Neuronal intranuclear inclusion disease tremor-dominant subtype: a mimicker of essential tremor.

BACKGROUND The GGC repeat expansion in the NOTCH2NLC gene was identified as the genetic cause for neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion-positive patients presenting with the tremor-dominant symptoms. OBJECTIVE This study aimed to clarify the clinical phenotype in tremor-dominant patients having the GGC repeat expansion in the NOTCH2NLC gene. METHODS We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically reevaluated the clinical features of the expansion-positive probands and their family members. RESULTS The pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in ten probands (1.66%). Seven of these probands were reevaluated and they showed systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of them had typical hyperintensity in the corticomedullary junction in diffusion-weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. CONCLUSIONS NIID tremor-dominant subtype (NIID-T) can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. The systemic areflexia could be an important clinical clue suggesting cranial MRI examination or even further genetic testing and skin biopsy examination confirm the diagnosis of NIID.