Clinical phenotypic diversity of <i>NOTCH2NLC</i>-related disease in the largest case series of inherited peripheral neuropathy in Japan.

Abstract

<i>NOTCH2NLC</i> GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few <i>NOTCH2NLC</i>-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of <i>NOTCH2NLC</i>-related IPNs. Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed <i>NOTCH2NLC</i> repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of <i>NOTCH2NLC</i> repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. <i>NOTCH2NLC</i> repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. These findings of this study help us understand the clinical heterogeneity of <i>NOTCH2NLC</i>-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.