IMPORTANCEThe presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening of NOTCH2NLC GGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. OBJECTIVE To investigate if NOTCH2NLC GGC expansions are present in a cohort of patients with PD and controls. DESIGN, SETTING, AND PARTICIPANTSThis case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence of NOTCH2NLC GGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. MAIN OUTCOMES AND MEASURESQualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID.RESULTS A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carrying NOTCH2NLC GGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P < .001). None of the patients with PD were carriers of known PD-associated genes. Ten patients with PD carried a GGC expansion of between 41 and 64 repeats (1% of patients with sporadic PD; mean [SD], 49.4 [9.2] repeats). The other 3 patients carried GGC repeats of 79 or more units, 2 with 122 and 79 repeats, respectively, exhibited typical parkinsonism and were responsive to small dosages of levodopa over many years, with no clinical or imaging features of NIID. The other patient with PD, who had 130 repeats, only developed cognitive impairment before death. Within the GGC expansions, there was no GGA interruptions (mean [SD] GGA percentage in the 3 patients with PD vs patients with NIID, 0% vs 12% [9%]), and the frequency of AGC interruptions was 3 times higher in these patients with PD than patients with NIID (mean [SD], 25% [12%] vs 8% [8%]). CONCLUSIONS AND RELEVANCEThis study demonstrated that individuals with sporadic PD who carried pathogenic NOTCH2NLC GGC repeat expansions can present with typical parkinsonism, requiring only low dosages of levodopa, without displaying other clinical or imaging features of NIID even after several years of follow-up. None of the patients with PD had GGA interruptions within their GGC expansions, and the frequency of AGC interruptions was much higher than that of patients with NIID. The functional significance of a higher moderate repeat expansion in patients with PD compared with healthy controls needs to be further investigated.

The use of consumer-grade wearables for purposes beyond fitness tracking has not been comprehensively explored. We generated and analyzed multidimensional data from 233 normal volunteers, integrating wearable data, lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and multiple clinical-grade cardiovascular and metabolic disease markers. We show that subjects can be stratified into distinct clusters based on daily activity patterns and that these clusters are marked by distinct demographic and behavioral patterns. While resting heart rates (RHRs) performed better than step counts in being associated with cardiovascular and metabolic disease markers, step counts identified relationships between physical activity and cardiac remodeling, suggesting that wearable data may play a role in reducing overdiagnosis of cardiac hypertrophy or dilatation in active individuals. Wearable-derived activity levels can be used to identify known and novel activity-modulated sphingolipids that are in turn associated with insulin sensitivity. Our findings demonstrate the potential for wearables in biomedical research and personalized health.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well‐characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion‐weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 “intermediate” repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614–618