Genetic heterogeneity in rapid onset dystonia-parkinsonism: description of a new family.

Rapid onset dystonia-parkinsonism (RDP) is a rare movement disorder with autosomal dominant inheritance, characterised by sudden onset of dystonic spasms and slowness of movement. To date, three families have been described that share linkage to the same location on chromosome 19q13, designated DYT12. Very recently, mutations in the ATP1A3 gene at the DYT12 locus have been demonstrated in seven unrelated patients, including the three previously linked families. A large RDP family is reported here, with eight definitely and one possibly affected members, that is not linked to the DYT12 region and has no mutation in the ATP1A3 gene. Predominant cranial-cervical involvement of dystonia occurred in this family, which has also been described in patients with idiopathic torsion dystonia linked to the DYT6 region on chromosome 8 and is a rare finding in DYT1 dystonia. Molecular genetic analysis also excluded linkage to the DYT6 locus and the GAG deletion in DYT1, suggesting at least one additional RDP gene.

High mutation rate in dopa-responsive dystonia: detection with comprehensive GCHI screening.

Mutations in GTP cyclohydrolase I (GCHI) are found in 50 to 60% of cases with dopa-responsive dystonia (DRD). Heterozygous GCHI exon deletions, undetectable by sequencing, have recently been described in three DRD families. We tested 23 individuals with DRD for the different mutation types by conventional and quantitative PCR analyses and found mutations, including two large exon deletions, in 87%. The authors attribute this high mutation rate to rigorous inclusion criteria and comprehensive mutational analysis.

Genetic heterogeneity in ten families with myoclonus-dystonia.

BACKGROUND: Myoclonus-dystonia (M-D) is a movement disorder with autosomal dominant inheritance and reduced penetrance but may also occur sporadically. Recently, mutations in the epsilon-sarcoglycan gene (SGCE) were shown to cause M-D. Furthermore, single variants in the dopamine D2 receptor (DRD2) and DYT1 genes were found in combination with SGCE mutations in two M-D families, and another M-D locus was recently mapped to chromosome 18p11 in one family. METHODS: The authors clinically and genetically characterised ten consecutive cases with myoclonus-dystonia; seven familial and three sporadic. Twenty nine M-D patients and 40 unaffected family members underwent a standardised clinical examination by a movement disorder specialist. Index cases were screened for mutations in the SGCE, DYT1, and DRD2 genes and for deletions of the SGCE gene. Suitable mutation negative families were tested for linkage to the SGCE region and to chromosome 18p11. RESULTS: Two SGCE mutations were detected among the seven familial but no mutation in the sporadic cases. Haplotype analysis at the new M-D locus was compatible with linkage in two families and excluded in another family, suggesting at least one additional M-D gene. There were no obvious clinical differences between M-D families with and without detected mutations. CONCLUSION: M-D is genetically heterogeneous with SGCE mutations accounting for the disease in only part of the clinically typical cases.

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.

Exon deletions in the GCHI gene in two of four Turkish families with dopa-responsive dystonia.

Most cases of dopa-responsive dystonia (DRD) are thought to be caused by mutations in the GCHI gene; however, by sequencing, mutations are found in only 40% to 60%. Recently, a single report identified, via Southern blot analysis, a large genomic GCHI deletion in a "mutation-negative" case. This report describes four families with DRD, two of which carry large deletions, thus confirming that deletions are an important subtype of GCHI mutations. These deletions were detected by quantitative duplex PCR that is amenable to DNA diagnostics.