Jared Cook

Psychiatric disorders in rapid-onset dystonia-parkinsonism.

Objective: Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals. Methods: Twenty-nine ATP1A3 mutation–positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinsons Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV, Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive-Compulsive Scale. Results: NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%). Conclusions: ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation.

Cognitive impairment in rapid-onset dystonia-parkinsonism

Rapid‐onset dystonia‐parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation‐negative controls. We studied 22 familial RDP patients, 3 non‐motor‐manifesting mutation‐positive family members, 29 mutation‐negative family member controls in 9 families, and 4 unrelated RDP patients, totaling 58 individuals. We administered a movement disorder assessment, including the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinsons Disease Rating Scale (UPDRS) and a cognitive battery of memory and learning, psychomotor speed, attention, and executive function. The cognitive battery was designed to evaluate a wide range of functions; recognition memory instruments were selected to be relatively pure measures of delayed memory, devoid of significant motor or vocal production limitations. Comparisons of standardized cognitive scores were assessed both with and without controlling for psychomotor speed and similarly for severity of depressive symptoms. A majority of RDP patients had onset of motor symptoms by age 25 and had initial symptom presentation in the upper body (face, mouth, or arm). Among patients, the BFMDRS (mean ± SD, 52.1 ± 29.5) and UPDRS motor subscore (29.8 ± 12.7) confirmed dystonia‐parkinsonism. The affected RDP patients performed more poorly, on average, than mutation‐negative controls for all memory and learning, psychomotor speed, attention, and executive function scores (all P ≤ 0.01). These differences persisted after controlling for psychomotor speed and severity of depressive symptoms. Impaired cognitive function may be a manifestation of ATP1A3 mutation and RDP.

Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings

Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.

ATP1A3 Mutation in Adult Rapid-Onset Ataxia

A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

Reduction in menopause-related symptoms associated with use of a noninvasive neurotechnology for autocalibration of neural oscillations.

ObjectiveIncreased amplitudes in high-frequency brain electrical activity are reported with menopausal hot flashes. We report outcomes associated with the use of High-resolution, relational, resonance-based, electroencephalic mirroring—a noninvasive neurotechnology for autocalibration of neural oscillations—by women with perimenopausal and postmenopausal hot flashes. MethodsTwelve women with hot flashes (median age, 56 y; range, 46-69 y) underwent a median of 13 (range, 8-23) intervention sessions for a median of 9.5 days (range, 4-32). This intervention uses algorithmic analysis of brain electrical activity and near real-time translation of brain frequencies into variable tones for acoustic stimulation. Hot flash frequency and severity were recorded by daily diary. Primary outcomes included hot flash severity score, sleep, and depressive symptoms. High-frequency amplitudes (23-36 Hz) from bilateral temporal scalp recordings were measured at baseline and during serial sessions. Self-reported symptom inventories for sleep and depressive symptoms were collected. ResultsThe median change in hot flash severity score was −0.97 (range, −3.00 to 1.00; P = 0.015). Sleep and depression scores decreased by −8.5 points (range, −20 to −1; P = 0.022) and −5.5 points (range, −32 to 8; P = 0.015), respectively. The median sum of amplitudes for the right and left temporal high-frequency brain electrical activity was 8.44 &mgr;V (range, 6.27-16.66) at baseline and decreased by a median of −2.96 &mgr;V (range, −11.05 to −0.65; P = 0.0005) by the final session. ConclusionsHot flash frequency and severity, symptoms of insomnia and depression, and temporal high-frequency brain electrical activity decrease after High-resolution, relational, resonance-based, electroencephalic mirroring. Larger controlled trials with longer follow-up are warranted.