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Parkinsonism Relat Disord. 2017 Aug;41:37-43. doi: 10.1016/j.parkreldis.2017.05.004. Epub 2017 May 10.

ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients.

Author information

1
Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy; Department of Pediatric Neurology, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy; Department of Medicine and Surgery, PhD Programme in Molecular and Translational Medicine, University of Milan Bicocca, Via Cadore 48, 20900 Monza, Italy.
2
Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, United Kingdom; Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, 60611 Illinois, USA. Electronic address: niccolo.mencacci@northwestern.edu.
3
Child Neurology and Psychiatry Unit, Department of Pediatrics, IRCCS Santa Maria Nuova Hospital, Viale Risorgimento 80, 42123 Reggio nell'Emilia, Italy.
4
First Pediatric Clinic, University of Athens, Agia Sofia Children's Hospital, Thivon and Levadias, 11527 Athens, Greece.
5
Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy.
6
Department of Pediatric Neurology, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy.
7
Second Department of Neurology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
8
Third Department of Paediatrics, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Athens, Greece.
9
Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 7200 Cambridge, Houston, TX 77030-4202, USA.
10
Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom.
11
Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, United Kingdom.
12
Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere, 100, 00133 Rome, Italy.
13
Movement Disorders Department, HYGEIA Hospital, Athens, Greece; Second Department of Neurology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Abstract

INTRODUCTION:

ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated.

METHODS:

We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders.

RESULTS:

We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence.

CONCLUSION:

Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.

KEYWORDS:

ADCY5; Chorea; Dyskinesia; Dystonia; Myoclonus

PMID:
28511835
PMCID:
PMC5549507
DOI:
10.1016/j.parkreldis.2017.05.004
[Indexed for MEDLINE]
Free PMC Article

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