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

Abstract

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.

An Update on the Phenotype, Genotype and Neurobiology of ADCY5‐Related Disease

“…Inheritance of ADCY5 mutations is usually autosomal dominant, and no reports of incomplete penetrance have been published to date. There are several reports of somatic mosaicism, where mosaic carriers may present with symptoms, although these are often less severe 23 . Mosaic parents may also be asymptomatic 20 .…”

“…The majority of affected individuals have normal intelligence, but intellectual disability does occur in a minority, 14 and acquisition of early milestones is often delayed by the movement disorder 21 . There is an impression that the incidence of mood disorder and psychotic illness may be increased, but this has not been reliably quantified 23,24 . ADCY5 encodes a specific adenylyl cyclase that is also highly expressed in the myocardium, 2 and there have been reports of cardiac complications such as congestive heart failure in patients 12 .…”

“…21 There is an impression that the incidence of mood disorder and psychotic illness may be increased, but this has not been reliably quantified. 23,24 ADCY5 encodes a specific adenylyl cyclase that is also highly expressed in the myocardium, 2 and there have been reports of cardiac complications such as congestive heart failure in patients. 12 Brain imaging is normal, 21 and diagnosis is usually confirmed by genetic testing.…”

Some New and Unexpected Tauopathies in Movement Disorders

“…Recently, the first neuropathological examination of a patient with a genetically confirmed (p.M1029K) ADCY5 gene mutation who died at the age of 46 years was reported. 11 This showed widespread (mixed 3R/4R) tau pathology, including neurofibrillary tangles, neuritic tau, and glial tau deposition involving the cerebral cortex, midbrain, thalamus, and hippocampus. Sulcal perivascular astroglial tau inclusions were identified, raising questions about whether this could have represented chronic traumatic encephalopathy pathology from severe choreodystonic head movements, but the pathology was not typical for this disorder.…”

“…Sulcal perivascular astroglial tau inclusions were identified, raising questions about whether this could have represented chronic traumatic encephalopathy pathology from severe choreodystonic head movements, but the pathology was not typical for this disorder. 11…”