Episodic headaches and cognitive decline: uncovering neuronal intranuclear inclusion disease in a young patient

A male in his 20s presented with episodic headache and subsequently developed episodic unilateral weakness, dysphasia and encephalopathy. These paroxysmal episodes persisted over time with the development of background cognitive impairment and neuropsychiatric symptoms. MRI surveillance demonstrated progressive T2 hyperintensity with focal cortical oedema correlating to symptoms observed during clinical episodes. Genetic testing for hemiplegic migraine, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes along with exome sequencing and high-density microarray did not reveal a cause for the clinical phenotype. The diagnosis of neuronal intranuclear inclusion disease (NIID) was confirmed by the detection of large guanine-guanine-cytosine repeat expansion in the Notch 2 N-terminal-like C gene using long-read nanopore sequencing. NIID is a genetic neurodegenerative disease, more common in Asian populations. It can present with a varied neurological phenotype, including an episodic event type that can mimic hemiplegic migraine and encephalopathy. This case report highlights the importance of considering NIID in cases of paroxysmal headache and encephalopathy.