GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease

  • Hiroyo Yoshino
  • Kenya Nishioka
  • Yuanzhe Li
  • Yutaka Oji
  • Genko Oyama
  • Taku Hatano
  • Yutaka Machida
  • Yasushi Shimo
  • Arisa Hayashida
  • Aya Ikeda
  • Kaoru Mogushi
  • Yasuro Shibagaki
  • Ai Hosaka
  • Hiroshi Iwanaga
  • Junko Fujitake
  • Takekazu Ohi
  • Daigo Miyazaki
  • Yoshiki Sekijima
  • Mitsuaki Oki
  • Hirofumi Kusaka
  • Ken-ichi Fujimoto
  • Yoshikazu Ugawa
  • Manabu Funayama
  • Nobutaka Hattori
Original Communication
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Abstract

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson’s disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Keywords

Genetics Dopa-responsive dystonia GCH1 Parkinson’s disease Dystonia 

Notes

Acknowledgements

This work was supported by JSPS KAKENHI Grant numbers, 16K09678 (to KN), 16K09700 (to YL), 16K09676 (to MF), 15KK0354 (to MF), 15H04842 (to NH), 23111003 (to NH), 22390181 (to YU), 25293206 (to YU), and 15H05881 (to YU). We are very grateful for these grants: AMED-CREST (Japanese Association of Medical Research and Development) (to N.H.), Practical Research Project for Rare/Intractable Diseases from AMED; 15ek0109029s0202 to NH.

Compliance with ethical standards

Conflicts of interest

The authors report no conflicts of interest relevant to the manuscript.

Ethical standards

This study was performed in compliance with the Helsinki Declaration and its later amendments.

Supplementary material

415_2018_8930_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 20 KB)

References

  1. 1.
    Wijemanne S, Jankovic J (2015) Dopa-responsive dystonia—clinical and genetic heterogeneity. Nat Rev Neurol 11:414–424CrossRefPubMedGoogle Scholar
  2. 2.
    Segawa M, Hosaka A, Miyagawa F et al (1976) Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 14:215–233PubMedGoogle Scholar
  3. 3.
    Ichinose H, Ohye T, Takahashi E et al (1994) Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 8:236–242CrossRefPubMedGoogle Scholar
  4. 4.
    Mencacci NE, Isaias IU, Reich MM et al (2014) Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain 137:2480–2492CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hagenah J, Saunders-Pullman R, Hedrich K et al (2005) High mutation rate in dopa-responsive dystonia: detection with comprehensive GCHI screening. Neurology 64:908–911CrossRefPubMedGoogle Scholar
  6. 6.
    Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Segawa M, Nomura Y, Nishiyama N (2003) Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 54(Suppl 6):S32–S45CrossRefPubMedGoogle Scholar
  8. 8.
    Schwarz JM, Rodelsperger C, Schuelke M et al (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575–576CrossRefPubMedGoogle Scholar
  9. 9.
    Kircher M, Witten DM, Jain P et al (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ioannidis NM, Rothstein JH, Pejaver V et al (2016) REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877–885CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Higasa K, Miyake N, Yoshimura J et al (2016) Human genetic variation database, a reference database of genetic variations in the Japanese population. J Hum Genet 61:547–553CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tossici-Bolt L, Hoffmann SM, Kemp PM et al (2006) Quantification of [123I]FP-CIT SPECT brain images: an accurate technique for measurement of the specific binding ratio. Eur J Nucl Med Mol Imaging 33:1491–1499CrossRefPubMedGoogle Scholar
  14. 14.
    Bandmann O, Nygaard TG, Surtees R et al (1996) Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity. Hum Mol Genet 5:403–406CrossRefPubMedGoogle Scholar
  15. 15.
    Trender-Gerhard I, Sweeney MG, Schwingenschuh P et al (2009) Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry 80:839–845CrossRefPubMedGoogle Scholar
  16. 16.
    Lucking CB, Durr A, Bonifati V et al (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342:1560–1567CrossRefPubMedGoogle Scholar
  17. 17.
    Tolosa E, Compta Y (2006) Dystonia in Parkinson’s disease. J Neurol 253(Suppl 7):Vii7–Vii13PubMedGoogle Scholar
  18. 18.
    Wider C, Melquist S, Hauf M et al (2008) Study of a swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5. Neurology 70:1377–1383CrossRefPubMedGoogle Scholar
  19. 19.
    Lewthwaite AJ, Lambert TD, Rolfe EB et al (2015) Novel GCH1 variant in Dopa-responsive dystonia and Parkinson’s disease. Parkinsonism Relat Disord 21:394–397CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Guella I, Sherman HE, Appel-Cresswell S et al (2015) Parkinsonism in GTP cyclohydrolase 1 mutation carriers. Brain 138:e349CrossRefPubMedGoogle Scholar
  21. 21.
    Mottet L (2016) Classification of dopa-responsive dystonia—a patient’s perspective. Nat Rev Neurol 12:427CrossRefPubMedGoogle Scholar
  22. 22.
    Lopez-Laso E, Sanchez-Raya A, Moriana JA et al (2011) Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease. J Neurol 258:2155–2162CrossRefPubMedGoogle Scholar
  23. 23.
    Shimoji M, Hirayama K, Hyland K et al (1999) GTP cyclohydrolase I gene expression in the brains of male and female HPH-1 mice. J Neurochem 72:757–764CrossRefPubMedGoogle Scholar
  24. 24.
    Jeon BS, Jeong JM, Park SS et al (1998) Dopamine transporter density measured by [123I]beta-CIT single-photon emission computed tomography is normal in dopa-responsive dystonia. Ann Neurol 43:792–800CrossRefPubMedGoogle Scholar
  25. 25.
    Nygaard TG, Takahashi H, Heiman GA et al (1992) Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. Ann Neurol 32:603–608CrossRefPubMedGoogle Scholar
  26. 26.
    Orimo S, Ozawa E, Nakade S et al (1999) (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 67:189–194CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chaudhuri KR, Martinez-Martin P, Schapira AH et al (2006) International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord Off J Mov Disord Soc 21:916–923CrossRefGoogle Scholar
  28. 28.
    Tadic V, Kasten M, Bruggemann N et al (2012) Dopa-responsive dystonia revisited: diagnostic delay, residual signs, and nonmotor signs. Arch Neurol 69:1558–1562CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Hiroyo Yoshino
    • 1
  • Kenya Nishioka
    • 2
  • Yuanzhe Li
    • 2
  • Yutaka Oji
    • 2
  • Genko Oyama
    • 2
  • Taku Hatano
    • 2
  • Yutaka Machida
    • 3
  • Yasushi Shimo
    • 2
  • Arisa Hayashida
    • 2
  • Aya Ikeda
    • 2
  • Kaoru Mogushi
    • 4
  • Yasuro Shibagaki
    • 5
  • Ai Hosaka
    • 5
    • 6
  • Hiroshi Iwanaga
    • 7
  • Junko Fujitake
    • 8
  • Takekazu Ohi
    • 9
  • Daigo Miyazaki
    • 10
  • Yoshiki Sekijima
    • 10
  • Mitsuaki Oki
    • 11
  • Hirofumi Kusaka
    • 11
  • Ken-ichi Fujimoto
    • 12
  • Yoshikazu Ugawa
    • 13
  • Manabu Funayama
    • 1
    • 2
    • 14
  • Nobutaka Hattori
    • 1
    • 2
    • 14
  1. 1.Research Institute for Diseases of Old Age, Graduate School of MedicineJuntendo UniversityTokyoJapan
  2. 2.Department of NeurologyJuntendo University School of MedicineTokyoJapan
  3. 3.Department of NeurologyTokyo Rinkai HospitalTokyoJapan
  4. 4.Intractable Disease Research Center, Graduate School of MedicineJuntendo UniversityTokyoJapan
  5. 5.Department of NeurologyHitachinaka General HospitalHitachinakaJapan
  6. 6.Department of Neurology, Hitachinaka Medical Education and Research CenterUniversity of Tsukuba HospitalHitachinakaJapan
  7. 7.Department of NeurologyNagasaki Medical CenterNagasakiJapan
  8. 8.Department of NeurologyKyoto City HospitalKyotoJapan
  9. 9.Department of NeurologyUji HospitalUjiJapan
  10. 10.Department of Medicine (Neurology and Rheumatology)Shinshu University School of MedicineNaganoJapan
  11. 11.Department of NeurologyKansai Medical UniversityHirakataJapan
  12. 12.Jichi-idai Station Brain ClinicTochigiJapan
  13. 13.Department of Neuro regeneration, School of MedicineFukushima Medical UniversityFukushimaJapan
  14. 14.Laboratory of Genomic Medicine, Center for genomic and Regenerative Medicine, Graduate School of MedicineJuntendo UniversityTokyoJapan

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