Joanne Leung

Parkin deletions in a family with adult-onset, tremor-dominant Parkinsonism : Expanding the phenotype

A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early‐onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult‐onset, clinically typical tremor‐dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinsons disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa‐induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late‐onset typical Parkinsons disease. Ann Neurol 2000;48:65–71

Dopamine transmission in DYT1 dystonia: A biochemical and autoradiographical study

Abstract—Indices of dopamine transmission were measured in the postmortem striatum of DYT1 dystonia brains. A significant increase in the striatal 3,4-dihydroxyphenylacetic acid/dopamine ratio was found. Quantitative autoradiography revealed no differences in the density of dopamine transporter or vesicular monoamine transporter-2 binding; however, there was a trend toward a reduction in D1 receptor and D2 receptor binding. One brain with DYT1 parkinsonism was similarly evaluated and marked reductions in striatal dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid content as well as the density of binding of all four dopaminergic ligands were measured.

Intrafamilial phenotypic variability of the DYT1 dystonia: From asymptomatic TOR1A gene carrier status to dystonic storm

When primary torsion dystonia is caused by a GAG deletion in the TOR1A gene (DYT1 dystonia), it typically presents with an early‐onset dystonia involving distal limbs, subsequently spreading to a generalized dystonia. We describe a large family with an unusually broad variability in the clinical features of their dystonia both with regard to severity and age of onset. The proband of this family succumbed in his second decade to malignant generalized dystonia, whereas other family members carrying the same mutation are either asymptomatic or display dystonia that may be focal, segmental, multifocal, or generalized in distribution. One family member had onset of her dystonia at age 64 years, probably the oldest reported in genetically confirmed DYT1 dystonia. We conclude that marked phenotypic heterogeneity characterizes some families with DYT1 dystonia, suggesting a role for genetic, environmental, or other modifiers. These findings have implications for genetic testing and counseling.

ε-Sarcoglycan mutations found in combination with other dystonia gene mutations

Myoclonus‐dystonia is a movement disorder associated with mutations in the ε‐sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus‐dystonia remain to be determined.

Mutations in DYT1 Extension of the phenotypic and mutational spectrum

Background: Most cases of early-onset primary torsion dystonia (PTD) are caused by the same three–base pair (bp) (GAG) deletion in the DYT1 gene. Exon rearrangements are a common mutation type in other genes and have not yet been tested for in DYT1. Several lines of evidence suggest a relationship of the DYT1 gene with Parkinson disease (PD). Objective: To investigate the frequency and type of DYT1 mutations and explore the associated phenotypes in a mixed movement disorders patient cohort and in controls. Methods: The authors screened 197 patients with dystonia (generalized: n = 5; focal/segmental: n = 126; myoclonus-dystonia: n = 34; neuroleptic-induced: n = 32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases. Results: The GAG deletion was detected in five patients: three with early-onset PTD, one with generalized jerky or clonic dystonia, and one with generalized dystonia and additional features (developmental delay, pyramidal syndrome). A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a putatively healthy blood donor. No exon rearrangements were identified in DYT1. Conclusions: In this mixed patient sample, the GAG deletion was rare and in two out of five cases associated with an unusual phenotype. In addition, a novel DYT1 truncating mutation of unknown clinical relevance was found in a putatively unaffected individual. DYT1 exon rearrangements, however, do not seem to be associated with PTD.

A Major Locus for Myoclonus-Dystonia Maps to Chromosome 7q in Eight Families

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.

Clinical findings of a myoclonus-dystonia family with two distinct mutations

Myoclonus-dystonia has recently been associated with mutations in the epsilon-sarcoglycan gene (SCGE) on 7q21. Previously, the authors reported a patient with myoclonus-dystonia and an 18-bp deletion in the DYT1 gene on 9q34. The authors have now re-evaluated the patient harboring this deletion for mutations in the SGCE gene and identified a missense change. In the current study, the authors describe the clinical details of this family carrying mutations in two different dystonia genes. Further analysis of these mutations separately and together in cell culture and in animal models should clarify their functional consequences.

Evaluation of the role of the D2 dopamine receptor in myoclonus dystonia

A novel Val154→Ile mutation in the D2 dopamine receptor (DRD2) on chromosome 11q23 has recently been shown to be associated with myoclonus dystonia (M‐D) in one large family. Sequence analysis of the DRD2 gene in 5 M‐D patients from different families did not reveal any mutations, nor was there evidence of linkage to the 11q23 region in the DRD2 gene in four other families. Receptor binding and signal transduction assays of the DRD2 mutant and wild‐type receptors revealed identical agonist and antagonist affinities and functional responses. These studies suggest that M‐D is genetically heterogeneous. The molecular mechanisms through which the Val→Ile mutation may contribute to M‐D remain to be determined. Ann Neurol 2000;47:369–373

The GAG deletion of the DYT1 gene is infrequent in musicians with focal dystonia

Dystonia is a clinically and genetically heterogeneous condition characterized by involuntary twisting, abnormal postures, and repetitive movements. Early-onset, generalized dystonia is an autosomal dominant disorder associated in most cases with a GAG deletion in the coding region of the DYT1 gene (TOR1A) on chromosome 9q34.1,2⇓ Not all individuals with the GAG deletion in the DYT1 gene develop dystonia; penetrance has been estimated at approximately 30 to 40%.3 Focal dystonia is the most common type of dystonia, but the pathophysiology remains obscure. We observed that many musicians with focal dystonia have associated peripheral nerve or soft tissue injuries.4 Because most musicians with these injuries do not develop focal dystonia, we hypothesized that susceptibility genes may underlie the development of sporadic, idiopathic focal dystonia in musicians. Both the GAG deletion in the DYT1 gene and the DYT1 founder haplotype have been observed in some patients with idiopathic focal dystonia2,5,6⇓ …

Molecular cloning and expression of rat torsinA in the normal and genetically dystonic (dt) rat.

Deletions within the TOR1A gene cause early-onset (DYT1) torsion dystonia. We have cloned and sequenced the rat cDNA homologue of TOR1A and found a 91% identity with the human sequence. Northern blot analysis detects a single transcript of approximately 1.5 kb. In situ hybridization reveals a widespread distribution of torsinA mRNA within brain. No mutations were identified in the coding region of the gene in the genetically dystonic (dt) rat.