Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing
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Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient’s genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.
KeywordsCombined dystonia Complex dystonia Exome Mutation Genetic heterogeneity
We thank all patients with dystonia and their family members who participated in this study.
This study was funded by in-house institutional funding from Technische Universität München, Munich, Germany, Helmholtz Zentrum München, Munich, Germany, and Medizinische Universität Innsbruck, Innsbruck, Austria, as well as the Czech Science Foundation (grant: GACR16-13323S), and Charles University, Prague, Czech Republic (project: Progres Q27/LF1).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
Disclosures concerning the present manuscript
Nothing to report.
Case 3 (PINK1 mutation) A 56-year-old woman presenting dystonia-parkinsonism syndrome. This video was taken after GPi-DBS at the age 51 years. Dystonic symptoms responded favorably to this intervention, whereas dysarthria and right-sided bradykinesia persisted. Case 5 (MRE11A mutation) A 27-year-old woman presenting generalized dystonia with predominant tremulous cervical dystonia, abnormal upper-limb posturing, and intermittent dystonic trunk movements. Dystonic symptoms were accompanied by myoclonic-like jerky movements. Case 7 (KMT2B mutation) A 13-year-old girl presenting generalized dystonia involving the neck, trunk, and extremities. Dystonia was combined with non-motor features including strabismus, mild facial dysmorphia (bulbous nasal tip), intellectual disability, and hearing impairment. Case 8 (ATM mutation) A 51-year-old woman with segmental cranio-cervical dystonia, consisting of tremulous torticollis and oromandibular dystonia. The latter symptom produced speech impairment. (MOV 27990 kb)
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