The Value of NOTCH2NLC Gene Detection and Skin Biopsy in the Diagnosis of Neuronal Intranuclear Inclusion Disease.

Jing Yang,Shiheng Fan,Yuming Xu,Changhe Shi,Yuan Gao,Jie Pang,Yanpeng Yuan

doi:10.3389/fneur.2021.624321

Abstract

The clinical manifestations of neuronal intranuclear inclusion disease (NIID) are heterogeneous, and the premortem diagnosis is mainly based on skin biopsy findings. Abnormal GGC repeat expansions in NOTCH2NLC was recently identified in familial and sporadic NIID. The comparison of diagnostic value between abnormal GGC repeat expansions of NOTCH2NLC and skin biopsy has not been conducted yet. In this study, skin biopsy was performed in 10 suspected adult NIID patients with clinical and imaging manifestations, and GGC repeat size in NOTCH2NLC was also screened by repeat primed-PCR and GC-rich PCR. We found that five cases had ubiquitin-immunolabelling intranuclear inclusion bodies by skin biopsy, and all of them were identified with abnormal GGC repeat expansions in NOTCH2NLC, among whom four patients showed typical linear hyperintensity at corticomedullary junction on DWI. Five (5/10) NIID patients were diagnosed by combination of NOTCH2NLC gene detection, skin biopsy or combination of NOTCH2NLC, and typical MRI findings. The diagnostic performance of NOTCH2NLC gene detection was highly consistent with that of skin biopsy (Kappa = 1). The unexplained headache was firstly reported as a new early phenotype of NIID. These findings indicate that NOTCH2NLC gene detection is needed to be a supplement in the diagnose flow of NIID and also may be used as an alternative method to skin biopsy especially in Asian population.

Highlights

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by the presence of eosinophilic hyaline nuclear inclusion bodies in the cells of the central and peripheral nervous system, internal organs, and skin
Among the 10 suspected adult neuronal intranuclear inclusion disease (NIID) patients, five cases were diognosed with NIID by combination of NOTCH2NLC GGC repeat detection, skin biopsy, and typical MRI imagings
The main findings of the present study included that [1] Five NIID cases among the 10 suspected NIID patients were diagnosed by combination of NOTCH2NLC GGC repeat detection, skin biopsy and typical DWI images; [2] The diagnostic efficiency of NOTCH2NLC GGC repeat expansions detection was completely consistent with skin biopsy; [3] The unexplained headache was reported as an early phenotype of NIID

Summary

Introduction

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by the presence of eosinophilic hyaline nuclear inclusion bodies in the cells of the central and peripheral nervous system, internal organs, and skin. The clinical manifestations are extremely heterogeneous such as, dementia, Parkinson’s syndrome, peripheral neuropathy, epilepsy, and encephalopathy. It is difficult to diagnose NIID based on clinical manifestations alone. The antemortem detection of intranuclear inclusions in NIID cases by skin biopsy was firstly reported in 2011 [1]. The number of NIID cases that have been diagnosed with skin biopsy has rapidly increased. Despite of the relative convenience and harmlessness, skin biopsy is undoubtedly invasive for patients with contraindications

Methods

Results

Conclusion