Distinctive hydrocephalus-like phenotype in NOTCH2NLC-related neuronal intranuclear inclusion disease: clinicopathological features and therapeutic implications.

NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder with marked clinical heterogeneity and an increasingly recognized phenotypic spectrum. Although hydrocephalus-like presentations, i.e. ventriculomegaly with concomitant with cognition, motor, and/or bladder dysfunctions, have been observed in NIID sporadically, their prevalence, clinicopathological characteristics, and potential clinical implications remain poorly understood. This retrospective cohort study systematically characterized this newly recognized hydrocephalus-like phenotype. We conducted an MRI-based screening to identify previously undiagnosed NIID cases from a cohort of 498 adults with imaging diagnosis of communicating hydrocephalus. Four such cases were identified and incorporated into our NIID cohort, with genetic and pathological confirmation. A total of 68 NIID patients were analyzed, of whom 19 (27.9%) exhibited marked ventriculomegaly (Evans index > 0.34) disproportionate to parenchymal atrophy and were grouped as ventriculomegalic NIID. Compared with those without ventriculomegaly, these patients were associated with male predominance, more frequent walking difficulty, and less frequent tremor. Nearly half of ventriculomegalic cases (9/19) fulfilled the idiopathic normal pressure hydrocephalus-like clinical triad. Radiological features included markedly enlarged ventricles, smaller callosal angle, less frequent diffusion-weighted imaging hyperintensities, and overrepresented periventricular-dominant white matter lesion pattern. A subset of ventriculomegalic NIID patients (5/8) showed improvement in gait, cognition, and/or urinary function following cerebrospinal fluid drainage, and two patients who underwent ventriculoperitoneal shunt surgery experienced sustained clinical benefit. Brain autopsy was performed in one ventriculomegalic NIID patient, revealing widespread intranuclear inclusions, particularly in ependymal and choroid plexus epithelial cells and astrocytes, alongside dysmorphic astrocytes and loss of aquaporin-4 polarization. Collectively, our findings suggest that a hydrocephalus-like phenotype with distinctive clinical and radiological features is relatively common in NIID and frequently misdiagnosed as idiopathic normal pressure hydrocephalus. Pathological alterations in the ependyma, choroid plexus, and astrocytes and subsequently disturbed cerebrospinal fluid dynamics may contribute to its pathogenesis. Some patients might benefit from shunt surgery, highlighting a possible symptomatic and partially reversible component and broadening therapeutic opportunities in this otherwise progressive neurodegenerative disorder.