To investigate further the clinical and
To investigate further the clinical and mutational spectrum associated with -related dyskinesia, we here performed a screen in a large series of patients affected with an unexplained hyperkinetic movement disorder, resulting in the identification of 2 pediatric patients presenting with a novel phenotype, ie, alternating hemiplegia of childhood (AHC).
The study was approved by the ethics committee of the University of Lübeck, and all patients or their parents gave written informed consent. We included 108 patients with either SGCE mutation-negative myoclonus-dystonia (n = 79), PRRT2 mutation-negative paroxysmal kinesigenic dyskinesia (n = 19), or persistent generalized, otherwise-unexplained hyperkinesia (n = 10). Diagnoses were established by a movement disorder specialist in all cases.
All 21 coding exons including intron/exon boundaries of the ADCY5 gene were sequenced and in silico analysis of detected nonsynonymous coding variants was performed with MutationTaster, PolyPhen2, SIFT, and combined annotation-dependent depletion (CADD).
Discussion We describe here paroxysmal paralysis as a novel phenotype to the clinical spectrum associated with ADCY5 mutations. There was generalized chorea in both patients, which has been described in many cases carrying ADCY5 mutations. They also had very characteristic perioral dyskinesia that was labeled previously as “myokymia.” A recent study, however, has clarified that these movements represent myoclonus-chorea (Tunc S, Baaske MK, Hartmann C, Brüggemann N, Westenberger A, Klein C, et al, submitted for publication, 2016). In addition, the 2 psoralen carriers we identified presented with attacks of inability to move. In patient 1, the attacks had led to a suspected diagnosis of AHC. In patient 2, AHC was considered only when the length of paroxysms increased in the course of the disease. The duration of attacks in typical AHC has been described to range from minutes to weeks, and the initial episodes of 1 minute in duration in the second patient were unusually short. outlines the diagnostic criteria in classical AHC, and the features we identified in our 2 patients. Of note, “classical” AHC is associated with sleep benefit (ie, attacks subside when children fall asleep) that is the only criterion not seen in both of our cases with ADCY5 mutations. The 2 missense changes we identified are very likely disease-causing based on (1) the level of their conservation, (2) their predicted pathogenicity and functional importance (high CADD score), and (3) their absence from the largest publicly available exome variant database. Both mutation carriers were from the group of patients with hyperkinesia of unknown origin. In contrast, ADCY5 mutations were not found in our cohorts of SGCE mutation-negative myoclonus dystonia nor in patients with PRRT2 mutation-negative paroxysmal kinesigenic dyskinesia, suggesting that these 2 complex movement disorders may be very rare phenotypes, if at all seen, in ADCY5 mutation carriers. The gain-of-function effect seen with missense mutations in ADCY5 appears to vary between specific changes. For example, the recurrent p.Arg418Trp change seems to induce a more severe clinical presentation than p.Ala726Thr. The 2 changes we detected are separated by only 9 amino acids and both affect the second cytoplasmic domain, which participates in the formation of a catalytic pocket for the conversion of adenosine triphosphate to 3′,5′-cyclic adenosine monophosphate. We speculate that our 2 ADCY5 mutation carriers have a similar clinical presentation as a consequence of the proximity of the pathogenic mutations they carry to this important protein domain. AHC also is associated with mutations in the ATP1A3 gene. Intriguingly, ATP1A3 mutation-associated disease shows a similar genotype-phenotype correlation in that, depending on the mutation in question, there are at least 4 different presentations: (1) rapid-onset dystonia-parkinsonism, (2) AHC, (3) cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome, and (4) catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. In conclusion, the clinical spectrum of ADCY5 mutations encompasses paroxysmal weakness in addition to paroxysmal dyskinesia and persistent hyperkinesia, nominating ADCY5 mutations as a genetic cause of unexplained AHC. ADCY5 mutation type may determine, at least in part, the phenotype.