To the Editor In the case-control study by Ma et al,1 the authors demonstrated an association between patients with sporadic Parkinson disease (PD) and NOTCH2NLC repeat expansions; 3 patients had GGC repeat expansions above the pathogenic threshold (>64 repeats), while 10 patients were in the intermediate range (41-64 repeats). These repeat expansions in NOTCH2NLC were recently discovered to cause adult-onset neuronal intranuclear inclusion disease (NIID), in which movement disorders are protean manifestations of the disease.2 However, key questions remains as to whether GGC repeat expansions in NOTCH2NLC are a novel monogenetic cause of PD and whether these patients represent a PD phenocopy of NIID. Both NIID and PD have distinctive histopathological features. Neuronal intranuclear inclusion disease is characterized by widespread eosinophilic neuronal and glial intranuclear inclusions that are positive for antiubiquitin antibody and anti–small ubiquitin-related modifier (SUMO) antibody; the same intranuclear inclusions can be seen in dermal cells.2 In contrast, the distinguishing pathological feature of PD is dopaminergic, neuromelanin-containing neuronal loss in the substantia nigra pars compacta, accompanied by intraneuronal inclusions called Lewy bodies.3 Three previously reported families4 with classic PD symptoms and GGC repeat expansions in NOTCH2NLC all possessed the hallmark features of NIID in their skin biopsies. Although establishing a causal link between NOTCH2NLC repeat expansion and PD was not an objective of the study by Ma et al,1 the authors may consider examining their patients’ skin biopsy or postmortem brain tissue, if available, to help answer this clinically relevant question. Furthermore, we performed repeat-primed polymerase chain reaction and bioinformatic screening of the GGC repeat expansions in NOTCH2NLC in 1208 White patients with PD but did not identify any positive cases.5 We had previously used a similar method to identify 1 patient with a typical NIID phenotype and inclusions on skin biopsy. Given that all the patients with PD identified in the study by Ma et al1 were Chinese, we posit that the association between these repeat expansions and PD may vary in different ethnic populations. To ascertain the role of NOTCH2NLC in the pathogenesis of PD, we agree with the authors1 that further longitudinal clinic-pathological study of patients with PD carrying these repeat expansions would be pertinent.
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Yau WY, Houlden H, Vandrovcova J. Questions on NOTCH2NLC Repeat Expansions in Parkinson Disease. JAMA Neurol. 2021;78(6):762–763. doi:10.1001/jamaneurol.2021.0747
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