Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders

Bohlega, Saeed; Abou‐Al‐Shaar, Hussam; AlDakheel, Amaal; Alajlan, Huda; Bohlega, Balsam; Meyer, Brian F.; Monies, Dorota; Cupler, Edward; Al-Saif, Amr

doi:10.1016/j.parkreldis.2019.02.039

Cited by 22 publications

(64 citation statements)

References 23 publications

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“…Identification of the ADCY5 alterations led to an end of an extensive diagnostic journey with numerous previous tests, referrals to specialists and accurate genetic counseling was able to be provided to the family. Since this patient's initial testing, autosomal recessive inheritance of ADCY5 alterations have since been characterized due to additional patient reports in the literature, and an upgraded reclassification report with a positive finding was issued to this patient.…”

Section: Resultsmentioning

confidence: 99%

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Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions

et al. 2019

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Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co-occurring non-movementrelated findings and a detection rate of 24.4%. Patients with childhood-onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early-adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P = .0093, .0397, .0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P = .0180). Our observations show utility of family-based DES in patients with dystonia and illustrate the complexity of testing. K E Y W O R D S dystonia, exome, genetic testing

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Section: Resultsmentioning

confidence: 99%

“…18 This current patient also has cerebral degenerative disease similar to the mouse homozygous Adcy5 null Parkinson-like phenotype. 19 20 and an upgraded reclassification report with a positive finding was issued to this patient.…”

Section: Uncharacterized Case Examplementioning

confidence: 96%

Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions

et al. 2019

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“…Finally, it is becoming clear that psychosis and other psychiatric disorders are likely part of the broader spectrum of ADCY5-dyskinesia. 1,3,5 Patients in the early stages of frontotemporal dementia, another tauopathy, 19 have been given a diagnosis of schizophrenia before development of substantial cognitive impairment. Additional brain autopsies will need to be evaluated to determine whether the tau abnormalities in our case comprise a pathological signature of ADCY5-dyskinesia and whether it is restricted to cases with psychosis.…”

Section: Discussionmentioning

confidence: 99%

“…1,3 The disease is usually transmitted as an autosomal-dominant trait, but two families with a recessive pattern of inheritance have been reported. 4,5 Many sporadic cases and some progenitors in multigenerational families are found to be somatic mosaics for the ADCY5 variant. 1 Adenylate cyclases are a family of enzymes that convert adenosine-5 0 -triphosphate to 3 0 ,5 0 -cyclic adenosine monophosphate (cAMP), a second messenger in signal transduction.…”

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confidence: 99%

“…All five missense and in-frame deletion variants that we studied in vitro confer increased ability to generate cAMP in response to beta-adrenergic or G αs -mediated stimulation and significantly reduce inhibition following D2 dopamine receptor activation. 7,8 The homozygous missense variants reported in two families 4,5 and a splice site variant in another 9 are thought to act through loss of function.…”

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Hyperphosphorylated Tau, Increased Adenylate Cyclase 5 (ADCY5) Immunoreactivity, but No Neuronal Loss in ADCY5‐Dyskinesia

Chen

Latimer

Spencer

et al. 2019

Movement Disord Clin Pract

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Background Background: Adenylate cyclase 5 (ADCY5)-related dyskinesia is a childhood-onset movement disorder. Manifestations vary in frequency and severity and may include chorea, tremor, dystonia, facial twitches, myoclonus, axial hypotonia, and limb hypertonia. Psychosis is likely part of the broader spectrum. ADCY5 is widely expressed in the brain, especially in the striatum. Previous reports of brain autopsies of 2 subjects with likely ADCY5-dyskinesia were limited by the absence of a molecular diagnosis. In 1 case, normal gross pathology was reported. In the other case, ADCY5 expression was not examined and neuropathological findings were confounded by age and comorbidities. Objectives Objectives: To examine ADCY5 expression and neuropathological changes in ADCY5-dyskinesia. Methods Methods: An extensive brain autopsy, including immunohistochemical analyses with antibodies to paired helical filament tau, α-synuclein, amyloid-β, microtubule-associated protein 2, and ADCY5, was performed. ResultsResults: The patient, with a p.M1029K ADCY5 variant, had severe dyskinesias from early childhood, later recurrent episodes of psychosis, and died at age 46. Gross pathology was unremarkable, but we detected increased immunoreactivity for ADCY5 in neurons in multiple brain regions. Despite no history of brain trauma to suggest chronic traumatic encephalopathy, we found tau deposits in the deep cortical sulci, midbrain, and hippocampus with minimal amyloid pathology and no Lewy bodies. Conclusions Conclusions: We present the first brain autopsy findings in a molecularly proven case of ADCY5-dyskinesia, showing increased ADCY5 immunoreactivity in neurons and evidence of tau deposition. Additional patients will need to be studied to determine whether increased immunoreactivity for ADCY5 is a signature for ADCY5-dyskinesia and whether this disease has a tauopathy component.

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ADCY5–Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder

Vijiaratnam

Bhatia

Lang

et al. 2019

Movement Disord Clin Pract

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Background The phenotypic spectrum of adenylyl cyclase 5 (ADCY5)‐related disease has expanded considerably since the first description of the disorder in 1978 as familial essential chorea in a multiplex family. Objective To examine recent advances in the understanding of ADCY5‐related dyskinesia and outline a diagnostic approach to enhance clinical detection. Methods A pragmatic review of the ADCY5 literature was undertaken to examine unique genetic and pathophysiological features as well as distinguishing clinical features. Results With over 70 cases reported to date, the phenotype is recognized to be broad, although distinctive features include prominent facial dyskinesia, motor exacerbations during drowsiness or sleep arousal, episodic painful dystonic posturing increased with stress or illness, and axial hypotonia with delayed developmental milestones. Uncommon phenotypes include childhood‐onset chorea, myoclonus‐dystonia, isolated nongeneralized dystonia, and alternating hemiplegia. Conclusion The ongoing expansion in clinical features suggests that ADCY5 remains underdiagnosed and may account for a proportion of “idiopathic” hyperkinetic movement disorders. Enhanced understanding of its clinical features may help clinicians improve the detection of complex or uncommon cases.

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Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders

Cited by 22 publications

References 23 publications

Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions

Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions

Hyperphosphorylated Tau, Increased Adenylate Cyclase 5 (ADCY5) Immunoreactivity, but No Neuronal Loss in ADCY5‐Dyskinesia

ADCY5–Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder

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