GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor–Sensory and Autonomic Neuropathy

Abstract

There is still a considerable proportion of patients with inherited peripheral neuropathy (IPN) whose pathogenic genes are unknown. This study was intended to investigate whether the GGC repeat expansion in the NOTCH2NLC is presented in some patients with IPN. A total of 142 unrelated mainland Chinese patients with highly suspected diagnosis of IPN without any known causative gene were recruited. Repeat-primed polymerase chain reaction (RP-PCR) was performed to screen GGC repeat expansion in NOTCH2NLC, followed by fluorescence amplicon length analysis-PCR (AL-PCR) to determine the GGC repeat size. Detailed clinical data as well as nerve, muscle, and skin biopsy were reviewed and analyzed in the NOTCH2NLC-related IPN patients. In total, five of the 142 patients (3.52%) were found to have pathogenic GGC expansion in NOTCH2NLC, with repeat size ranging from 126 to 206 repeats. All the NOTCH2NLC-related IPN patients presented with adult-onset motor–sensory and autonomic neuropathy that predominantly affected the motor component of peripheral nerves. While tremor and irritating dry cough were noted in four-fifths of the patients, no other signs of the central nervous system were presented. Electrophysiological studies revealed both demyelinating and axonal changes of polyneuropathy that were more severe in lower limbs and asymmetrically in upper limbs. Sural nerve pathology was characterized by multiple fibers with thin myelination, indicating a predominant demyelinating process. Muscle pathology was consistent with neuropathic changes. P62-positive intranuclear inclusions were observed in nerve, skin, and muscle tissues. Our study has demonstrated that GGC expansion in NOTCH2NLC is associated with IPN presenting as predominant motor–sensory and autonomic neuropathy, which expands the phenotype of the NOTCH2NLC-related repeat expansion spectrum. Screening of GGC repeat expansions in the NOTCH2NLC should be considered in patients presenting with peripheral neuropathy with tremor and irritating dry cough.

NOTCH2NLC-related oculopharyngodistal myopathy type 3 complicated with focal segmental glomerular sclerosis: a case report

“…Subsequently, the pleiotropy of NOTCH2NLC was identified as being causative for many types of neurodegenerative diseases [ 15 , 19 , 20 ]. Recent research further expanded the clinical spectrum of NOTCH2NLC-related disorders to OPDM3[ 9 ] and other peripheral neuropathies and myopathies [ 13 , 21 ]. An increasing number of studies have shown evidence of NOTCH2NLC CGG repeat expansions in various central and peripheral nervous system disorders; however, descriptions of systemic organ disorders have rarely been recognized in previous reports.…”

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

“…Therefore it was necessary to measure the CGG repeat number to determine its pathogenicity in the genetic diagnosis of NIID patients. The repeat expansion in NOTCH2NLC also showed some rare clinical phenotypes, such as neurodegenerative dementia ( Jiao et al, 2020 ), non-vascular leukoencephalopathy ( Liu et al, 2022 ), motor neuron disease ( Yuan et al, 2020 ), sensorimotor with autonomic neuropathy ( Wang et al, 2021 ), distal motor neuropathy ( Wu et al, 2022 ), as well as oculopharyngeal distal myopathy (OPDM) ( Yu et al, 2021 ). Because of the small number of these cases, the relationship between the clinical phenotype and the number of CGG repeat had not been established, but distal motor neuropathy and OPDM were generally considered to have more repeats.…”

“…leukoencephalopathy (Liu et al, 2022), motor neuron disease (Yuan et al, 2020), sensorimotor with autonomic neuropathy (Wang et al, 2021), distal motor neuropathy (Wu et al, 2022), as well as oculopharyngeal distal myopathy (OPDM) (Yu et al, 2021). Because of the small number of these cases, the relationship between the clinical phenotype and the number of CGG repeat had not been established, but distal motor neuropathy and OPDM were generally considered to have more repeats.…”

“…Abnormal CGG repeat expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene is the genetic cause of NIID ( Deng et al, 2019 ; Ishiura et al, 2019 ; Sone et al, 2019 ; Tian et al, 2019 ). In addition, studies have shown that the repeat expansion is also associated with Parkinson’s disease (PD) ( Shi et al, 2021 ), essential tremor ( Sun et al, 2020 ), multiple system atrophy ( Fang et al, 2020 ), motor neuron disease ( Yuan et al, 2020 ), peripheral neuropathy ( Wang et al, 2021 ), and oculopharyngodistal myopathy (OPDM) ( Yu et al, 2021 ). Collectively, these phenotypes are referred to as NOTCH2NLC -related repeat expansion disorders (NREDs) ( Lu and Hong, 2021 ).…”

The polyG diseases: a new disease entity

“…Nevertheless, several studies have indicated that carriers with more than 300 repeats of expanded CGG show a mild or asymptomatic phenotype [ 20 , 127 ]. Beyond NIID, expanded CGG repeats in NOTCH2NLC are occasionally related to a small proportion of Parkinson's disease (PD) [ 65 , 97 , 110 ], multiple system atrophy (MSA) [ 29 ], essential tremor (ET) [ 105 ], degenerative dementia [ 4 , 101 ], ALS [ 46 , 130 ], inherited peripheral neuropathy [ 118 ], distal motor neuropathy [ 122 , 128 ], mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) [ 57 , 123 ], and oculopharyngodistal myopathy (OPDM) [ 127 ]. Intriguingly, CGG expansion in NOTCH2NLC was rarely detected in NIID cases reported in people of Caucasian descent, suggesting that NIID is likely to be genetically heterogeneous among different ethnic groups [ 15 ].…”