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)

Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I). We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Eleven heterozygous mutations were identified, including five missense mutations, one splice site mutation, two small deletions and two nonsense mutations, in 12 families that included 27 patients and 13 asymptomatic carriers. Six mutations were new and five had already been reported. Four of the mutations caused truncation of the GTPCH I protein. One family carried a base-pair change in the 5'-untranslated region, not detected in controls, that could be responsible for the phenotype. Three of the remaining 10 families had deletions in the parkin gene on chromosome 6, underlining how difficult it is to distinguish, in some cases, between DRD and parkin mutations. No mutations were identified in seven families. The clinical spectrum extended from the classical DRD phenotype to parkinsonism with levodopa-induced dyskinesias, and included spastic paraplegia as well as the absence of dystonia.
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PMID:Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? 1082 51

We have investigated the presence of mutations in the parkin gene in patients with early-onset parkinsonism. Direct sequencing of the polymerase chain reaction (PCR) products showed a homozygous G deletion in the exon 7 (c.871delG) in one patient. This was a 38-year-old Moroccan woman with a history of parkinsonism of 18 years of duration. The disease appeared as an apparently sporadic case and was characterized by dystonia of the legs at onset and a rapid progression to severe generalized parkinsonism but with an excellent maintained response to dopamine agonists treatment. The deletion was a frameshift mutation resulting in a stop codon at position 297 which causes truncation of the parkin protein. Mutations in the parkin gene can be encountered in patients with an apparently sporadic early-onset parkinsonism, rapidly progressive course and marked and maintained response to dopamine agonists.
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PMID:A new mutation in the parkin gene in a patient with atypical autosomal recessive juvenile parkinsonism. 1089 10

In the nosological viewpoint concerning diseases with a pathophysiological dysfunction of the nigro-striatal dopaminergic system, juvenile parkinsonism (JP) is discussed in this paper in relation to hereditary progressive dystonia (HPD) and Parkinson's disease (PD). Most cases of JP have dystonia with parkinsonism, which is the main symptom of HPD. In the symptomatological analysis of complication with dystonia, an interesting observation arose as regards on the anatomical and functional development of the basal ganglia through patients with childhood onset HPD and JP. Genetic analysis revealed the disease entity of HPD to be an abnormality of the GTP-CH I gene. Consequently, it has been clarified that clinical differences between HPD and JP were not merely derived from differences in developmental processes. Furthermore, the autosomal recessive type of JP (AR-JP) was confirmed to be a disease entity by the detection of an abnormality of the 'parkin' gene. The nosological controversy about JP and PD in the clinical standpoint has been clarified. However, as more than half of patients with JP do not carry a mutation in the 'parkin' gene, more investigations concerning nosological entities should be carried out. The absence of Lewy bodies in most patients with AR-JP has been confirmed to be a characteristic neorupathological finding as compared with those with typical PD pathology. In this paper, we discuss the above findings.
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PMID:Development of the nosological analysis of juvenile parkinsonism. 1098 65

Autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF, syn. autosomal recessive juvenile parkinsonism, PARK2) is one of the hereditary parkinsonian syndromes. We examined subjects consisting of 43 patients from 22 families with AR-EPDF. The clinical features were relatively homogeneous, including the average age at onset of 26.1 years, beginning with dystonic gait disturbance, diurnal fluctuation of the symptoms (sleep benefit) unrelated to medication, dystonia (mainly foot dystonia), hyperactive tendon reflex, remarkable effect of levodopa and other antiparkinsonism drugs, susceptibility to dopa-induced dyskinesia, mild autonomic symptoms, absence of dementia, and slow progression of disease. Some patients had hysteric character or psychic symptoms provoked by medication. Pathologic study revealed neuronal loss in the substantia nigra pars compacta and locus coeruleus without Lewy body formation. We performed extensive molecular genetic analysis of the parkin gene in 16 families to identify a total of six different deletional mutations. In AR-EPDF loss of newly discovered 'Parkin' protein is responsible for selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus. Compared with autosomal dominant Parkinson's disease, AR-EPDF appears to be more prevalent and present in several ethnic groups.
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PMID:Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification. 1098 66

We review here familial Parkinson's disease (PD) from clinical as well as molecular genetic aspects. The contribution of genetic factors to the pathogenesis of PD is supported by the demonstration of the high concordance in twins, increased risk among relatives of PD patients in case control and family studies, and the existence of familial PD and parkinsonism based on single gene defects. Recently, several genes have been mapped and/or identified in patients with familial PD. Alpha-synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features and Lewy body positive pathology. In contrast, parkin is responsible for autosomal recessive form of early-onset PD with Lewy body-negative pathology. This form is identified world-wide among patients with young-onset PD. Furthermore, ubiquitin carboxy terminal hydrolase L1 gene is responsible for an autosomal dominant form of typical PD, although only a single family has so far been identified with a mutation of this gene, and tau has been identified as a causative gene for frontotemporal dementia and parkinsonism. In addition, five other chromosome loci have been identified to be linked to familial PD or dystonia-parkinsonism. The presence of different loci or different causative genes indicates that PD is not a single entity but a highly heterogeneous. Identification and elucidation of the causative genes should enhance our understanding of the pathogenesis of sporadic PD.
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PMID:Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease. 1120 33

A mutation of the DYT1 gene on chromosome 9q34 has recently been identified as the cause of one form of autosomal-dominantly inherited dystonia. TorsinA, the protein product of this gene, has homology with the family of heat shock proteins, and is found in many peripheral tissues and brain regions. We used a polyclonal antibody to torsinA, developed in our laboratory, to systematically examine the regional distribution of torsinA in rat brain. We find that neurons in all examined structures are immunoreactive for this protein. There is intense immunoreactivity in most neuronal nuclei, with slightly less labeling of cytoplasm and proximal processes. Terminals also are labeled, especially in striatum, neocortex and hippocampus. Double-labeling fluorescence immunohistochemistry using antibodies to neurotransmitters and other neurochemical markers demonstrated that the majority of neurons of all studied neurochemical types are immunoreactive for torsinA. Our findings indicate that torsinA is widely distributed in the central nervous system implicating additional, localized factors, perhaps within the basal ganglia, in the development of dystonia. Many other proteins have a similar widespread distribution, including some which have been implicated in other movement disorders and neurodegenerative processes, such as parkin, alpha-synuclein, ubiquitin and huntingtin. The distribution of torsinA in rat brain as demonstrated by immunohistochemistry contrasts with the results of in situ hybridization studies of torsinA mRNA in human postmortem brain in which a more limited distribution was found.
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PMID:Distribution and immunohistochemical characterization of torsinA immunoreactivity in rat brain. 1133 19

Mutations in the PARKIN gene are associated with early-onset (juvenile) Parkinson's disease. We analyzed the coding sequence of this gene (exons 1-12) in patients from a family with three affected siblings, born to first-degree consanguineous parents, with an onset before 23 years and foot dystonia as the initial clinical symptom. The three patients were alive without cognitive impairment at ages of 70, 69, and 65 years, showing a marked response to levodopa treatment. A 2 bp-deletion at exon 11 (1276-1277 del GA) was found. The three patients were homozygous for this frameshift mutation, which would introduce a Stop at codon 394. This is a new PARKIN-mutation that would produce a truncated protein, lacking exon 12 and most the 11th. This region includes the C-terminal ring-finger domain of parkin, essential for its function as a ubiquitin-protein ligase. Compared to patients from other families with truncating mutations, our patients had an earlier onset. In addition, the three patients had dystonia at onset. In conclusion, we described a new PARKIN truncating mutation associated with an early onset parkinsonism, and the presence of foot dystonia as the initial symptom.
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PMID:Early-onset Parkinson's disease associated with a new parkin mutation in a Spanish family. 1168 52

The authors describe a 37-year-old woman with early-onset hemiparkinsonism (HP) and ipsilateral body hemiatrophy (HA). Genetic analysis revealed a missense mutation (Arg275Trp) and a duplication of exon 7 of parkin. The complementary metabolic and receptor pattern of PET ligands corresponded to that typically found in idiopathic PD, although tracer binding asymmetry was lacking. Parkin mutations should be considered in HPHA, particularly when there is a younger age at onset and dystonia is an early sign.
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PMID:Parkin mutations in a patient with hemiparkinsonism-hemiatrophy: a clinical-genetic and PET study. 1188 48

Dopa-responsive dystonia (DRD) is an eminently treatable condition and its recognition is therefore of crucial importance. In classical cases, the disease manifests in early childhood with walking problems due to dystonia of the lower limbs. The dystonia is frequently accompanied by "parkinsonian" features such as reduced facial expression or slowing of fine finger movements. Biochemically, the disorder is typically characterized by low levels of the neurotransmitter metabolite homovanillic acid and reduced levels of neopterin and tetrahydrobiopterin (BH4) in the cerebrospinal fluid. This is due to heterozygote mutations of the GTP cyclohydrolase I gene, which is the rate-limiting enzyme in the synthesis of BH4. BH4 is an essential co-factor for tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. Reduced levels of BH4 lead to the dopamine-deficit syndrome DRD because of reduced TH activity. Other genes implicated in the pathogenesis of this disorder are the TH gene itself and the parkin gene. This article summarizes all relevant aspects of DRD including recent advances in the genetics of this disorder and the widening phenotype. Particular emphasis is given to clinically relevant aspects such as diagnostic difficulties and atypical presentations in infancy and early childhood.
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PMID:Dopa-responsive dystonia -- the story so far. 1193 Feb 68

Mutations in the parkin gene cause autosomal recessive inherited juvenile parkinsonism (ARJP) and account for the majority of cases of inherited Parkinson's disease (PD) of young onset (<45 years of age). Patients with parkin mutations commonly have atypical clinical features such as dystonia at onset, hyper-reflexia, diurnal fluctuations, and sleep benefit; however, parkin mutation patients with both typical PD symptoms and older age of onset have been identified. Parkin is a ubiquitin protein ligase (E3), a component in the pathway that attaches ubiquitin to specific proteins, designating them for degradation by the proteasome. Several substrates for parkin have been identified (CDCrel-1, o-glycosylated alpha-synuclein, parkin associated endothelin-like cell receptor, and synphilin). The role of these substrates in the pathogenesis of ARJP is under active study. Most patients with parkin mutations lack Lewy bodies, suggesting that functional parkin is involved in the formation of these highly ubiquitinated inclusions. Furthermore, the recognition that parkin mutations can lead to a disorder clinically similar to sporadic PD, but presumably lacking Lewy bodies, calls into question the necessity of Lewy bodies for the diagnosis of PD and nigral cell death. Studies of parkin are increasing the focus on the role of the ubiquitin-proteasome system in the pathogenesis of both familial and sporadic PD.
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PMID:Significance of the parkin gene and protein in understanding Parkinson's disease. 1204 48


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