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

Abstract

Aim: 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.

Keywords: NOTCH2NLC; Neuronal Intranuclear Inclusion Disease; neurodegenerative disease; repeat disease; repeat primed PCR.

Fig. 1

Distribution of NOTCH2NLC GGC repeat lengths in non‐expanded cases. (a) The frequency of ICD‐10 classification. (b) The frequency of clinical diagnosis in F0 group. (c) A histogram showing repeat length distribution of ICD‐10 classification. (d) A histogram showing repeat length distribution of cases classified in F0 group.

Fig. 2

Clinical and pathological details of three cases of NIID. (a, b) Brain MR image of case 1 at age 37. (a) T2‐weighted fluid‐attenuated inversion recovery (T2‐FLAIR) image, (b) diffusion weighted image (DWI). Hyperintensity area was observed in periventricular (PV) region and was rated as Fazekas (Fz) score = 1. No findings characteristic of NIID can be identified. (c) Electropherogram of the repeat‐primed polymerase chain reaction (RP‐PCR) of NIID case 1. (d) Electropherogram of the fluorescence amplicon length polymerase chain reaction (AL‐PCR) confirmed 186 GGC repeats in the NOTCH2NLC 5′ UTR in case 1. (e, f) Immunohistochemical staining of skin tissue in case 1. (e) Ubiquitin‐positive inclusion bodies (arrowheads) in the nuclei of sweat gland duct cells. 1000×. Scale bar = 10 μm. (f) p62‐positive inclusion bodies (arrowheads) in the nuclei of arrector pili muscle cells. 1000×. Scale bar = 10 μm. (g) Immunofluorescence staining of skin tissue in case 1. A p62‐positive inclusion body in the nucleus of sweat gland duct cell. From left to right: DAPI, p62, and merged images. 2000×. Scale bar = 5 μm. (h, i) MR images of case 1 at age 39. (h) T2‐FLAIR, (i) DWI. Hyperintensity area was rated as Fz score = 1 at PV region. No findings characteristic of NIID can be identified. (j, k) MRI of case 2. (j) T2‐FLAIR at age 66, (k) DWI at age 68. Hyperintensity areas were rated as Fz score = 2 at PV region and 1 at deep white matter (DWM) region. (l, m) MRI of case 2 at age 73. (l) T2‐FLAIR, (m) DWI. White matter lesions in T2‐FLAIR and hyperintensity at the corticomedullary border in DWI were observed. Hyperintensity areas were rated as Fz score = 3 at both PV and DWM regions. (n, o) Immunohistochemical examination of skin tissue in case 2. (n) p62‐positive intranuclear inclusions (arrowheads) in sweat gland duct cells. 1000×. Scale bar = 10 μm. (o) Ubiquitin‐positive intranuclear inclusion (arrowhead) in fat cells. 1000×. Scale bar = 10 μm. (p) Immunofluorescence staining of the skin in case 2. A p62‐positive inclusion body in the nucleus of sweat gland duct cell. From left to right: DAPI, p62, and merged images. 2000×. Scale bar = 5 μm. (q–s) MRI of case 3 at age 66. (q) T2‐FLAIR, (r) DWI, (s) T1 sagittal images. Hyperintensity area was observed rated as Fz score = 3 at PV region.

Fig. 3

Distribution of NOTCH2NLC GGC repeat lengths for non‐expanded cases on ICD‐10 classification. (a) Boxplot of NOTCH2NLC GGC repeat lengths on each ICD‐10 classification. The boxes show the first quartile (1Q), the median, and the third quartile (3Q). The median of each classification is expressed as a notch. The whiskers show the maximum value at the top and the minimum value at the bottom. Values outside the range of 1Q or 3Q ± 1.5 × IQR were defined as outliers. (b) Boxplot of NOTCH2NLC GGC repeat lengths on each clinical diagnosis of the F0 group. Alzheimer Disease (AD), mild cognitive impairment (MCI) due to AD, cerebral amyloid angiopathy (CAA), Dementia with Lewy bodies (DLB), MCI due to DLB, Parkinson's disease (PD), semantic dementia (SD), progressive nonfluent aphasia (PNFA), behavioral variant frontotemporal dementia (bvFTD), FTD/ALS, other FTLD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), idiopathic normal pressure hydrocephalus (iNPH), secondary NPH (sNPH), vascular cognitive impairment (VCI), MCI due to VCI, other organic disorders, other symptomatic disorders, other MCI, delirium, and subjective cognitive impairment (SCI).

Fig. 4

The Fazekas (Fz) scores for short and long repeat length groups extracted from non‐expanded cases. (a) Protocol of case selection. (b–d) Mosaic plots of Fz scores. (b) Periventricular hyperintensity (PVH), (c) Deep white matter hyperintensity (DWMH), (d) Combined Fz score.