Wednesday, July 13, 2022

ADCY5 mutations

Inspired by a patient (and perhaps a grandpatient)


ADCY5-related dyskinesia is a neurologic disorder with a variety of movement abnormalities. Dyskinesia means that affected individuals have trouble controlling voluntary movements. Voluntary movements are any movements that a person does intentionally such as lifting their arms, walking, or turning one’s head. Affected individuals experience uncontrolled, involuntary movements including sudden jerks, writhing motions, twitches, twisting, or tremors. The arms and legs, neck, and face are commonly affected. Symptoms usually begin during infancy, childhood, or adolescence and continue throughout life, although there are periods of time when no symptoms occur (remission). The severity of the disorder can vary significantly from one person to another. Intelligence and life span are generally not affected. ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. This variation may be inherited from a parent, or it may occur spontaneously as a new variation without a previous family history (de novo mutation).,walking%2C%20or%20turning%20one's%20head.

Ferrini A, Steel D, Barwick K, Kurian MA. An Update on the Phenotype, Genotype and Neurobiology of ADCY5-Related Disease. Mov Disord. 2021 May;36(5):1104-1114. doi: 10.1002/mds.28495. Epub 2021 May 2. PMID: 33934385.


Adenylyl cyclase 5 (ADCY5)-related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5-related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, developmental delay, and intellectual disability may be present. The causative gene encodes adenylyl cyclase, the enzyme responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). cAMP is a second messenger that exerts a wide variety of effects via several intracellular signaling pathways. ADCY5 is the most commonly expressed isoform of adenylyl cyclase in medium spiny neurons (MSNs) of the striatum, and it integrates and controls dopaminergic signaling. Through cAMP pathway, ADCY5 is a key regulator of the cortical and thalamic signaling that control initiation of voluntary movements and prevention of involuntary movements. Gain-of-function mutations in ADCY5 have been recently linked to a rare genetic disorder called ADCY5-related dyskinesia, where dysregulation of the cAMP pathway leads to reduced inhibitory activity and involuntary hyperkinetic movements. Here, we present an update on the neurobiology of ADCY5, together with a detailed overview of the reported clinical phenotypes and genotypes. Although a range of therapeutic approaches has been trialed, there are currently no disease-modifying treatments. Improved in vitro and in vivo laboratory models will no doubt increase our understanding of the pathogenesis of this rare genetic movement disorder, which will improve diagnosis, and also facilitate the development of precision medicine approaches for this, and other forms of hyperkinesia. 

Méneret A, Roze E, Maranci JB, Dodet P, Doummar D, Riant F, Tranchant C, Fraix V, Anheim M, Ekmen A, McGovern E, Vidailhet M, Arnulf I, Leu-Semenescu S. Sleep in ADCY5-Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements. J Clin Sleep Med. 2019 Jul 15;15(7):1021-1029. doi: 10.5664/jcsm.7886. PMID: 31383240; PMCID: PMC6622513.


Study objectives: ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia.

Methods: Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls.

Results: We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements.

Conclusions: In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal.


1 comment:

  1. The grandpatient (patient who is the child of a patient) also has a ADCY5 mutation.