Clinical Features of Adult-Onset Neuronal Intranuclear Inclusion Disease: A Multi-Centre Study in China

Background: The full clinical spectrum of neuronal intranuclear inclusion disease (NIID) and its relationship with genotype have not been documented. We aimed to identify the clinical, neuroimaging, and genetic features of adult-onset NIID. Methods: An adult-onset NIID registry was launched in multiple centres throughout China. Clinical data, routine brain magnetic resonance imaging, and skin pathologies were evaluated. Arterial spin labelling magnetic resonance imaging and electrophysiological studies were conducted. Repeat-primed and amplicon length polymerase chain reaction were used to screen (GGC)n repeat expansions in the 5’ untranslated region of the NOTCH2NLC gene. Findings: In total, 134 adult-onset patients with NIID (66% female) from 72 clinical centres were included; 23 cases were familial. The mean age of onset was 56·9±9·4 years. The median disease duration was 4 (IQR 2–9) years. Adult-onset NIID was divided into three subtypes based on primary manifestations: dementia-dominant type (n=65), parkinsonism-dominant type (n=19), and episodic neurogenic event-dominant type (n=45). Among the patients, 90·5% presented with mild demyelinating polyneuropathy. All patients presented with high intensities along the corticomedullary junction on diffusion-weighted imaging, and 53·7% of them presented with abnormal hyperintensity in the paravermal area on T2/fluid-attenuated inversion recovery images. Cerebral blood flow in the whole brain was lower and that in globus pallidus was higher in patients with NIID than in healthy controls. (GGC) n repeat number in the 5’-untranslated region of the NOTCH2NLC gene ranged from 82 to 173 repeats. A significant inverse correlation between (GGC) n repeat number and age of onset was observed (r=–0·203, p=0·018). Interpretation: This study provides a novel classification of adult-onset NIID for clinical application. Decreased cerebral perfusion may underpin the pathogenesis of NIID and highlight the potential of perfusion modulation therapy. (GGC) n repeat number was inversely correlated with the age of onset, and the pathogenetic effect may have a cumulative effect. Funding: None Declaration of Interest: We declare no competing interests. Ethical Approval: This study was approved by the Medical Ethics Committee of Beijing Tiantan Hospital, Capital Medical University, and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all individuals or their authorised surrogates at enrolment.