Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy

Abstract

Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5’-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum, and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsy from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patents presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%, 4/34), and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesion on diffusion weighted imaging (DWI) was the best biomarker to diagnose NIID with high specificity (98.4%) and sensitivity (88.2%). However, such DWI abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, presence of white matter hyperintensity lesions (WMH) either in paravermis or middle cerebellar peduncles also favored the diagnosis of NIID with a specificity of 85.3% and a sensitivity of 76.5%. Among the ten patients’ MRI performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical DWI hyperintense lesions and two revealed focal brain edema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients ever developed encephalitis-like episodes with restricted diffusion in the cortical regions at the acute stage DWI. Corticomedullary junction hyperintense lesions, WMH in paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnose NIID.

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

“…Our patients also presented with symmetrical distribution of white matter lesions, which were thought to be closely associated with oligodendrocyte degeneration. Abnormal CGG repeat expansion in the NOTCH2NLC gene was a major cause of non-vascular white matter lesions, so the characteristics of white matter lesions should be emphasized when interpreting the images of NIID patients ( Liu et al, 2022 ). Meanwhile, two patients had persistent DWI hyperintensities in the corpus callosum.…”

“…Therefore it was necessary to measure the CGG repeat number to determine its pathogenicity in the genetic diagnosis of NIID patients. The repeat expansion in NOTCH2NLC also showed some rare clinical phenotypes, such as neurodegenerative dementia ( Jiao et al, 2020 ), non-vascular leukoencephalopathy ( Liu et al, 2022 ), motor neuron disease ( Yuan et al, 2020 ), sensorimotor with autonomic neuropathy ( Wang et al, 2021 ), distal motor neuropathy ( Wu et al, 2022 ), as well as oculopharyngeal distal myopathy (OPDM) ( Yu et al, 2021 ). Because of the small number of these cases, the relationship between the clinical phenotype and the number of CGG repeat had not been established, but distal motor neuropathy and OPDM were generally considered to have more repeats.…”

“…leukoencephalopathy (Liu et al, 2022), motor neuron disease (Yuan et al, 2020), sensorimotor with autonomic neuropathy (Wang et al, 2021), distal motor neuropathy (Wu et al, 2022), as well as oculopharyngeal distal myopathy (OPDM) (Yu et al, 2021). Because of the small number of these cases, the relationship between the clinical phenotype and the number of CGG repeat had not been established, but distal motor neuropathy and OPDM were generally considered to have more repeats.…”

General Anesthesia in a Patient With Neuronal Intranuclear Inclusion Disease: A Case Report

“…[1][2][3][4] MRI of the brain has shown leukoencephalopathy in NIID, and DWI has shown high-signal lesions mainly at the cerebral cortex-medullary border. 1,8 Bladder dysfunction has been an important symptom of autonomic neuropathy in patients with NIID. 8,9 Moreover, autonomic neuropathy was reported to be associated with hypotension after induction of anesthesia.…”

“…1,8 Bladder dysfunction has been an important symptom of autonomic neuropathy in patients with NIID. 8,9 Moreover, autonomic neuropathy was reported to be associated with hypotension after induction of anesthesia. 10 In the present case, the patient had bladder dysfunction and developed hypotension after anesthesia induction, which highlights the influence of autonomic neuropathy associated with NIID.…”