Objective: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. Methods:We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases.Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation.Conclusions: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis. Neurology ® 2015;85:2026-2035 GLOSSARY ADCY5 5 adenylate cyclase 5; ATP 5 adenosine-59-triphosphate; cAMP 5 39,59-cyclic adenosine monophosphate; ChDys 5 chorea-dystonia; EHC 5 essential hereditary chorea; FDFM 5 familial dyskinesia with facial myokymia; MIP 5 molecular inversion probe; SNP 5 single nucleotide polymorphism; STRP 5 short tandem repeat marker.

Parkinson's disease (PD) exacts a physical and emotional toll on both patients and family. The aim of this study was to compare patient and caregiver perceptions of the social consequences of basic symptoms of PD and levodopa-induced dyskinesias. Forty patients with PD and dyskinesias and 35 of their caregivers completed a self-report questionnaire on the impact of PD and dyskinesias on their feelings of security and embarrassment and participation in family/social events, and indicated their preference for the "on" (with dyskinesias) or the "off" (without dyskinesias) state. The patients scored significantly higher than the caregivers did on the negative social impact of the disease in general (p = 0.002) and of the dyskinesias in particular (p = 0.03). Nevertheless, the patients expressed a significantly greater preference for the "on" state (83 %) than the caregivers (59 %) (p = 0.03). Preferences turned to be reverse in direction among spouse-caregivers who significantly preferred the "off" state (54 %) than the patients (25 %) (p = 0.04). Although patients have a worse perception of the effects of PD than their caregivers do, they prefer the more independent "on" state, whereas their caregivers prefer the "off" state.

HD patients exhibit prominent unique oropharyngeal dysphagia features that may serve as a marker of disease progression. The FEES and the SDQ are valuable tools for detecting these features in HD patients with swallowing disturbance.