Patients with NOTCH2NLC GGC Repeat Expansion Presenting with Vascular Leukoencephalopathy (S36.003)

Objective:

To investigate GGC repeat expansion in the 5'untranslated region of NOTCH2NLC, the genetic cause of neuronal intranuclear inclusion disease (NIID), and its contribution to vascular leukoencephalopathy.

Background:

NIID is an autosomal-dominantly inherited neurodegenerative disease with pathological hallmarks of eosinophilic, ubiquitin-, and p62-positive intranuclear inclusions in cells of the nervous systems, skin, and visceral organs. NIID has several clinico-radiological features akin to cerebral small vessel disease (cSVD). Besides, ubiquitin- and p62-positive staining had been detected in the blood vessels of ten autopsied cases with NIID, suggesting a link between NIID and vascular pathology.

Design/Methods:

We screened 197 unrelated patients with vascular leukoencephalopathy and 730 healthy individuals for NOTCH2NLC GGC repeat expansion using repeat-primed PCR, fragment analysis, southern blot analysis, and/or nanopore sequencing with Cas9-mediated enrichment. Skin biopsy with immuno-histochemistry staining and electric microscopic imaging was performed. For patients with vascular leukoencephalopathy, the clinical and neuroimaging characteristics were compared between individuals with and without NOTCH2NLC GGC repeat expansion.

Results:

Six of the 197 patients with vascular leukoencephalopathy carried NOTCH2NLC GGC repeat expansion, while none of the 730 controls harbored the expanded GGC repeats (3.0% vs. 0%, p = 0.00009). Skin biopsy revealed ubiquitin-, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing a pathologic evidence for the involvement of small vessels in NIID. Comparing vascular leukoencephalopathy patients with and without the GGC expansion, there was no difference in the clinical manifestations and severity of cSVD imaging markers, including white matter hyperintensities, enlarged perivascular spaces, lacunes, and cerebral microbleeds. Characteristic imaging features of NIID were detected in five of the six patients carrying GGC expansion and manifesting with vascular leukoencephalopathy.

Conclusions:

The NOTCH2NLC GGC repeat expansion accounts for 3% of the patients with genetically undetermined vascular leukoencephalopathy in the Taiwanese cohort, suggesting that NIID is an under-diagnosed and important cause of cSVD. Disclosure: Dr. Liao has nothing to disclose. Prof. Chung has nothing to disclose. Dr. Lee has nothing to disclose.