Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder categorized into 3 phenotypic variants: infantile, juvenile, and adult. Four recent reports have linked NIID to CGG expansions in the NOTCH2NLC gene in adult NIID (aNIID) and several juvenile patients. Infantile NIID (iNIID) is an extremely rare neuropediatric condition. We present a 7-year-old male patient with severe progressive neurodegenerative disease that included cerebellar symptoms with cerebellar atrophy on brain MRI, psychomotor developmental regression, pseudobulbar syndrome, and polyneuropathy. The diagnosis of iNIID was established through a postmortem neuropathology work-up. We performed long-read sequencing of the critical NOTCH2NLC repeat motif and found no expansion in the patient. We also re-evaluated an antemortem skin biopsy that was collected when the patient was 2 years and 8 months old and did not identify the intranuclear inclusions. In our report, we highlight that the 2 methods (skin biopsy and CGG expansion testing in NOTCH2NLC) used to identify aNIID patients may provide negative results in iNIID patients.

Biomedical Center Faculty of Medicine in Pilsen Charles University Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Department of Pediatrics

Department of Pediatrics and Adolescent Medicine Research Unit for Rare Diseases

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Institute of Pathology

Sikl's Department of Pathology

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Genetic heterogeneity of neuronal intranuclear inclusion disease: What about the infantile variant?