High mutation rate in dopa-responsive dystonia: Detection with comprehensive
            <i>GCHI</i>
            screening

Hagenah, Johann; Saunders‐Pullman, Rachel; Hedrich, Katja; Kabakci, Kemal; Habermann, Kristin; Wiegers, Karin; Mohrmann, K.; Lohnau, Thora; Raymond, Deborah; Vieregge, P.; Nygaard, T G; Ozelius, L. J.; Bressman, S. B.; Klein, Christine

doi:10.1212/01.wnl.0000152839.50258.a2

Cited by 86 publications

(73 citation statements)

References 9 publications

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“…Nine percent of our cases had a large deletion which can explain the difference between the published and our observed SGCE mutation frequency. In our sample, gene dosage alterations accounted for 33% of the detected mutations, emphasizing the importance of qPCR as previously shown for other genes, such as GTP cyclohydrolase I (GCH1; MIM# 600225), Parkin (PARK2; MIM# 602544) or alpha-synuclein (SNCA; PARK1; MIM# 163890) [Singleton et al, 2003;Hedrich et al, 2004b;Hagenah et al, 2005].…”

Section: Frequency and Type Of Sgce Mutationssupporting

confidence: 73%

Myoclonus-dystonia: significance of largeSGCEdeletions

et al. 2008

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Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE.We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

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Section: Frequency and Type Of Sgce Mutationssupporting

confidence: 73%

Myoclonus-dystonia: significance of largeSGCEdeletions

et al. 2008

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“…The proportion of Chinese DRD patients with GCH1 mutations is up to 90.3%, which is much higher than the 50%-87% reported previously. 7,8 The rate of the large GCH1 deletion was very high in Chinese DRD patients (20.1%), especially in the mutation-negative ones testing by gene sequencing (68.4%). Furthermore, the proportion 20.1% is much higher than the 8.0% reported in a European population, 16 which suggests the need to test for the large deletion by multiplex ligation-dependent probe amplification in Chinese DRD patients.…”

Section: Discussionmentioning

confidence: 99%

“…This proportion is much higher than the 50%-87% observed among non-Chinese ethinicities' . 7,8,15 The proportion of sporadic DRD patients with GCH1 variants was 84.0%, compared with 94.6% for family DRD patients (P ¼ 0.21). The large exonic deletion of GCH1 was present in 13 of 62 Chinese patients (20.1%), much higher than the 8.0% reported in a European population.…”

Section: Clinical Descriptions and Genotypes Of Chinese Drd Patientsmentioning

confidence: 95%

Two novel mutations of the GTP cyclohydrolase 1 gene and genotype–phenotype correlation in Chinese Dopa-responsive dystonia patients

Zhou

et al. 2012

Eur J Hum Genet

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The most common form of Dopa-responsive dystonia (DRD) is caused by heterozygous mutations in the GTP cyclohydrolase I (GCH1) gene. We screened two unrelated, DRD-symptomatic Chinese Han individuals, for GCH1 gene mutations by direct sequencing. As the clinical manifestations of DRD are highly variable, we also explored the association between genotype and phenotype in all Chinese DRD patients reported so far in the literature, comprising 62 DRD-affected patients from 36 Chinese families. Two novel missense mutations (T94M, L145F) and a novel variant (c. 453 þ 6 G4T) were identified in our two new patients. None of these variants was detected in 200 healthy controls. On the basis of this and other reports, heterozygous mutations were detected in 90.3% of Chinese Han subjects with DRD. Seeming the age of onset for males and females, the mean age was 13 years older in males than in females (P ¼ 0.006). Different mutation types did not show any significant differences in age of onset, gender composition, initial symptoms, or the L-dopa dose that abolished the symptoms. Among DRD patients lacking missense or exon-intron boundary mutations, 68.4% were found to possess a large deletion in GCH1, which were detected by multiplex ligation-dependent probe amplification. Most GCH1 mutations were found to cluster in two regions of the coding sequence, suggesting the probable existence of mutation hotspot for the first time. The genotype-phenotype correlation described here may improve our understanding of DRD in Chinese individuals.

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“…In these cases, the mutational analysis of the GCH1 gene is an alternative to detect asymptomatic and oligosymptomatic carriers. Alterations in the gene sequence have been found, through single strand confor-mation polymorphism (SSCP) analyses, in about 50 to 60% of clinically identified cases (Hagenah et al, 2005). Recently, a heterozygous deletion, not detectable through conventional sequencing, was identified by Southern blot analysis (Furukawa et al, 2000).…”

mentioning

confidence: 99%

Mutation in intron 5 of GTP cyclohydrolase 1 gene causes dopa-responsive dystonia (Segawa syndrome) in a Brazilian family

Souza¹,

Valadares²,

Trindade³

et al. 2008

Genet. Mol. Res.

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ABSTRACT. Dopa-responsive dystonia (DRD), also known as Segawa syndrome or hereditary progressive dystonia with diurnal fluctuation, is clinically characterized by the occurrence of simultaneous or late Parkinsonism and by an excellent response to treatment with low doses of L-dopa. Diagnosis of DRD is essentially clinical. It is based on clinical history and the response to treatment with low doses of L-dopa. However, due to the low penetrance of the disease, asymptomatic carriers may exist. In these cases, mutational analysis of the GCH1 gene is an alternative to diagnose DRD. In the present study, we investigated a large DRD-carrier family in an attempt to identify the disease-causing mutation. The proband, a young woman diagnosed at the age of 13 years, is the daughter of a healthy non-consanguineous couple with history of several cases, on the maternal side of the family, of tip-toeing, disturbance of gait, Parkinsonism, rigidity and cramps in the lower limbs. Using single strand conformational polymorphism and DNA sequencing techniques to analyze DNA extracted from blood samples, we identified a mutation in the GCH1 gene, IVS5+3insT, which would preclude the formation of the active enzyme due to the formation of truncated peptides.

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

Cited by 86 publications

References 9 publications

Myoclonus-dystonia: significance of largeSGCEdeletions

Myoclonus-dystonia: significance of largeSGCEdeletions

Two novel mutations of the GTP cyclohydrolase 1 gene and genotype–phenotype correlation in Chinese Dopa-responsive dystonia patients

Mutation in intron 5 of GTP cyclohydrolase 1 gene causes dopa-responsive dystonia (Segawa syndrome) in a Brazilian family

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