ADCY5 -related dyskinesia

Abstract

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.

ADCY5-related dyskinesia: Comments on characteristic manifestations and variant-associated severity

“…2,3 However, the titles of these tables imply they are comprehensive tallies of all cases published to date, yet they completely ignore the 15 new families we described in detail in 2015, 4 even though they cite this publication. Not only do those 3 multigenerational and 12 single-case families (26 total cases) represent a sizeable proportion of published cases, but 4 affected individuals in 1 family carry a pathogenic variant, p.M1029K, not mentioned by Chang and colleagues.…”

“…Although they indicate they are the first to describe a p.R418Q mutation, we had already documented this variant in 3 patients, 1 of whom was shown in a video. 4,5 The omissions in these tables are of great concern, as they are likely to serve as a basis for future literature reviews of ADCY5-related dyskinesia.…”

“…4 Although they acknowledge that the small number of families evaluated limits the ability to determine genotype-phenotype correlations, they suggest that p.R418Q and p.R418G may result in milder disease than p.R418W. In our much-larger cohort, we found that, with the exception of p.A726T, which causes a distinctive mild form of disease in 2 multigenerational families, a broad range of disease severity is seen with other pathogenic variants, including p.R418W and p.R418Q.…”

“…An important caveat is the somatic mosaicism we detected in ~43% of de novo cases sometimes resulted in considerably milder disease. 4 Chang and colleagues do not mention mosaicism as a possible contributor to phenotypic variability – an omission that might lead readers to give families incorrect prognoses and recurrence risks.…”

16p11.2 deletion in patients with paroxysmal kinesigenic dyskinesia but without intellectual disability

“…It has been demonstrated to be associated with mutations in several genes, including PRRT2 (proline‐rich region transmembrane protein‐2) (Chen et al, 2011), SLC2A1 (solute carrier family 2, member 1), MR‐1 (myofibrillogenesis regulator 1), CLCN1 (chloride voltage‐gated channel 1) (Wang, Li, Liu, Wen, & Wu, 2016), SCN8A (sodium voltage‐gated channel alpha subunit 8) (Chen et al, 2015), and ADCY5 (adenylyl cyclase 5) (Gardella et al, 2016). PRRT2 is the most common known causative gene for PKD.…”