NOTCH2NLC – Neuronal Intranuclear Inclusion Disease

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by eosinophilic p62-positive intranuclear inclusions across central, peripheral, and visceral tissues. NIID is caused by a pathogenic GGC repeat expansion in the 5′-untranslated region of the NOTCH2NLC gene, leading to neuronal and systemic dysfunction (PMID:31413119). Genetic confirmation and skin biopsy findings are essential for diagnosis.

Genetic evidence supports an autosomal dominant inheritance pattern. Long-read sequencing in 15 unrelated NIID patients identified GGC repeat expansions in the NOTCH2NLC 5′UTR, confirmed by repeat-primed PCR in seven familial and eight sporadic cases (PMID:31413119). Segregation analysis in a three-generation family demonstrated co-segregation in four affected siblings (PMID:33271601) and further familial clustering was observed in three siblings in another pedigree (PMID:39496005).

The most recurrent mutation is a GGC repeat insertion, described as c.-124_-123insGGC in NOTCH2NLC (NM_001364013.2), which correlates with intranuclear inclusion formation in neurons, fibroblasts, and adipocytes.

Functional studies elucidate a toxic RNA gain-of-function mechanism. Patient-derived induced pluripotent stem cells harboring expanded GGC repeats exhibit nuclear inclusions, aberrant transcript processing, and impaired neuronal differentiation, mirroring human pathology (PMID:35772299). Neuropathological analyses confirm p62- and ubiquitin-positive inclusions in multiple cell types, supporting a repeat-mediated protein aggregation model.

Clinical presentations of NIID are highly heterogeneous, ranging from episodic encephalitic attacks with reversible corticomedullary DWI changes to chronic dementia, parkinsonism, peripheral neuropathy, autonomic dysfunction, and ophthalmological involvement. Common features include cognitive impairment, tremor, unsteady gait, bradykinesia, and urinary incontinence, underscoring the multi-systemic impact of repeat expansions.

Despite variability in onset and phenotype, the consistent detection of intranuclear inclusions on skin biopsy and identification of GGC expansions in NOTCH2NLC across diverse populations confirm a definitive gene–disease relationship. Molecular testing of NOTCH2NLC should be prioritized in suspected NIID cases, especially when DWI abnormalities or systemic inclusions are present.

Key Take-home: NOTCH2NLC GGC repeat expansions definitively cause autosomal dominant NIID; genetic testing and skin biopsy expedite diagnosis and guide management for this heterogeneous neurodegenerative disease.

References

• Journal of medical genetics • 2019 • Long-read sequencing identified repeat expansions in the 5'UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. PMID:31413119
• Journal of neuropathology and experimental neurology • 2020 • Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease. PMID:33271601
• Stem cell research • 2022 • Generation of an induced pluripotent stem cell line (ZZUi036-A) derived from skin fibroblasts of a Neuronal intranuclear inclusion disease patient with GGC repeat expansion in the NOTCH2NLC gene. PMID:35772299

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