Objective: To report three new cases with pathogenic ADCY5 mutations and describe their clinical phenotype.

Background: ADCY5 is a recently identified gene responsible for a wide spectrum of mixed hyperkinetic early-onset movement disorders including chorea, myoclonus and dystonia. Similarly to benign hereditary chorea (BHC) due to TITF-1 mutations, the disease course seems to be non-progressive, but severe abrupt diurnal and nocturnal exacerbations of movement disorder are often present. To date, 7 pathogenic mutations in 21 unrelated dominant families and sporadic cases have been reported.

Methods: 35 Italian unrelated cases with pediatric onset hyperkinetic movement disorder featuring a combination of chorea, myoclonus and dystonia who tested negative for TITF-1 mutations were recruited. ADCY5 exons 2 and 10, in which mutations have been identified in ∼86% of families published to date, were Sanger sequenced.

Results: 3/35 cases (8.5%) tested positive for mutations in ADCY5 exon 2. Two sporadic cases carried previously reported pathogenic mutations (c.1252 C>T;p.R418W, c.1253 G>A;p.R418Q) and one familial case with autosomal dominant inheritance carried a novel mutation (c.1252 C>G; p.R418G). Mutations were de novo in the sporadic cases. The R418G mutation was transmitted from the patient’s father, affected by childhood onset generalized dystonia. All patients presented between 1 and 4 years of age with delayed milestones and a movement disorders characterized by generalized dyskinesias, myoclonic jerks and mild dystonia. One patient showed prominent pyramidal signs in the lower limbs and perioral dyskinesia. In two cases exacerbations of hyperkinesias at night and during the day without specific triggers were described. In adolescence one patient switched from a choreic to a prominent myoclonic phenotype. Clinical features of mutated patients are listed in .

Conclusions: ADCY5 mutations are an important cause of early-onset, mixed hyperkinetic movement disorders. Paroxysmal worsening of movement disorders both during the day and at night seems to be a key diagnostic element in these cases. We confirm that mutations involving the amino acid p.R418 are particularly frequent (18/24; 75% of all cases identified so far). Screening of the remaining coding exons is warranted to establish whether pathogenic mutations are located also in other portions of the gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/adcy5-screening-in-paediatric-onset-hyperkinetic-movement-disorders-report-of-three-new-italian-families/