RESUMO
OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237.
Assuntos
Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/genética , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/genética , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Distonia/enzimologia , Distonia/genética , Epilepsia/genética , Variação Genética , Humanos , Mitocôndrias/genética , Translocases Mitocondriais de ADP e ATP/genética , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Modelos Moleculares , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Proteômica , Sequenciamento do ExomaRESUMO
Sepiapterin reductase (SR) catalyses the last step in the tetrahydrobiopterin biosynthesis pathway; it converts 6-pyruvoyl-tetrahydropterin (6-PTP) to BH(4) in an NADPH-dependent reaction. SR deficiency is a very rare autosomal recessive disorder with normal phenylalanine (Phe) concentration in blood and diagnostic abnormalities are detected in CSF. We present a 16-month-old girl with SR deficiency. From the newborn period she presented with an adaptation regulatory disorder. At the age of 3 months, abnormal eye movements with dystonic signs and at 4.5 months psychomotor retardation were noticed. Since that time axial hypotonia with limb spasticity (or rather delayed reflex development), gastro-oesophageal reflux and fatigue at the end of the day has been observed. Brain MRI was normal; EEG was without epileptiform discharges. Analysis of biogenic amine metabolites in CSF at the age of 16 months showed very low HVA and 5-HIAA concentrations. Analysis of CSF pterins revealed strongly elevated dihydrobiopterin (BH(2)), slightly elevated neopterin and elevated sepiapterin levels. Plasma and CSF amino acids concentrations were normal. A phenylalanine loading test showed increased Phe after 1 h, 2 h and 4 h and very high Phe/Tyr ratios. SR deficiency was confirmed in fibroblasts and a novel homozygous g.1330C>G (p.N127K) SPR mutation was identified. On L-dopa and then additionally 5-hydroxytryptophan, the girl showed slow but remarkable progress in motor and intellectual ability. Now, at the age of 3 years, she is able to sit; expressive speech is delayed (to 1 1/2 years), passive speech is well developed. Her visual-motor skills, eye-hand coordination and social development correspond to the age of 2 1/2 years.
Assuntos
Oxirredutases do Álcool/deficiência , Distonia/tratamento farmacológico , Erros Inatos do Metabolismo/tratamento farmacológico , Transtornos Psicomotores/tratamento farmacológico , 5-Hidroxitriptofano/uso terapêutico , Oxirredutases do Álcool/genética , Aminas Biogênicas/metabolismo , Pré-Escolar , Distonia/enzimologia , Distonia/psicologia , Feminino , Seguimentos , Homozigoto , Humanos , Levodopa/uso terapêutico , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/psicologia , Mutação de Sentido Incorreto , Transtornos Psicomotores/enzimologia , Transtornos Psicomotores/psicologiaRESUMO
BACKGROUND: PLA2G6 mutations are known to be responsible for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA). In addition, novel mutations in PLA2G6 have recently been associated with dystonia-parkinsonism in two unrelated consanguineous families. METHODS: Direct sequencing analysis of the PLA2G6 gene. RESULTS: Here, we report the segregation of R632W with disease in an Iranian consanguineous dystonia-parkinsonism pedigree. The identical mutation was previously observed in a patient affected with NBIA. CONCLUSION: We conclude that different and even identical PLA2G6 mutations may cause neurodegenerative diseases with heterogeneous clinical manifestations, including INAD, NBIA and dystonia-parkinsonism.
Assuntos
Distonia/enzimologia , Distonia/genética , Predisposição Genética para Doença/genética , Fosfolipases A2 do Grupo VI/genética , Transtornos Parkinsonianos/genética , Mutação Puntual/genética , Adulto , Consanguinidade , Feminino , Genótipo , Humanos , Irã (Geográfico) , Masculino , Transtornos Parkinsonianos/enzimologia , Linhagem , Adulto JovemRESUMO
Torsin ATPases are the only members of the AAA+ ATPase family that localize to the endoplasmic reticulum and contiguous perinuclear space. Accordingly, they are well positioned to perform essential work in these compartments, but their precise functions remain elusive. Recent studies have deciphered an unusual ATPase activation mechanism relying on Torsin-associated transmembrane cofactors, LAP1 or LULL1. These findings profoundly change our molecular view of the Torsin machinery and rationalize several human mutations in TorsinA or LAP1 leading to congenital disorders, symptoms of which have recently been recapitulated in mouse models. Here, we review these recent advances in the Torsin field and discuss the most pressing questions in relation to nuclear envelope dynamics.
Assuntos
Adenosina Trifosfatases/metabolismo , Distonia/genética , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Distonia/enzimologia , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico HSC70/genética , Humanos , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutação , Membrana Nuclear/metabolismoRESUMO
A consistent neurochemical abnormality in Parkinson's disease (PD) is degeneration of dopaminergic neurons in substantia nigra, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-DOPA, the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Similarly, some patients with hereditary L-DOPA-responsive dystonia, a neurological disorder with clinical similarities to PD, have mutations in the TH gene and decreased TH activity and/or stability. Thus, a logical and efficient treatment strategy for PD is based on correcting or bypassing the enzyme deficiency by treatment with L-DOPA, DA agonists, inhibitors of DA metabolism, or brain grafts with cells expressing TH. A direct pathogenetic role of TH has also been suggested, as the enzyme is a source of reactive oxygen species (ROS) in vitro and a target for radical-mediated oxidative injury. Recently, it has been demonstrated that L-DOPA is effectively oxidized by mammalian TH in vitro, possibly contributing to the cytotoxic effects of DOPA. This enzyme may therefore be involved in the pathogenesis of PD at several different levels, in addition to being a promising candidate for developing new treatments of this disease.
Assuntos
Doença de Parkinson/enzimologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Processamento Alternativo , Animais , Antiparkinsonianos/uso terapêutico , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Distonia/enzimologia , Distonia/genética , Distonia/fisiopatologia , Humanos , Monoaminoxidase/metabolismo , Mutação , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Tirosina 3-Mono-Oxigenase/deficiênciaRESUMO
Guanosine 5'-triphosphate cyclohydrolase I (GCH) mutants (H144P and T186K) associated with dominant dopa-responsive dystonia were enzymatically inactive and inhibited the normal enzyme, suggesting that GCH activity in a heterozygote was <50% of control. The M211I mutant associated with recessive hyperphenylalaninemia was slightly active and had no inhibitory effects, so GCH activity in a heterozygote would be <50% of normal; therefore hyperphenylalaninemia would be evident only in homozygotes.
Assuntos
Distonia/genética , GTP Cicloidrolase/genética , Genes Dominantes , Genes Recessivos , Fenilalanina/sangue , Animais , Células COS , Distonia/enzimologia , Ativação Enzimática , GTP Cicloidrolase/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Mutação de Sentido Incorreto , Fenótipo , Fenilalanina/genética , RNA Mensageiro/análise , TransfecçãoRESUMO
We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.
Assuntos
Distonia/genética , GTP Cicloidrolase/genética , Penetrância , Mutação Puntual , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Análise Mutacional de DNA , Dopaminérgicos/uso terapêutico , Distonia/tratamento farmacológico , Distonia/enzimologia , Éxons/genética , Saúde da Família , Feminino , Genes Dominantes , Humanos , Íntrons/genética , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
The authors describe a patient with dopa-responsive dystonia who developed neuroleptic malignant syndrome with prolonged catatonia following treatment with neuroleptic agents. Use of these agents probably expanded the patient's neuronal dysfunction beyond the nigrostriatal system to involve multiple dopaminergic systems. Electroconvulsive treatment alleviated the prolonged catatonia.
Assuntos
Catatonia/fisiopatologia , Distonia/tratamento farmacológico , Levodopa/uso terapêutico , Síndrome Maligna Neuroléptica/fisiopatologia , Adulto , Catatonia/diagnóstico , Catatonia/terapia , Distonia/enzimologia , Distonia/genética , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/estatística & dados numéricos , Feminino , GTP Cicloidrolase/genética , Humanos , Síndrome Maligna Neuroléptica/diagnóstico , Síndrome Maligna Neuroléptica/terapiaRESUMO
The authors report a kindred in which GTP-CH deficiency resulted in a myoclonus-dystonia syndrome. The proband, a 17-year-old boy, presented with early-onset myoclonus and later, dystonia and bradykinesia. Blood prolactin was increased and CSF homovanillic acid, 5-hydroxyindoleacetic acid, and biopterin were all reduced. L-Dopa/carbidopa administration resulted in clinical improvement. In the paternal branch, the grandfather and three relatives had myoclonus-dystonia and resting or postural tremor of limbs. The authors found a missense mutation in the exon 6 of GCH-1 gene (K224R).
Assuntos
Distonia/genética , GTP Cicloidrolase/deficiência , GTP Cicloidrolase/genética , Levodopa/uso terapêutico , Mioclonia/genética , Adolescente , Adulto , Diagnóstico Diferencial , Distonia/diagnóstico , Distonia/tratamento farmacológico , Distonia/enzimologia , Feminino , Genes Dominantes/genética , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Mioclonia/diagnóstico , Mioclonia/tratamento farmacológico , Mioclonia/enzimologia , Linhagem , SíndromeRESUMO
The neural mechanisms underlying idiopathic dystonia are currently unknown. Genetic animal models, such as the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, may be helpful to providing insights into the pathophysiology of this common movement disorder. Recent metabolic mapping studies in the hamster model, using 2-deoxyglucose autoradiography, demonstrated altered 2-deoxyglucose uptake in motor areas such as the striatum, ventral thalamic nuclei, red nucleus, and deep cerebellar nuclei, during dystonic attacks. Whereas the 2-deoxyglucose method is thought to reflect mainly acute alterations of synaptic activity, determination of cytochrome oxidase activity has been suggested as a method of choice to examine sustained baseline changes in neuronal activity. Therefore, in the present study quantitative cytochrome oxidase histochemistry was used to identify chronic regional alterations in the absence of dystonic attacks in mutant hamsters. For comparison with recent 2-deoxyglucose studies, cytochrome oxidase activity was also determined during a dystonic attack, which was induced by mild stress. Cytochrome oxidase was determined in 109 brain regions of dystonic hamsters and non-dystonic, age-matched control hamsters. In the absence of a dystonic attack, a tendency to decreased cytochrome oxidase activity was found in most brain regions, possibly due to retarded brain development in mutant hamsters. Significant decreases in cytochrome oxidase activity were found in motor areas and limbic structures, such as hippocampus, piriform cortex, fundus striatum, globus pallidus, substantia nigra pars reticulata, mediodorsal nucleus of the thalamus, ventral pallidum, and interpositus nucleus of the cerebellum. After induction of a dystonic attack, the trend of decreased cytochrome oxidase activity disappeared, except in globus pallidus and interpositus nucleus of the cerebellum. Although the significant alterations in cytochrome oxidase activity in the absence of a dystonic attack were moderate, the data are in line with previous findings in the mutant hamsters, indicating that dysfunctions of the basal ganglia and their output nuclei are involved in the dystonic condition. Altered neural activity in limbic structures, found in the absence of dystonic attacks in mutant hamsters, may contribute to the stress-susceptibility of the animals.
Assuntos
Encéfalo/enzimologia , Distonia/fisiopatologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Neurônios/enzimologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Cricetinae , Distonia/enzimologia , Distonia/genética , Histocitoquímica , Mesocricetus , Mutação , Neurônios/patologia , Neurônios/fisiologia , Especificidade de Órgãos , Valores de ReferênciaRESUMO
The genetically dystonic rat exhibits a motor syndrome that closely resembles the human disease, generalized idiopathic dystonia. Although in humans dystonia is often the result of pathology in the basal ganglia, previous studies have revealed electrophysiological abnormalities and alterations in glutamate decarboxylase, the synthetic enzyme for GABA, in the cerebellum of dystonic rats. In this study, we further characterized the alterations in cerebellar GABAergic transmission in these mutants by examining the expression of the messenger RNA encoding glutamate decarboxylase (67000 mol. wt) with in situ hybridization histochemistry at the single cell level in Purkinje cells and neurons of the deep cerebellar nuclei. Glutamate decarboxylase (67000 mol. wt) messenger RNA levels were increased in the Purkinje cells and decreased in the deep cerebellar nuclei of dystonic rats compared to control littermates, suggesting opposite changes in GABAergic transmission in Purkinje cells and in their target neurons in the deep cerebellar nuclei. In contrast, levels of glutamate decarboxylase (67000 mol. wt) messenger RNA in the pallidum, and of enkephalin messenger RNA in the striatum, were unaffected in dystonic rats. The data indicate that both the Purkinje cells and GABAergic neurons of the deep cerebellar nuclei are the site of significant functional abnormality in the dystonic rat.
Assuntos
Núcleos Cerebelares/enzimologia , Distonia/enzimologia , Glutamato Descarboxilase/biossíntese , Células de Purkinje/enzimologia , RNA Mensageiro/biossíntese , Animais , Gânglios da Base/enzimologia , Núcleos Cerebelares/patologia , Distonia/genética , Distonia/patologia , Encefalinas/biossíntese , Globo Pálido/enzimologia , Hibridização In Situ , Peso Molecular , Neostriado/enzimologia , Ratos , Ratos EndogâmicosRESUMO
Recent pharmacological studies and receptor analyses have suggested that dopamine neurotransmission is enhanced in mutant dystonic hamsters (dt(sz)), a model of idiopathic paroxysmal dystonia which displays attacks of generalized dystonia in response to mild stress. In order to further characterize the nature of dopamine alterations, the present study investigated possible changes in the number of dopaminergic neurons, as defined by tyrosine hydroxylase immunohistochemistry, as well as binding to the dopamine transporter labelled with [3H]WIN 35,428 in dystonic hamsters. No differences in the number of tyrosine hydroxylase-immunoreactive neurons were found within the substantia nigra and ventral tegmental area of mutant hamsters compared to non-dystonic control hamsters. Similarly, under basal conditions, i.e. in the absence of a dystonic episode, no significant changes in [3H]WIN 35,428 binding were detected in dystonic brains. However, in animals killed during the expression of severe dystonia, significant decreases in dopamine transporter binding became evident in the nucleus accumbens and ventral tegmental area in comparison to controls exposed to the same external stimulation. Since stimulation tended to increase [3H]WIN 35,428 binding in control brains, the observed decrease in the ventral tegmental area appeared to be due primarily to the fact that binding was increased less in dystonic brains than in similarly stimulated control animals. This finding could reflect a diminished ability of the dopamine transporter to undergo adaptive changes in response to external stressful stimulation in mutant hamsters. The selective dopamine uptake inhibitor GBR 12909 (20 mg/kg) aggravated dystonia in mutant hamsters, further suggesting that acute alterations in dopamine transporter function during stimulation may be an important component of dystonia in this model.
Assuntos
Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Inibidores da Captação de Dopamina/metabolismo , Distonia/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Cocaína/metabolismo , Cricetinae/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Distonia/enzimologia , Distonia/genética , Imuno-Histoquímica , Núcleo Accumbens/metabolismo , Tegmento Mesencefálico/metabolismo , TrítioRESUMO
Glutamic acid decarboxylase (GAD) activity was measured in specific divisions of the deep cerebellar nuclei of rats with an inherited dystonia. In 16-day-old dystonic rats there was a significant increase in GAD activity only in the nucleus interpositus (+26%). In 20-day-old dystonic rats GAD activity in all 3 cerebellar nuclei (fastigial, interpositus, dentate) was significantly increased compared to normal controls. The results indicate a spread of the anatomical locus of the neurochemical abnormality with time. During this period (postnatal days 16-20) there is a progressive worsening of the motor disorder in the affected animals.
Assuntos
Núcleos Cerebelares/enzimologia , Distonia/enzimologia , Glutamato Descarboxilase/metabolismo , Animais , Núcleos Cerebelares/crescimento & desenvolvimento , Distonia/genética , Ratos , Ratos MutantesRESUMO
The effects of the novel kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro 61-8048) on severity of dystonia were examined in dt(sz) mutant hamsters, an animal model of paroxysmal dystonia, in which stress precipitates dystonic episodes. Ro 61-8048 (50, 100 and 150 mg/kg i.p.) significantly reduced the severity of dystonia in dt(sz) hamsters without leading to marked central side effects. Determinations of kynurenic acid concentrations in brain homogenates demonstrated that Ro 61-8048 (100 mg/kg i.p.) provoked a two- to threefold increase of the endogeneous broad spectrum glutamate receptor antagonist kynurenic acid in the striatum, cerebellum and brainstem of mutant hamsters. The antidystonic efficacy of Ro 61-8048 at well-tolerated doses suggests that kynurenine 3-hydroxylase inhibitors should be considered as new therapeutic candidates for the treatment of dyskinesias.
Assuntos
Coreia/tratamento farmacológico , Modelos Animais de Doenças , Distonia/tratamento farmacológico , Oxigenases de Função Mista/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Tiazóis/uso terapêutico , Animais , Coreia/enzimologia , Coreia/genética , Cricetinae , Relação Dose-Resposta a Droga , Distonia/enzimologia , Distonia/genética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Quinurenina 3-Mono-Oxigenase , Masculino , Mesocricetus , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Sulfonamidas/farmacologia , Tiazóis/farmacologiaRESUMO
GTP cyclohydrolase I activity in mononuclear blood cells from patients with juvenile parkinsonism (JP) was found to be normal compared to healthy controls. The normal activity in JP contrasts strongly with the decreased activity of 2-20% normal levels in hereditary progressive dystonia with marked diurnal fluctuation (HPD) or dopa responsive dystonia (DRD). The result indicates that the decreased dopamine level in the basal ganglia in JP is not due to decreased activity of GTP cyclohydrolase I, the enzyme for the biosynthesis of the tetrahydrobiopterin cofactor of tyrosine hydroxylase (TH), and the enzyme activity in mononuclear blood cells could be a reliable method for differential diagnosis between JP and HPD/DRD.
Assuntos
GTP Cicloidrolase/metabolismo , Linfócitos/enzimologia , Monócitos/enzimologia , Doença de Parkinson/enzimologia , Gânglios da Base/enzimologia , Distonia/tratamento farmacológico , Distonia/enzimologia , Distonia/genética , Humanos , Levodopa/uso terapêuticoRESUMO
Dopa-responsive dystonia (DRD) due to mutant GTP cyclohydrolase I (GCH) shows the considerable heterogeneity of clinical phenotypic expression. To explain the clinical diversity, we studied a Japanese family with a novel mutant GCH (GCH-G90V), where an affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote. Coexpression experiments using the mutant with wild-type GCH showed that GCH-G90V inactivated the normal enzyme in a dose-dependent manner, suggesting that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms for the clinical heterogeneity of DRD.
Assuntos
Di-Hidroxifenilalanina/farmacologia , Dopaminérgicos/farmacologia , Distonia/enzimologia , Distonia/genética , GTP Cicloidrolase/genética , Mutação de Sentido Incorreto/fisiologia , Adulto , Relação Dose-Resposta a Droga , Distonia/tratamento farmacológico , Feminino , Humanos , Isoenzimas/genética , Fenótipo , Plasmídeos/genética , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Dopamine-beta-hydroxylase (DBH) has been reported to be elevated in the serum of patients with idiopathic torsion dystonia. We have examined the levels in jewish patients suffering from that disease and found levels comparable to those of age-and sex-matched controls.
Assuntos
Dopamina beta-Hidroxilase/metabolismo , Distonia/enzimologia , Humanos , Israel , JudeusRESUMO
We found that mutations of GTP cyclohydrolase I, the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is the cofactor of dopamine-synthesizing tyrosine hydroxylase, cause dominantly inherited hereditary progressive dystonia with marked diurnal fluctuation (HPD, Segawa's disease) probably owing to the decrease of dopamine in the basal ganglia. These results indicate that tyrosine hydroxylase in the nigrostriatal dopamine neurons may be most sensitive to tetrahydrobiopterin deficiency causing dystonia.
Assuntos
Distonia/genética , GTP Cicloidrolase/genética , Genes Dominantes , Genes Recessivos , Criança , Distonia/enzimologia , GTP Cicloidrolase/deficiência , Humanos , Mutação , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
GTP cyclohydrolase I is the rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin, which is the cofactor for tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We found that dominantly inherited, hereditary progressive dystonia (HPD), first described by Segawa and also called dopa responsive dystonia (DRD), is caused by the mutations of GTP cyclohydrolase I gene, the partial decrease in the enzyme activity, and probably in striatal dopamine level, to less than 20% of the normal values. Juvenile parkinsonism and Parkinson's disease are also striatal dopamine deficiency, but no mutation in the enzyme has not been found, and they are supposed to be different from HPD/DRD in which no cell death of the nigrostriatal dopamine neurons occurs.
Assuntos
Distonia/genética , GTP Cicloidrolase/genética , Doença de Parkinson/genética , Mutação Puntual , Adulto , Idade de Início , Animais , Corpo Estriado/enzimologia , Dopamina/metabolismo , Distonia/enzimologia , Distonia/fisiopatologia , GTP Cicloidrolase/metabolismo , Humanos , Doença de Parkinson/enzimologia , Doença de Parkinson/fisiopatologiaRESUMO
The local concentration of 6-[18F]fluoro-L-dopa(18F) reflects the activity of aromatic acid decarboxylase (AADC), the enzyme that generates dopamine from its precursor amino acid, L-dopa. In young healthy adults, the local concentration of 18F, and hence AADC activity, is constant in coronal slices taken in a rostrocaudal direction. With increasing age a gradient representing decreasing activity in the putamen develops. This decrease is less marked than was expected from the literature. In five children with primary dystonia, the striatal distribution of 18F resembled that seen in the normal older adults. In established clinical Parkinson's disease the rostrocaudal gradient becomes steep; the putamen is more damaged.