Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3' untranslated region of TH. An frt-flanked neomycin-resistance (neo(r)) cassette was placed in the 3' end of the targeting constructs. Mice homozygous for the knock-in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neo(r) cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down-regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neo(r)-positive TH hypomorphic mice as examined by markers for L-aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neo(r) cassette from the knock-in alleles partially restored TH and dopamine levels. The present neo(r)-positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L-dihydroxyphenylalanine-responsive dystonia/infantile parkinsonism.
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PMID:Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles. 1270 6

l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia consists of involuntary choreiform and dystonic movements. Here we report whether intrastriatal l-DOPA itself is able to trigger dyskinetic behavior and which role the neurotransmitter dopamine (DA) and its metabolites play. Intrastriatal l-DOPA as well as DA administration at the 6-hydroxydopamine (6-OHDA) lesioned side led to a significant appearance of dyskinetic behavior, whereas DA metabolites were ineffective. Intrastriatal inhibition of the enzyme aromatic amino acid decarboxylase (AADC) by benserazide prevented the appearance of l-DOPA-induced dyskinetic movements at the lesioned side. Principle component analysis of DA and DA metabolite levels with dyskinesia scores after l-DOPA/benserazide (6/15 mg/kg) administration indicated a significant correlation only for DA, whereas DA metabolites did not show any significant correlation with the occurrence of dyskinetic behavior. We conclude that intrastriatal l-DOPA itself is not able to induce dyskinetic movements, whereas the increase of intrastriatal DA levels is instrumental for l-DOPA- and DA-induced dyskinetic behavior.
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PMID:Intrastriatal inhibition of aromatic amino acid decarboxylase prevents l-DOPA-induced dyskinesia: a bilateral reverse in vivo microdialysis study in 6-hydroxydopamine lesioned rats. 1792 Feb 84

The causative variant in a consanguineous family in which the three patients (two siblings and a cousin) presented with intellectual disability, Marfanoid habitus, craniofacial dysmorphisms, chronic diarrhea and progressive kyphoscoliosis, has been identified through whole exome sequencing (WES) analysis. WES study identified a homozygous DDC variant in the patients, c.1123C>T, resulting in p.Arg375Cys missense substitution. Mutations in DDC cause a recessive metabolic disorder (aromatic amino acid decarboxylase, AADC, deficiency, OMIM #608643) characterized by hypotonia, oculogyric crises, excessive sweating, temperature instability, dystonia, severe neurologic dysfunction in infancy, and specific abnormalities of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF). In our family, analysis of neurotransmitters and their metabolites in patient's CSF shows a pattern compatible with AADC deficiency, although the clinical signs are different from the classic form. Our work expands the phenotypic spectrum associated with DDC variants, which therefore can cause an additional novel syndrome without typical movement abnormalities.
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PMID:Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant. 2559 65