Neuronal intranuclear inclusion disease: a diagnostic pitfall for MELAS

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaluronan inclusions in the nervous system and internal organs. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is the most common neurological mitochondrial disease involving multiple organs. The complex and overlapping clinical manifestations of both diseases pose a significant risk for misdiagnosis. We present a case of NIID that closely mimicked the phenotype of MELAS. A 60-year-old Chinese man presented with recurrent headaches and cognitive impairment. Upon the first clinical presentation, brain magnetic resonance imaging (MRI) revealed multiple lacunar infarction foci. During the second presentation, the cranial MRI indicated lesions in the left occipital and parietal cortex. Cerebrospinal fluid (CSF) analysis ruled out common infectious, autoimmune, and paraneoplastic etiologies. Screening for Alzheimer’s disease (AD) biomarkers was also unremarkable. Muscle biopsy pathology revealed ragged-red fibers (RRFs), a finding consistent with MELAS. Based on the muscle biopsy findings, a provisional diagnosis of MELAS was made, and the patient received a course of intravenous arginine therapy. However, genetic testing for the NOTCH2NLC gene via capillary electrophoresis identified a heterozygous CGG repeat expansion (15 and 97 repeats), confirming the diagnosis of NIID. This case highlights the diagnostic challenge in distinguishing NIID from MELAS and underscores the necessity of genetic testing for NOTCH2NLC in patients with compatible phenotypes, even in the presence of MELAS-suggestive features like RRFs.