Objective: This study aimed to clarify the clinical phenotype in tremor-dominant patients having the GGC repeat expansion in the NOTCH2NLC gene.

Background: The GGC repeat expansion in the 5′ UTR region of 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 phenotype and clinical diagnosis of these NOTCH2NLC-GGC repeat expansion–positive patients presenting with the tremor-dominant symptom.

Method: All probands, preliminarily enrolled by the essential tremor diagnostic criteria, were screened for the GGC repeat expansion in the NOTCH2NLC gene using the repeat-primed polymerase chain reaction. Subsequently, the GGC repeat expansion-positive probands and their positive family members were called back to the hospital and systematically reevaluated to identify their clinical phenotype.

Results: Initially, 602 patients diagnosed with ET were recruited. The pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in ten probands, accounting for approximately 1.66%. Seven GGC repeat expansion–positive probands were called back to our hospital. All seven patients showed absent tendon reflexes, abnormal nerve conduction, and cognitive impairment. After the systematic re-evaluation, the clinical diagnosis in all seven recalled patients could be revised from ET to NIID. Meanwhile, none of five probands and none of four probands who tried a beta-blocker or primidone, respectively, reported a response. Brain MRI revealed heterogeneous leukoencephalopathy from mild to severe, with typical hyperintensity in the corticomedullary junction in diffusion-weighted imaging observed in three of seven patients. Intranuclear inclusions were present in the skin of all four probands who underwent biopsy.

Conclusion: The NIID tremor-dominant subtype mimics and is easily misdiagnosed as ET. We propose that the absence of tendon reflexes, presence of cognitive impairment, and poor response to a beta-blocker or primidone could be important clinical clues suggesting genetic testing and skin biopsy to check for NIID.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuronal-intranuclear-inclusion-disease-tremor-dominant-subtype-a-mimicker-of-essential-tremor/