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 Parkinson's 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.

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

Delayed detection of tonal targets in background noise in dyslexia.

Individuals with developmental dyslexia are often impaired in their ability to process certain linguistic and even basic non-linguistic auditory signals. Recent investigations report conflicting findings regarding impaired low-level binaural detection mechanisms associated with dyslexia. Binaural impairment has been hypothesized to stem from a general low-level processing disorder for temporally fine sensory stimuli. Here we use a new behavioral paradigm to address this issue. We compared the response times of dyslexic listeners and their matched controls in a tone-in-noise detection task. The tonal signals were either Huggins Pitch (HP), a stimulus requiring binaural processing to elicit a pitch percept, or a pure tone-perceptually similar but physically very different signals. The results showed no difference between the two groups specific to the processing of HP and thus no evidence for a binaural impairment in dyslexia. However, dyslexic subjects exhibited a general difficulty in extracting tonal objects from background noise, manifested by a globally delayed detection speed.

New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism.

BACKGROUND: A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized. METHODS: The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews. RESULTS: In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder. CONCLUSIONS: The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.

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 Parkinson's 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.

Predictive assessment of reading.

Study 1 retrospectively analyzed neuropsychological and psychoeducational tests given to N=220 first graders, with follow-up assessments in third and eighth grade. Four predictor constructs were derived: (1) Phonemic Awareness, (2) Picture Vocabulary, (3) Rapid Naming, and (4) Single Word Reading. Together, these accounted for 88%, 76%, 69%, and 69% of the variance, respectively, in first, third, and eighth grade Woodcock Johnson Broad Reading and eighth grade Gates-MacGinitie. When Single Word Reading was excluded from the predictors, the remaining predictors still accounted for 71%, 65%, 61%, and 65% of variance in the respective outcomes. Secondary analyses of risk of low outcome showed sensitivities/specificities of 93.0/91.0, and 86.4/84.9, respectively, for predicting which students would be in the bottom 15% and 30% of actual first grade WJBR. Sensitivities/specificities were 84.8/83.3 and 80.2/81.3, respectively, for predicting the bottom 15% and 30% of actual third grade WJBR outcomes; eighth grade outcomes had sensitivities/specificities of 80.0/80.0 and 85.7/83.1, respectively, for the bottom 15% and 30% of actual eighth grade WJBR scores. Study 2 cross-validated the concurrent predictive validities in an N=500 geographically diverse sample of late kindergartners through third graders, whose ethnic and racial composition closely approximated the national early elementary school population. New tests of the same four predictor domains were used, together taking only 15 minutes to administer by teachers; the new Woodcock-Johnson III Broad Reading standard score was the concurrent criterion, whose testers were blind to the predictor results. This cross-validation showed 86% of the variance accounted for, using the same regression weights as used in Study 1. With these weights, sensitivity/specificity values for the 15% and 30% thresholds were, respectively, 91.3/88.0 and 94.1/89.1. These validities and accuracies are stronger than others reported for similar intervals in the literature.