Expanding the clinical phenotype of DYT5 mutations: Is multiple system atrophy a possible one?

From the University of Pisa (R.C., V.N., L.K., U.B.), Pisa
Neurology (Impact Factor: 8.29). 06/2013; 81(3). DOI: 10.1212/WNL.0b013e31829bfd7c
Source: PubMed

ABSTRACT Autosomal dominantly inherited mutations in the GTP cyclohydrolase 1 (GCH1) gene are associated with dopamine-responsive dystonia (DRD), also known as DYT5.(1) Rare atypical presentations have been described,(2) including adulthood Parkinson disease (PD) with in vivo evidence of nigrostriatal degeneration.(3.)

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Available from: Barbara Garavaglia, Feb 22, 2014
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    • "Origin Sex/age at scan/age at onset (y) Mutation Relatives with DRD Age at levodopa start (y) Current treatment dose (mg/day) Parkinsonian features H&Y score Dystonic features Levodopa-induced complications Scan result Reference UK M/65/59 c.343 + 5G- C/w Son and grandson 60 L-DOPA 300 Hypomimia, R hand rest and re-emergent postural tremor, and bilateral rigidity and bradykinesia (R4L) 2 No No Bilateral (L4R) reduced DAT density Present study (Family A) Germany F/47/39 F104L/ P23L Daughter and mother 41 L-DOPA 800 Hypomimia, bilateral rigidity , bradykinesia, reduced arm swinging (R4L), and mild gait difficulties 2 R foot dystonia Dyskinesias after 6 y of therapy Bilateral (L4R) reduced DAT density Present study (Family B) Germany M/67/66 R241Q/w Daughter / Rasagiline 1 Pramipexole 0.375 Hypomimia, L hand rest tremor, bilateral bradykinesia and rigidity (L4R), and mild gait difficulties 2 No No Bilateral (R4L) reduced DAT- density Present study (Family C) Italy F/58/44 c.626 + 1 - G4C/w Sister 53 L-DOPA 400 Rotigotine 4 Hypomimia, bilateral rigidity and bradykinesia (R4L), mild postural instability, and gait difficulties 2 Bilateral (R4L) upper limb dystonic tremor Dyskinesias after 6 y of therapy Bilateral (L4R) reduced DAT density Present study (Family D) Japan M/54/39 R184H/w No 40 L-DOPA 600 Cogwheel rigidity, akinesia, and postural instability NA Dystonic posture in the four limbs (R4L) Wearing-off and dyskinesias after 10 y of therapy Bilateral reduced FD intake Kikuchi et al., 2004 Denmark M/38/28 P199S/w Brother 33 L-DOPA 350 Entacapone Selegiline 5 Bradykinesia and rigidity in the L arm NA Dystonia of neck, trunk and four limbs, action tremor (L4R) Dyskinesias after 2 y of therapy Bilateral (R4L) reduced DAT density Hjermind et al., 2006 Germany F/65/50 Complete deletion of the GCH1 gene/w Daughter 60 (for 10 y on dopa- mine agonist only) L-DOPA 200 Selegiline 5 Tremor in the R hand, reduced dexterity and mild gait disturbance NA No No Bilateral (L4R) reduced DAT density Eggers et al., 2012 Italy M/59/NA Deletion of exons 5-6/w Son with DRD, sister with MSA NA NA Hypomimia, L hand rest tremor. bradykinesia (L4R), mild gait difficulties NA No Dyskinesias after 10 y of therapy Bilateral reduced DAT density Ceravolo et al., 2013 "
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    ABSTRACT: GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
    Brain 09/2014; 137(9):2480-2492. DOI:10.1093/brain/awu179 · 9.20 Impact Factor
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    ABSTRACT: Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. Results: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.
    Parkinsonism & Related Disorders 01/2015; 21(4). DOI:10.1016/j.parkreldis.2015.01.004 · 3.97 Impact Factor