NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long‐Term Follow‐up

Abstract

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well‐characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion‐weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 “intermediate” repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614–618

Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders

“…A limitation of our study was our inability to obtain a skin sample and MRI head images of patient B, which may provide pathological and radiological evidence to support the diagnosis of NIID. Recent studies described 3 East Asian ET patients carrying this repeat expansion and intranuclear inclusions in skin biopsy: 2 of them manifested classical clinical and radiological features of NIID 10 years after initial tremor onset, but 1 patient continued to display pure ET phenotype after 4 decades of follow‐up 18,19 . These studies illustrate the variable clinical expressivity of NIID, which may be caused by genetic factors such as GGC‐repeat length, interruptions in the repeat tracts, or other unknown modifiers.…”

“…Recent studies described 3 East Asian ET patients carrying this repeat expansion and intranuclear inclusions in skin biopsy: 2 of them manifested classical clinical and radiological features of NIID 10 years after initial tremor onset, but 1 patient continued to display pure ET phenotype after 4 decades of follow-up. 18,19 These studies illustrate the variable clinical expressivity of NIID, which may be caused by genetic factors such as GGC-repeat length, interruptions in the repeat tracts, or other unknown modifiers. Thereby, it is plausible that our patient displayed an ET phenocopy of NIID.…”

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

“…NIID is a neurodegenerative condition characterized by eosinophilic intranuclear inclusions in neuronal and glial cells, which have characteristic findings on brain MRI, including high diffusion-weighted imaging signals along the corticomedullary junction [ 4 , 95 , 152 ]. The NOTCH2NLC expansion has also been found in a rapidly growing number of phenotypes, including leukoencephalopathy, essential tremor, Parkinson’s disease, multiple system atrophy (MSA) and amyotrophic lateral sclerosis [ 38 , 69 , 95 , 117 , 119 , 175 ]. Further long-read sequencing studies have found noncoding CGG repeat expansions in LOC642361/NUTM2B-AS1 , LRP12 and GIPC1 [ 69 , 172 ].…”

GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy

“…To date, GGC repeat expansion of NOTCH2NLC has been reported to not only be responsible for typical NIID, [1][2][3][4] but also associated with a group of NOTCH2NLC-related repeat expansion disorders (NRED). 14 These disorders include Alzheimer's disease (AD), 3 frontotemporal dementia, 15 parkinsonism-related disorders, 3,16,17 multiple system atrophy (MSA), 18 essential tremor (ET), 19,20 adult leukoencephalopathy, 21 amyotrophic lateral sclerosis (ALS), 22 and oculopharyngodistal myopathy (OPDM), 23,24 Studies so far showed an indefinite tendency between the length of GGC repeat expansion in the NOTCH2NLC and the variable NRED phenotypes: intermediate-length from 41 to 130 repeats (median 47 repeats) are potentially associated with Parkinson disease, 16,17 length from 44 to 143 repeats (median 75 repeats) are related to ALS, 22 around 100 repeats usually dominantly associated with dementia-type NIID, and long expansions with more than 200 repeats may be associated with muscle-type NIID or OPDM. 14,23,24 This indicates that the spectrum of NRED is highly complicated and may be closely related to the number of expanded GGC repeats, whereby it is worthy to further investigate whether there are new clinical subtypes of NRED and understand the relationship between the GGC repeat numbers and the heterogeneity of NRED.…”

“…To date, GGC repeat expansion of NOTCH2NLC has been reported to not only be responsible for typical NIID, 1‐4 but also associated with a group of NOTCH2NLC ‐related repeat expansion disorders (NRED) 14 . These disorders include Alzheimer’s disease (AD), 3 frontotemporal dementia, 15 parkinsonism‐related disorders, 3,16,17 multiple system atrophy (MSA), 18 essential tremor (ET), 19,20 adult leukoencephalopathy, 21 amyotrophic lateral sclerosis (ALS), 22 and oculopharyngodistal myopathy (OPDM), 23,24 …”