for early genetic diagnosis to enable timely targeted therapies, offer precise genetic counseling to families, and prevent recurrence in the family.
2024-06-21 | Catecholamines and Parkinson's disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview.
The author identified the genes and proteins of human enzymes involved in the biosynthesis of catecholamines (dopamine, norepinephrine, epinephrine) and tetrahydrobiopterin (BH4): tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and GTP cyclohydrolase I (GCH1). In Parkinson's disease (PD), the activities and levels of mRNA and protein of all catecholamine-synthesizing enzymes are decreased, especially in dopamine neurons in the substantia nigra. Hereditary GCH1 deficiency results in reductions in the levels of BH4 and the activities of TH, causing decreases in dopamine levels. Severe deficiencies in GCH1 or TH cause severe decreases in dopamine levels leading to severe neurological symptoms, whereas mild decreases in TH activity in mild GCH1 deficiency or in mild TH deficiency result in only modest reductions in dopamine levels and symptoms of DOPA-responsive dystonia (DRD, Segawa disease) or juvenile Parkinsonism. DRD is a treatable disease and small doses of L-DOPA can halt progression. The death of dopamine neurons in PD in the substantia nigra may be related to (i) inflammatory effect of extra neuronal neuromelanin, (ii) inflammatory cytokines which are produced by activated microglia, (iii) decreased levels of BDNF, and/or (iv) increased levels of apoptosis-related factors. This review also discusses progress in gene therapies for the treatment of PD, and of GCH1, TH and AADC deficiencies, by transfection of TH, AADC, and GCH1 via adeno-associated virus (AAV) vectors.
2006-06-01 | Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ–liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning
To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ–liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca2+-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ–liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ–liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ–liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.
2002-09-27 | Generation of human artificial chromosomes expressing naturally controlled guanosine triphosphate cyclohydrolase I gene
Human artificial chromosomes (HACs) are generated from the precursor DNA constructs containing alpha-satellite DNA with CENP-B boxes, and the process could be used for the incorporation of large genes in the HACs. Guanosine triphosphate cyclohydrolase I (GCH1) is the first and rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin, the essential co-factor of aromatic amino acid hydroxylases and nitric oxide synthase.We constructed HACs carrying a 180 kb genome segment encoding the human GCH1 gene and its control region from the bacterial artificial chromosome (BAC) with the GCH1 segment by co-transfection with the alpha-satellite DNA-containing BAC to a human fibroblast cell line. Two cell lines carrying a HAC with GCH1 genes were obtained. Both HACs were composed of multiple copies of precursor BACs and were maintained stably in human and mouse cell lines. The GCH1 activities of the HAC-carrying human fibroblast cell lines were elevated but still highly sensitive to IFN-gamma induction, mimicking the response of the gene expression from the authentic chromosomal genes.These HACs will provide a useful system for analysis of the complex regulatory circuit of the GCH1 gene in vivo and also function as a tool for gene delivery in animal models or in therapeutic trials.
small molecules
2026-07-30 | Beyond the Diagnosis of Cerebral Palsy: A Decade of Misdiagnosis Before Clinical Reappraisal Revealed GCH1-Associated Dopa-Responsive Dystonia
Dopa-responsive dystonia (DRD) is an uncommon but highly treatable movement disorder that may closely mimic cerebral palsy (CP). We report a 16-year-old female who carried a diagnosis of spastic cerebral palsy for nearly ten years despite progressive symptoms, prolonged rehabilitation, and bilateral Achilles tendonlengthening procedures. During routine neurological reassessment at Iashvili Children's Central Hospital, careful history-taking identified marked diurnal fluctuation. Re-evaluation of previously performed genetic testing revealed a GCH1 variant of uncertain significance in the appropriate phenotypic context. Treatment with levodopa/benserazide resulted in remarkable functional recovery, including independent ambulation within three months. This case highlights the importance of longitudinal reassessment, avoidance of diagnostic anchoring, and phenotype-guided interpretation of genetic findings.
2026-05-31 | Segawa Syndrome (Dopa-Responsive Dystonia): Current Concepts in Pathogenesis, Clinical Spectrum, Diagnosis, and Contemporary Management
Segawa syndrome, also known as dopa-responsive dystonia (DRD), is a rare inherited neurometabolic movement disorder characterized by childhood-onset dystonia, gait abnormalities, marked diurnal fluctuation, and dramatic responsiveness to low-dose levodopa therapy. [1,2] Since its original description by Segawa and colleagues in 1976, substantial advances have occurred in the understanding of the molecular genetics, neurotransmitter biochemistry, clinical heterogeneity, and therapeutic responsiveness of this disorder. [1,3] Classical Segawa syndrome is most commonly associated with autosomal dominant mutations involving the guanosine triphosphate cyclohydrolase I (GCH1) gene, resulting in impaired tetrahydrobiopterin (BH4) synthesis and subsequent dopamine deficiency within the nigrostriatal pathway. [3,4] Additional pathogenic variants involving TH, SPR, and related neurotransmitter biosynthetic pathways have expanded the phenotypic spectrum to include atypical and complex forms associated with parkinsonism, developmental delay, autonomic dysfunction, psychiatric manifestations, and cognitive impairment. [5,11] The disorder frequently presents diagnostic challenges because of significant phenotypic overlap with cerebral palsy, hereditary spastic paraplegia, juvenile Parkinson disease, idiopathic dystonia, and neurodegenerative disorders. [6,10,21] Delayed diagnosis remains common despite the existence of highly effective treatment, resulting in avoidable disability, skeletal deformities, psychosocial impairment, and reduced quality of life. [18,21] The hallmark clinical feature remains a dramatic and sustained response to levodopa therapy, which distinguishes DRD from most progressive neurodegenerative movement disorders. [8] Recent advances in molecular diagnostics, next-generation sequencing, cerebrospinal fluid neurotransmitter analysis, and functional neuroimaging have improved disease recognition and expanded understanding of genotype–phenotype correlations. [5,10,11] Nevertheless, contemporary controversies persist regarding diagnostic classification, atypical phenotypes, long-term disease progression, neuropsychiatric involvement, and optimization of individualized therapeutic strategies. [17,22] This comprehensive descriptive review examines the epidemiology, molecular pathogenesis, neurochemical mechanisms, clinical presentation, diagnostic evaluation, differential diagnosis, treatment approaches, prognosis, contemporary controversies, limitations of current evidence, and future research directions related to Segawa syndrome.
2026-04-16 | Long-Term Outcomes in Tyrosine Hydroxylase Deficiency: A Case Series of Four Paediatric Patients.
This study aims to investigate the clinical characteristics and long-term outcomes of patients with TH gene-related dopa-responsive dystonia (DRD), which providing further insights into this disorder. In this study, we analysed the clinical data, genetic test results and 3-year follow-up information of four patients treated with levodopa. Detailed clinical information was collected on these patients, and the results of genetic testing were analysed. Among the four patients, there were two males and two females with the age of onset ranging from 5 months to 2 years. At the same time, we review relevant literature about the clinical spectrum, treatment and prognosis.
2026-04-12 | Genetic analysis reveals phenotypic variability in three Colombian families with dopa-responsive dystonia: novel genotype-phenotype correlations.
BACKGROUND: Dopa-responsive Dystonia (DRD) due to GTP cyclohydrolase 1 (GTPCH1) deficiency is a neurogenetic disorder caused by pathogenic GCH1 variants. Tetrahydrobiopterin (BH4) deficiency impairs dopamine synthesis in the basal ganglia, leading to childhood-onset dystonia with excellent response to levodopa. CASE PRESENTATION: We report eight patients from three unrelated families with GCH1 (NM_000161.3) variants: c.142 C > T; p.(Gln48*), c.241T > C; p.(Ser81Pro), and c.607G > A; p.(Gly203Arg). Two individuals homozygous for c.142 C > T showed phenotypic discordance. Mean age at onset was 7.3 years (range: 6–12), with an average diagnostic delay of 13.4 years. All symptomatic individuals responded well to low-dose levodopa. DISCUSSION: This is the first report to describe variable expressivity among individuals homozygous for p.(Gln48*). Previous literature has focused on heterozygous carriers with incomplete penetrance, and homozygous variability remains scarcely documented. CONCLUSIONS: Our findings expand the clinical and molecular spectrum of DRD and challenge the assumption that autosomal recessive GCH1 variants invariably cause a severe phenotype. This report underscores the importance of family-based genetic studies, detailed pedigrees, and careful clinical surveillance of asymptomatic carriers. A low threshold for levodopa trials is warranted, even when inheritance patterns or symptom severity deviate from classical expectations. These insights are critical to improving early recognition and timely treatment.
2026-03-24 | A novel heterozygous GCH1 gene variant in a family with dopa-responsive dystonia: a case report
Dopa-responsive dystonia (DRD), also known as Segawa disease, is a treatable childhood-onset movement disorder most commonly caused by heterozygous variants in the GCH1 gene. Reduced penetrance and sex-related differences in disease expression may obscure recognition of autosomal dominant inheritance in affected families. An 11-year-old girl developed a right-predominant in-toeing gait at age 10, followed by limitation of ankle dorsiflexion and diurnal worsening of dystonia. Brain and spinal magnetic resonance imaging and dopamine transporter imaging were normal. Cerebrospinal fluid (CSF) analysis revealed reduced neopterin and biopterin levels with decreased active tetrahydrobiopterin (BH 4 ), while CSF homovanillic acid and 5-hydroxyindoleacetic acid levels were normal. Oral levodopa/carbidopa administration completely resolved dystonia, confirming the diagnosis of DRD. Genetic testing identified a heterozygous GCH1 variant (c.704G>C, p.Arg235Pro). Her paternal cousin, a 12-year-old girl, showed early-childhood onset of progressive gait disturbance with lower-limb stiffness, equinus gait, and marked diurnal fluctuation. CSF pteridine analysis demonstrated markedly reduced neopterin levels with only mildly decreased biopterin levels, accompanied by profoundly decreased active BH 4 . Brain imaging was normal, and symptoms responded to levodopa therapy. Despite carrying the identical GCH1 variant, the two patients differed substantially in age at onset and clinical severity, whereas the proband's father and paternal uncle were asymptomatic. This family highlights marked intrafamilial variability in GCH1 -related DRD. Awareness of such variability, together with low penetrance and sex-related differences in disease expression, is important for accurate diagnosis and genetic counseling.
gene therapies
2025-04-30 | Spectrum of Inherited Childhood‐Onset Dystonia: Case Series of 19 Families With Genotype and Phenotype Characterization Highlighting the Treatable Causes
Childhood-onset dystonia, a clinically and genetically diverse group of disorders, can be challenging to diagnose. Information on the genotype and phenotype spectrum in the Indian population is limited. This study reports the clinical and molecular findings of monogenic childhood-onset dystonia in 22 individuals from 19 Indian families. Complex dystonia was the most frequent type, followed by combined and isolated forms. A total of 23 variants across 17 genes were identified, including nine novel ones. These disorders include four autosomal dominant, one X-linked recessive, one mitochondrial, and the remaining 11 autosomal recessive conditions. Five potentially treatable disorders were identified, and treatment was initiated in three families, showing satisfactory responses, particularly in dopa-responsive dystonias. Our study contributes four additional genes-CYP27A1, NDUFAF3, FUCA1, and FIG4-to the list of genes associated with complex dystonia. Exome sequencing proved crucial in diagnosing the etiology of dystonia, identifying treatable forms, and aiding genetic counseling. This study emphasizes the significance of using NGS for early genetic diagnosis to enable timely targeted therapies, offer precise genetic counseling to families, and prevent recurrence in the family.
2024-06-21 | Catecholamines and Parkinson's disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview.
The author identified the genes and proteins of human enzymes involved in the biosynthesis of catecholamines (dopamine, norepinephrine, epinephrine) and tetrahydrobiopterin (BH4): tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and GTP cyclohydrolase I (GCH1). In Parkinson's disease (PD), the activities and levels of mRNA and protein of all catecholamine-synthesizing enzymes are decreased, especially in dopamine neurons in the substantia nigra. Hereditary GCH1 deficiency results in reductions in the levels of BH4 and the activities of TH, causing decreases in dopamine levels. Severe deficiencies in GCH1 or TH cause severe decreases in dopamine levels leading to severe neurological symptoms, whereas mild decreases in TH activity in mild GCH1 deficiency or in mild TH deficiency result in only modest reductions in dopamine levels and symptoms of DOPA-responsive dystonia (DRD, Segawa disease) or juvenile Parkinsonism. DRD is a treatable disease and small doses of L-DOPA can halt progression. The death of dopamine neurons in PD in the substantia nigra may be related to (i) inflammatory effect of extra neuronal neuromelanin, (ii) inflammatory cytokines which are produced by activated microglia, (iii) decreased levels of BDNF, and/or (iv) increased levels of apoptosis-related factors. This review also discusses progress in gene therapies for the treatment of PD, and of GCH1, TH and AADC deficiencies, by transfection of TH, AADC, and GCH1 via adeno-associated virus (AAV) vectors.
2006-06-01 | Nigral injection of antisense oligonucleotides to synaptotagmin I using HVJ–liposome vectors causes disruption of dopamine release in the striatum and impaired skill learning
To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ–liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca2+-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ–liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ–liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ–liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.
2002-09-27 | Generation of human artificial chromosomes expressing naturally controlled guanosine triphosphate cyclohydrolase I gene
Human artificial chromosomes (HACs) are generated from the precursor DNA constructs containing alpha-satellite DNA with CENP-B boxes, and the process could be used for the incorporation of large genes in the HACs. Guanosine triphosphate cyclohydrolase I (GCH1) is the first and rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin, the essential co-factor of aromatic amino acid hydroxylases and nitric oxide synthase.We constructed HACs carrying a 180 kb genome segment encoding the human GCH1 gene and its control region from the bacterial artificial chromosome (BAC) with the GCH1 segment by co-transfection with the alpha-satellite DNA-containing BAC to a human fibroblast cell line. Two cell lines carrying a HAC with GCH1 genes were obtained. Both HACs were composed of multiple copies of precursor BACs and were maintained stably in human and mouse cell lines. The GCH1 activities of the HAC-carrying human fibroblast cell lines were elevated but still highly sensitive to IFN-gamma induction, mimicking the response of the gene expression from the authentic chromosomal genes.These HACs will provide a useful system for analysis of the complex regulatory circuit of the GCH1 gene in vivo and also function as a tool for gene delivery in animal models or in therapeutic trials.
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