Psychiatric-onset neuronal intranuclear inclusion disease in a psychiatry-based dementia-enriched cohort in Japan.

Objective: A GGC repeat expansion in the 5' untranslated region of NOTCH2NLC is a genetic cause of Neuronal Intranuclear Inclusion Disease (NIID) that exhibits cognitive, motor, and autonomic dysfunction. Our objective is to determine whether there are undiagnosed NIID cases in a psychiatry-based dementia-enriched cohort and to identify their clinical characteristics.

Methods: A retrospective clinical cohort study was conducted in an inpatient and outpatient psychiatric clinic in a University Hospital in Osaka, Japan. Genomic DNA and clinical information were collected with written informed consent. Nine hundred fifty-eight cases were clinically classified according to the International Classification of Diseases (ICD)-10 system. Genetic analysis with Repeat-Primed PCR and Amplicon-Length PCRs were performed.

Results: Of the 958 cases, three were confirmed to have an aberrant GGC repeat expansion in NOTCH2NLC. Cases 1 and 2 had preceding anxiety and depressive episodes, and one of these cases also had a mild cognitive impairment. Case 3 met the diagnostic criteria for progressive supranuclear palsy. All three cases lacked hyperintensity at the corticomedullary border on diffusion-weighted MRI, which is known as a characteristic for NIID. Interestingly, one case exhibited the corticomedullary hyperintensity later in the disease course with apparent neurocognitive decline. All three cases exhibited a mix of slow waves in electroencephalogram and elevated total protein level in cerebrospinal fluid.

Conclusions: NIID is a rare cause of cognitive dysfunction in a psychiatry-based dementia-enriched cohort in Japan. Our data implicates psychiatric symptoms can be prodromal or early manifestation of a subset of NIID cases, thereby extending its phenotypic spectrum.