Exploring the electrocardiogram as a potential tool to screen for premotor Parkinson's disease.

The aim of this study was to test the hypothesis that patients with REM sleep behavior disorder, many of whom will develop Parkinson's disease (PD) or a related synucleinopathy, will demonstrate decreased heart rate variability (HRV) compared with a group of age-matched controls as measured by an electrocardiogram during wakefulness. We compared HRV in 11 untreated idiopathic REM sleep behavior disorder patients (9 men and 2 women; mean age, 63.3 years; SD, 7.5 years) and 11 control subjects with idiopathic insomnia without REM sleep behavior disorder (7 men and 4 women; mean age, 59.5 years; SD, 8.7 years). Subjects with other causes of reduced HRV were excluded. HRV was determined from 5-minute presleep segments of a single channel electrocardiogram recorded during polysomnographic evaluations, using R-R intervals during wakefulness. Time domain, geometric measures, and spectral analysis of the R-R intervals were significantly different between cases and controls. A discriminant function analysis correctly classified 95.5% of subjects (overall model fit, P = 0.016). Leave-one-out cross-validation correctly classified 77.3% of subjects. HRV during wakefulness is significantly decreased in patients with idiopathic REM sleep behavior disorder compared with control subjects, suggesting abnormalities of both sympathetic and parasympathetic function. Patients with RBD may later develop motor and cognitive features of a Lewy body disorder, such as PD. Cardiac autonomic dysfunction is also impaired in PD, suggesting that impaired HRV may be an early sign of PD. HRV measured by routine electrocardiograms could be used to screen for Lewy body disorders such as PD.

Genetic fine-mapping of the Iowan SNCA gene triplication in a patient with Parkinson's disease.

The "Iowa kindred," a large Iowan family with autosomal-dominant Parkinson's disease, has been followed clinically since the 1920s at the Mayo Clinic. In 2003, the genetic cause was determined to be a 1.7 Mb triplication of the alpha-synuclein genomic locus. Affected individuals present with an early-onset, severe parkinsonism-dementia syndrome. Here, we present a descendant of the Iowa kindred with novel, disease-associated non-motor findings of reduced heart rate variability, complete anosmia, and a rare skin condition called colloid milium. At autopsy, key neuropathological findings were compatible with diffuse Lewy body disease. Using high-resolution comparative genomic hybridization (CGH) array analysis to fine-map the genomic breakpoints, we observed two independent recombination events of the SNCA locus that resulted in a genomic triplication of twelve genes, including SNCA, and the disruption of two genes, HERC6 and CCSER1, at the genomic breakpoints. In conclusion, we provide further evidence that the mere two-fold overexpression of alpha-synuclein leads to a fulminant alpha-synucleinopathy with rapid progression and severe clinical and neuropathological features.