Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 report on two sisters with a childhood-onset form of predominantly axial dystonia with marked diurnal fluctuations. Onset of clinical features was at approximately 6 years of age. Associated features included marked fatigue, slight facial dysmorphism, short stature, obesity, and learning disability*. Dystonia and fatigue responded to 3,4-dihydroxyphenylalanine (DOPA) therapy, with recurrence of symptoms upon withdrawal; the efficacy has been maintained over 7 years. Other symptoms were not influenced. There was no other case in the family (which included an older, healthy brother), except for non-specific fatigue without dystonia in the mother, and there was no significant family history except for obesity on the father's side. These observations are discussed in relation to the classical descriptions of Segawa syndrome, and to more recent reports of childhood onset, age-related, and transient benign paroxysmal tonic upgaze and ataxia. The combination of symptoms, their sensitivity to DOPA, and their persistence throughout childhood constitute, to our knowledge, a new clinical entity, which we propose to categorize as a DOPA-sensitive dystonia-plus syndrome.
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PMID:DOPA-sensitive dystonia-plus syndrome. 1573 26

We used [(18)F]-fluorodeoxyglucose and positron emission tomography to determine a discrete cerebral pattern of abnormal glucose utilization in dopa-responsive dystonia. Network analysis demonstrated that dopa-responsive dystonia is associated with a specific pattern of regional metabolic covariation, characterized by increases in the dorsal midbrain, cerebellum, and supplementary motor area, as well as reductions in motor and lateral premotor cortex and in the basal ganglia. This pattern was not expressed in mutation carriers for primary torsion dystonia. Dopa-responsive dystonia has a unique metabolic architecture that differs from other inherited forms of dystonia.
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PMID:The metabolic pathology of dopa-responsive dystonia. 1578 54

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. There are at least three causative genes for DRD: (1) the GCH1 gene on chromosome 14q22.1-q22.2, which encodes GTP cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway for tetrahydrobiopterin (BH4; the essential cofactor for tyrosine hydroxylase [THI]), (2) the TH gene on 11 p15.5, coding for the enzyme TH that catalyzes the rate-limiting step in the catecholamine biosynthesis, and (3) an as yet undefined gene on 14q13 (DYT14). In reports on DRD, in which conventional genomic DNA sequencing of GCH1 was conducted in a relatively large number of pedigrees, mutations in the coding region (including the splice sites) of this gene were found in approximately 60% (range: 49-79%) of DRD families. In our series, after conducting additional GCH1 testing (Southern blotting, cDNA sequencing, etc.) and TH analysis, 86% of families with DRD or dystonia with motor delay (an intermediate phenotype between GTPCH-deficient DRD [mild] and GTPCH-deficient hyperphenylalaninemia [severe]) had identifiable GCH1 or (rarely) TH mutations. Up to the present, only one pedigree with autosomal dominant DRD linked to the DYT14 locus has been reported. Neuropathological findings (no Lewy bodies and a normal population of cells with reduced melanin in the substantia nigra) in DRD patients with GTPCH dysfunction were similar to those in a patient with DYT14 dystonia. There have been no reports of autopsied patients with TH-deficient DRD. Neurochemical data suggest that striatal dopamine reduction in GTPCH-deficient DRD is caused not only by decreased TH activity resulting from a low cofactor (BH4) level but also by actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum, especially in the putamen, may be due to a diminished regulatory effect of BH4 on stability (rather than expression) of TH molecules or to a dysfunction of TH protein transport from the substantia nigra to the striatum. The extent of striatal TH protein loss may be critical in determining DRD symptomatology and could contribute to gender-related incomplete penetrance of GCH1 mutations in GTPCH-deficient DRD families. Notwithstanding the discovery of the three causative loci for DRD, a therapeutic trial with low doses of levodopa is still the most practical approach to the diagnosis of this treatable disorder. The trial should be considered in all children with dystonic and/or parkinsonian symptoms or with unexplained gait disorders. Analyses of total biopterin and neopterin as well as neurotransmitter metabolites in CSF appear to be useful for the diagnosis of GTPCH-deficient DRD (the major form of DRD) and of TH-deficient DRD (the mild form of TH deficiency). Findings of the precise mechanism of striatal TH protein loss in GTPCH-deficient DRD, the actual status of dopaminergic systems in TH-deficient DRD, and the novel causative gene on the DYT14 locus will better define the pathogenesis of DRD.
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PMID:[Dopa-responsive dystonia: clinical, genetic, and biochemical studies]. 1654 91

Dopa-responsive dystonia (DRD) causes dystonia-parkinsonism, which is abolished by levodopa. The authors assessed short intracortical inhibition and facilitation, silent period, blink reflex recovery cycle, and reciprocal inhibition in seven patients with DRD on and off treatment. Short intracortical inhibition and blink reflex recovery cycle were reduced, but increased with treatment. Silent period was normal on and off treatment. Third phase of reciprocal inhibition was reduced on and off treatment. A discrete pattern of motor inhibitory dysfunction occurs in DRD.
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PMID:Motor system inhibition in dopa-responsive dystonia and its modulation by treatment. 1661 Jan 1

Tetrahydrobiopterin (BH(4)) deficiencies are a highly heterogeneous group of disorders with several hundred patients, and so far a total of 193 different mutant alleles or molecular lesions identified in the GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes. The spectrum of mutations causing a reduction in one of the three biosynthetic (GTPCH, PTPS, and SR) or the two regenerating enzymes (PCD and DHPR) is tabulated and reviewed. Furthermore, current genomic variations or SNPs are also compiled. Mutations in GCH1 are scattered over the entire gene, and only 5 out of 104 mutant alleles, present in a homozygous state, are reported to cause the autosomal recessive form of inheritable hyperphenylalaninemia (HPA) associated with monoamine neurotransmitter deficiency. Almost all other 99 different mutant alleles in GCH1 are observed together with a wild-type allele and cause Dopa-responsive dystonia (DRD, Segawa disease) in a dominant fashion with reduced penetrance. Compound heterozygous or homozygous mutations are spread over the entire genes for PTS with 44 mutant alleles, for PCBD with nine mutant alleles, and for QDPR with 29 mutant alleles. These mutations cause an autosomal recessive inherited form of HPA, mostly accompanied by a deficiency of the neurotransmitters dopamine and serotonin. Lack of sepiapterin reductase activity, an autosomal recessive variant of BH(4) deficiency presenting without HPA, was diagnosed in patients with seven different mutant alleles in the SPR gene in exons 2 or 3 or in intron 2. Details on all mutations presented here are constantly updated in the BIOMDB database (www.bh4.org).
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PMID:Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. 1691 93

Deficient activity of the Dihydropteridine Reductase enzyme (DHPR; EC 1.5.1.34; OMIM 261630) is due to mutations in the Quinoid Dihydropteridine Reductase gene on 4p15.3 (QDPR; RefSeq NM_000320). It results in defective recycling of tetrahydrobiopterin (BH(4)) and homozygotes have a rare form of atypical Hyperphenylalaninaemia and Phenylketonuria (aPKU). The heterozygote frequency in the Maltese population is high at 3.3%. The more recently described and rarer type of BH(4) deficiency due to Sepiapterin Reductase enzyme deficiency (SR; EC 1.1.1.153; OMIM 182125), which presents as an atypical form of Dopa Responsive Dystonia (DRD) [L. Bonafe, B. Thony, J.M. Penzien, B. Czarnecki, N. Blau, Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia, Am. J. Hum. Genet. 69 (2001) 269-277; B.R.G. Neville, R. Parascandalo, S. Attard Montalto, R. Farrugia, A.E. Felice, A congenital dopa responsive motor disorder: a Maltese variant due to sepiapterin reductase deficiency, Brain 128 (Pt10) (2005) 2291-2296.] has also been identified at high frequency (4.6%) in this population. Two mutations, the c.68G>A in QDPR (p.G23D), and the new SPR, IVS2-2A>G mutation at the splice site consensus sequence in intron 2 of the Sepiapterin Reductase gene (SPR; RefSeq NM_003124) on 2p14-p12, were found to be the sole causative mutations in all the patients with DHPR deficiency and SR deficiency studied. All parents were heterozygotes for the corresponding mutation and showed no clinical symptoms. Three polymorphisms, c.96C>T (p.A32A), c. 345G>A (p.S115S) and c. 396G>A (p.L132L), have also been identified in the QDPR gene, defining four wild-type frameworks, useful in molecular epidemiology studies. The c. 68G>A mutation in QDPR was found only on framework I, suggesting a founder effect. In contrast no additional sequence diversity was found in the SPR gene whether in wild-type or mutant alleles which is also consistent with a founder effect.
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PMID:Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population. 1718 38

Dopa-responsive dystonia (DRD) is a rare, autosomal dominant (GTP-cyclohydroxylase gen mutation on chromosome 14q) or rarely recessive (tyrosine hydroxylase gene mutation on chromosome 11p) inherited disorder. Both enzymes take part in dopamine synthesis. Their deficiencies cause the dopamine level reduction. The first clinical symptoms occur in the childhood. The authors present the case of a 24-year-old woman in whom the lower limb dystonia occurred when she was five. Then the trunk and upper limbs dystonia appeared with skeleton deformities leading to deep disability. DRD was recognized when she was 19 and L-Dopa was administered. The clinical status improved, dystonic movements disappeared completely. The authors indicate that DRD must be taken into account in differential diagnosis of movement disorders in children, mostly in progressive cases. Good effect of L-Dopa treatment is one of the basic phenomena helpful in DRD recognition.
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PMID:[Dopa-responsive dystonia (Segawa syndrome) with secondary skeleton deformity]. 1733 36

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to relatively low doses of levodopa. There are at least three causative genes for DRD: 1) the GCH1 gene on chromosome 14q22.1-q22.2, coding for the enzyme GTP cyclohydrolase I (GTPCH) that catalyzes the rate-limiting step in the tetrahydrobiopterin (BH4; the cofactor for tyrosine hydroxylase [TH]) biosynthesis, 2) the TH gene on 11p15.5, and 3) an as yet undefined gene on 14q13 (DYT14). In our series, 86% of families with DRD or dystonia with motor delay (an intermediate phenotype between GTPCH-deficient DRD [mild] and GTPCH-deficient hyperphenylalaninemia [severe]) had identifiable GCH1 or (rarely) TH mutations. Neurochemical data suggest that striatal dopamine reduction in GTPCH-deficient DRD (the major form of DRD) is caused not only by decreased TH activity resulting from a low cofactor level but also by actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum (especially in the putamen) may be due to a diminished regulatory effect of BH4 on stability of TH molecules or to a dysfunction of TH protein transport from the substantia nigra to the striatum.
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PMID:[Dopa-responsive dystonia]. 1743 76

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

Dopa responsive Dystonia (DRD) was first described in 1971 and typically begins at childhood with gait dysfunction caused by foot dystonia progressing to affect other extremities. There is marked diurnal fluctuation and sustained improvement of symptoms with low dose levodopa therapy. Heterozygous mutation of the gene GCH1 has been shown to cause DRD. We studied GCH1 in nine patients with DRD from six families of Federal University of Minas Gerais Movement Disorders Clinic. We identified three mutations; two affected siblings carried a novel T209P mutation and two siblings from another family were compound heterozygous carriers of Met211Val and Lys224Arg mutations. To our knowledge this is the first report of GCH1 mutations underlying DRD in patients from Brazil.
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PMID:Novel GCH1 mutation in a Brazilian family with dopa-responsive dystonia. 1804 25


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