Abstract
IntroductionADCY5 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. MethodsWe 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. ResultsWe 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. ConclusionMutations 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.
Highlights
ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders
A second de novo mutation (p.R418W) in ADCY5 was subsequently found in two unrelated patients presenting with childhood-onset chorea and dystonia [3] and mutation-positive subjects were found in a cohort of patients with a clinical diagnosis of benign hereditary chorea (BHC) but no NKX2-1 mutations [4]
Four patients were sporadic and carried de novo changes, while one had an autosomal dominant family history and inherited the mutation from his 47-year-old father, who suffered from childhood-onset generalized chorea and dystonia
Summary
ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated. A second de novo mutation (p.R418W) in ADCY5 was subsequently found in two unrelated patients presenting with childhood-onset chorea and dystonia [3] and mutation-positive subjects were found in a cohort of patients with a clinical diagnosis of benign hereditary chorea (BHC) but no NKX2-1 mutations [4]. The clinical phenotype associated with ADCY5 mutations includes in most cases childhood-onset chorea with episodic exacerbations observed more frequently upon awakening, when falling asleep or during intercurrent illnesses [5e8]. The aim of this study was to establish the contribution of ADCY5 mutations in a multi-centric cohort of patients with early-onset hyperkinetic movement disorder who lacked a definite genetic diagnosis Various hyperkinetic movement disorders such as myoclonus and dystonia have been described in ADCY5 positive subjects, but the prevalence of ADCY5 mutations in such patients is unknown.
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