Disease relevance of Dystonia

• Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of one glutamic acid in the carboxyl terminus of a protein named torsinA [1].
• X-linked dystonia parkinsonism (XDP) is an X-linked recessive adult onset movement disorder characterized by both dystonia and parkinsonism [2].
• We describe a pedigree in which 3 members in the same generation are affected by Rolandic epilepsy (RE), paroxysmal exercise-induced dystonia (PED), and writer's cramp (WC) [3].
• The MF pattern was present in DYT1 carriers with and without clinical manifestations and persisted in DYT1 dystonia patients in whom involuntary movements were suppressed by sleep [4].
• Fifty-six patients with BEB and 40 patients with HFS completed the SCL 90R, a screening instrument for psychiatric symptomatology, and the Freiburg Questionnaire for Dystonia (FQD), a questionnaire about psychosocial changes in subjects with movement disorders [5].

Psychiatry related information on Dystonia

• The role of the pedunculopontine and cuneiform nuclei, and related brainstem brainstem structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia [corrected][6]
• We have, therefore, analysed all published clinical studies of DYT1 dystonia to guide clinical decision making concerning DYT1 gene testing based on current information [7].

High impact information on Dystonia

• One example is DYT1 dystonia, a neurodevelopmental disease caused by an in-frame deletion (Deltagag) in the gene encoding torsinA [8].
• A glutamic acid deletion (DeltaE) in the AAA+ protein torsinA causes DYT1 dystonia [9].
• DYT1 dystonia appears to be a previously uncharacterized NE disease and the first, to our knowledge, to selectively affect CNS function [10].
• Recently, we described a point mutation in hTH (Q381K) in a family of two siblings suffering from progressive L-DOPA-responsive dystonia (DRD), representing the first reported mutation in this gene [11].
• This study supports the notion that DYT1 dystonia is associated with impaired protein handling and the nuclear envelope [6].

Chemical compound and disease context of Dystonia

• That torsinA mRNA is enriched in several basal ganglia nuclei, including the dopamine neurons in the substantia nigra, is intriguing since it suggests that DYT1 dystonia may be associated with a dysfunction in dopamine transmission [12].
• Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I) [13].
• Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals [14].
• We administered tetrahydrobiopterin (BH4) to 4 patients with progressive dystonia with diurnal variation (PDDV) [15].
• To determine if there is abnormal phenylalanine and biopterin metabolism in patients with dopa-responsive dystonia (DRD), we measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1, 2, 4, and 6 hours after an oral phenylalanine load (100 mg/kg) [16].

Biological context of Dystonia

• They also suggest possible connections between the allelic polymorphism at residue 216 and the penetrance of DYT1 dystonia, as well as a possible role for this polymorphism in related disease states [17].
• Although it is assumed that most patients with autosomal dominant dopa-responsive dystonia (DRD) have a GTP cyclohydrolase I dysfunction, conventional genomic DNA sequencing of the gene (GCH1) coding for this enzyme fails to reveal any mutations in about 40% of DRD patients, which makes molecular genetic diagnosis difficult [18].
• RESULTS: Ketamine produced dose-related increases in parkinsonian bradykinesia and dystonia as well as salivation [19].
• Haloperidol and reduced haloperidol-induced exacerbation of the dystonia produced by the kappa opioid U50,488H in guinea-pigs is associated with inhibition of sigma binding sites: behavioural and autoradiographical studies [20].
• We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994 [21].

Anatomical context of Dystonia

• These observations demonstrate that neurons have a unique requirement for nuclear envelope localized torsinA function and suggest that loss of this activity is a key molecular event in the pathogenesis of DYT1 dystonia [8].
• A case is reported, which is unusual in having flexor dystonia of the neck and marked signs of lower motor neuron involvement [22].
• To explore the pathobiology of DYT1 dystonia, we generated PC12 neural cell lines that inducibly express wild-type or mutant torsinA [23].

Gene context of Dystonia

• Consequently, torsinA interacts directly or indirectly with a novel class of transmembrane proteins that are localized in different subdomains of the ER system, either or both of which may play a role in the pathogenesis of DYT1 dystonia [9].
• We describe two previously unrecognized splice site mutations of GCH1 in Dopa responsive dystonia (DRD) [24].
• The human family of Deafness/Dystonia peptide (DDP) related mitochondrial import proteins [25].
• One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis [26].
• The hph-1 mice have defective tetrahydrobiopterin biosynthesis and share many neurochemical similarities with l-dopa-responsive dystonia (DRD) in humans [27].
• The 3697G>A/ND1 mitochondrial DNA mutation causes the LHON and spastic dystonia phenotype in the same family [28].

Analytical, diagnostic and therapeutic context of Dystonia

• These results support the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease [29].

References