<scp><i>NOTCH2NLC</i> GGC</scp> Repeat Expansion Presenting as Adult‐Onset Cervical Dystonia

Neuronal intranuclear inclusion disease (NIID) is the pathological hallmark of a heterogeneous neurodegenerative disease spanning dementia, neuropathy, parkinsonism, encephalitic episodes, and seizures.1 Onset may be in infancy, childhood, or adulthood and be sporadic or familial. Adult-onset disease is divided into dementia- and limb-weakness dominant subtypes. Recent novel presentations include isolated tremor,2 migraine,3 recurrent vomiting,4 and oromandibular dystonia.5 Identification of GGC expansions in the 5'UTR of the Notch-2 N-terminal-like-C (NOTCH2NLC) gene have enhanced diagnosis.1 We report a patient with an 11-year history of adult-onset cervical dystonia (CD), without other symptoms, in association with imaging and biopsy appearances of NIID and a monoallelic “GGC” repeat expansion in NOTCH2NLC (genetic findings reported elsewhere).6 Our patient expands the spectrum of NOTCH2NLC and highlights the importance of considering NIID in familial movement disorders with leukoencephalopathy. A 59-year-old Chinese woman was referred with gradually progressive head tremor and neck discomfort. There has been no symptom evolution over 7 years of follow-up. Her father and sister experience upper limb tremor, but were not available for examination. This sister and another sister were subsequently diagnosed with dementia. Four other siblings and one daughter are well. Propranolol, topiramate, and trihexyphenidyl were ineffective, and botulinum toxin is of moderate symptomatic benefit. Examination age 66 years reveals an irregular, predominantly “no-no” head tremor, varying in amplitude (Video 1). There is retrocollis and mild right torticollis. There is no vocal tremor. There were no cognitive symptoms, however, she scored 24/30 on Montreal Cognitive Assessment performed in light of imaging findings, losing points on executive functioning, semantic fluency, abstraction, and delayed recall. The rest of her examination remains normal. Serial magnetic resonance imaging (MRI) between the ages of 56 and 66 years (Fig. 1) showed progressive, extensive, frontally predominant non-enhancing white matter hyperintensities, which also involve occipitoparietal and splenial fibers on fluid-attenuated inversion recovery and T2 sequences. Diffusion-weighted (DWI) sequences revealed corticomedullary high signal affecting frontal, parietal, and occipital lobes and the splenium of the corpus callosum. A leukodystrophy gene panel in 2015, ANT1 and FMR1 testing found no abnormalities. Imaging prompted suspicion of NIID and a skin biopsy in 2019 revealed intranuclear p62-positive inclusions in the nuclei of fibroblasts and appendage cells (Figure S1). Ultrastructural examination confirmed filamentous inclusions within the nuclei of isolated fibroblasts. Although non-specific, these findings are consistent with NIID. Programmable targeted nanopore sequencing revealed a monoallelic GGC expansion of 127 repeats6 (4–41 for healthy controls).7 This was confirmed on repeat primed polymerase chain reaction. Short tandem repeat expansions of GGC at the 5'UTR in NOTCH2NLC were linked to NIID in 20191, 8 (NOTC2NLC-NIID) and are the most common cause for NIID in Asian populations. Associated adult-onset phenotypes now encompass essential tremor (NOTCH2NLC-ET),7 dementia, parkinsonism and muscle weakness-dominant subtypes, seizures, ataxia, oculopharyngodistal myopathy, autonomic dysfunction, and recurrent encephalopathy. A handful of restricted phenotypes include vocal tremor,2 recurrent vomiting, and oromandibular dystonia.5 A single report of isolated head tremor is noted without dystonia.9 Isolated CD is not described. Our patient presented with a syndrome mimicking adult-onset isolated tremulous CD, which remained stable over many years. Mild cognitive impairment was apparent on testing, but remained subclinical 11 years after motor onset. It is possible that dystonia was an incidental finding however, 127 GGC repeats are within the range described for NIID with movement disorders and phenotypic fidelity of tremor in family members with dementia supports a single etiology. MRI findings in NIID encompass periventricular and frontal predominant white matter hyperintensities on T2 sequences involving the subcortical U-fibers. Corpus callosum involvement is common. DWI sequences reveal high signal along the corticomedullary junction. However, normal imaging is also reported. An unresolved debate is whether NOTCH2NLC-NIID and more clinically restricted presentations are separate disorders, or whether the latter represent formes frustes of, or precursors to, a classical NIID picture. Anatomic or cell-specific localization of intranuclear inclusions, GGC repeat length, and GAA interruptions are proposed to account for clinical and radiographic heterogeneity. Sun et al7 report enlarged GGC repeat expansions in NOTC2NLC-ET patients with associated intranuclear inclusions, but with normal imaging. They also report longer expansions and younger onset for NIID-muscle weakness dominant subtype versus their NOTCH2NLC-ET cohort, arguing for distinct pathological processes. However, in this same study, age at onset in NOTCH2NLC-ET patients was 13 and 15 years earlier than NIID-dementia and NIID-parkinsonism respectively, and future evolution could not be excluded. Tian et al1 also report muscle weakness-, dementia-, and parkinsonism-dominant subtypes with defined, but overlapping repeat size ranges. “Biopsy-positive” NOTCH2NLC-ET with normal imaging, however, may later progress to the characteristic DWI change of NIID.10 NOTCH2NLC-NIID with typical imaging findings may present as stable adult-onset CD. Our case helps confirm dystonia or tremor as a presenting phenotype of NOTCH2NLC-NIID. Larger studies and long-term follow-up of focal presentations will enhance our understanding of disease spectrum and modifying factors in NOTCH2NLC-related disease. Manuscript: A. Writing of the first draft, B. Review and Critique. L.J.W.: A. J.Q.: B. O.T.L.: B. I.D.: B. I.S.: B. S.R.C.: B. A.F.: B. W.K.: B. H.M.B.: B. M.T.: B. K.R.K.: B. V.S.C.F.: A, B. Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Written informed consent has been obtained from all patients involved in this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No funding was received for this work and the authors have no relevant conflicts of interest in relation to this work. Financial Disclosures for Previous 12 Months: L.J.W., J.Q., O.T.L., I.D., I.S., S.R.C., A.F., W.K., H.M.B., M.T., K.R.K., V.S.C.F., have no relevant disclosures. FIGURE S1. Skin biopsy. P62 immunohistochemistry staining demonstrating dense, dot-like brown-colored inclusions in the nuclei of fibroblasts and cells of appendage (arrow-heads) (A). Electron microscopy shows intranuclear non-membrane bound inclusions (arrows) in the nucleus of an appendage cell (B) and a fibroblast (C). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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