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  • Review Article
  • Published:

Dopa-responsive dystonia—clinical and genetic heterogeneity

Key Points

  • Dopa-responsive dystonia (DRD) encompasses a clinically and genetically heterogeneous group of disorders that typically manifest as limb-onset dystonia that fluctuates diurnally and improves with levodopa treatment

  • DRD usually results from genetic defects in enzymes that are involved in the biosynthesis of dopamine; the most common condition is autosomal dominant GTP cyclohydrolase 1 deficiency (Segawa disease)

  • In rare cases, conditions that do not involve the biosynthesis of dopamine—for example, hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia—can manifest as DRD

  • DRD is readily treated with levodopa, but is often misdiagnosed, thereby delaying appropriate treatment

  • Accurate and early diagnosis of DRD requires diagnostic testing that is appropriate to the presentation; whole-exome sequencing and other genetic studies are often required to determine the specific aetiology

  • Clinicians should be aware of the wide spectrum of clinical manifestations observed in conditions that are classified as DRD, so as to minimize delays in diagnosis

Abstract

Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment.

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Figure 1: Biosynthesis of BH4 and monoamine neurotransmitters.

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Acknowledgements

J.J. has received Research and Centre of Excellence Grants from the CHDI Foundation, the Huntington's Disease Society of America, the Huntington Study Group, the Michael J. Fox Foundation for Parkinson Research, the NIH, the National Parkinson Foundation, the Parkinson Study Group and the University of Rochester, USA.

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S.W. wrote the first draft of the article. S.W. and J.J. researched data for the article, made substantial contributions to discussion of content, and reviewed and/or edited the manuscript before submission.

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Correspondence to Joseph Jankovic.

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J.J. has received Research and Centre of Excellence Grants from Allergan, Auspex Pharmaceuticals, GE Healthcare, Great Lakes NeuroTechnologies, Ipsen, Kyowa Hakko Kirin Pharma, Lundbeck, Medtronic, Merz, Omeros, Pharma Two B, Prothena, Psyadon Pharmaceuticals, St. Jude Medical, Teva Pharmaceutical Industries and UCB. He receives royalty payments from Cambridge University Press, Elsevier, Future Science Group, Hodder Education, Lippincott Williams and Wilkins, and Wiley Blackwell. S.W. declares no competing interests.

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Wijemanne, S., Jankovic, J. Dopa-responsive dystonia—clinical and genetic heterogeneity. Nat Rev Neurol 11, 414–424 (2015). https://doi.org/10.1038/nrneurol.2015.86

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