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GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies.
Neurology. 2022 01 11; 98(2):e199-e206.Neur

Abstract

BACKGROUND AND OBJECTIVES

The GGC repeat expansion in the 5' untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy.

METHODS

This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed.

RESULTS

One hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21-55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID.

DISCUSSION

The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort.

CLASSIFICATION OF EVIDENCE

This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.

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Authors+Show Affiliations

Liao YC
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Chang FP
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Huang HW
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Chen TB
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Chou YT
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Hsu SL
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Jih KY
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Liu YH
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Hsiao CT
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Fukukda H
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Mizuguchi T
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Lin KP
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Lin CK
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Matsumoto N
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Kennerson M
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia.
Lee YC
From the Departments of Neurology (Y.-C. L., Y.-T.C., S.-L.H., K.J., Y.-H.L., C.-T.H., K.-P.K.P.L., Y.-C. L.), Pathology (F.-P.C.), and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital; Department of Neurology (Y.-C.L., K.J., C.-T.H., K.-P.K.P.L., Y.-C. L.), Brain Research Center (Y.-C.L., Y.-C. L.), and Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei; Department of Neurology (H.-W.H., C.-C.K.L.), School of Medicine, National Cheng Kung University Hospital, Tainan; Department of Neurology (T.-B.C.), Neurological Institute, Taichung Veterans General Hospital, Taiwan; Departments of Human Genetics (H.F., T.M., N.M.) and Neurology and Stroke Medicine (H.F.), Yokohama City University Graduate School of Medicine, Japan; Northcott Neuroscience Laboratory (M.K.), ANZAC Research Institute, Concord; Sydney Medical School (M.K.), University of Sydney; and Molecular Medicine Laboratory (M.K.), Concord Hospital, NSW, Australia. ycli@vghtpe.gov.tw.

MeSH

AdultCase-Control StudiesCohort StudiesHumansIntercellular Signaling Peptides and ProteinsIntranuclear Inclusion BodiesMiddle AgedNerve Tissue ProteinsNeurodegenerative DiseasesPeripheral Nervous System DiseasesTrinucleotide Repeat ExpansionYoung Adult

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34675106

Citation

Liao, Yi-Chu, et al. "GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies." Neurology, vol. 98, no. 2, 2022, pp. e199-e206.
Liao YC, Chang FP, Huang HW, et al. GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies. Neurology. 2022;98(2):e199-e206.
Liao, Y. C., Chang, F. P., Huang, H. W., Chen, T. B., Chou, Y. T., Hsu, S. L., Jih, K. Y., Liu, Y. H., Hsiao, C. T., Fukukda, H., Mizuguchi, T., Lin, K. P., Lin, C. K., Matsumoto, N., Kennerson, M., & Lee, Y. C. (2022). GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies. Neurology, 98(2), e199-e206. https://doi.org/10.1212/WNL.0000000000013008
Liao YC, et al. GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies. Neurology. 2022 01 11;98(2):e199-e206. PubMed PMID: 34675106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies. AU - Liao,Yi-Chu, AU - Chang,Fu-Pang, AU - Huang,Han-Wei, AU - Chen,Ting-Bing, AU - Chou,Ying-Tsen, AU - Hsu,Shao-Lun, AU - Jih,Kang-Yang, AU - Liu,Yi-Hong, AU - Hsiao,Cheng-Tsung, AU - Fukukda,Hiromi, AU - Mizuguchi,Takeshi, AU - Lin,Kon-Ping, AU - Lin,Chou-Ching K, AU - Matsumoto,Naomichi, AU - Kennerson,Marina, AU - Lee,Yi-Chung, Y1 - 2021/10/21/ PY - 2021/05/27/received PY - 2021/10/15/accepted PY - 2021/10/23/pubmed PY - 2022/4/6/medline PY - 2021/10/22/entrez SP - e199 EP - e206 JF - Neurology JO - Neurology VL - 98 IS - 2 N2 - BACKGROUND AND OBJECTIVES: The GGC repeat expansion in the 5' untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy. METHODS: This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed. RESULTS: One hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21-55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID. DISCUSSION: The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/34675106/GGC_Repeat_Expansion_of_NOTCH2NLC_in_Taiwanese_Patients_With_Inherited_Neuropathies_ DB - PRIME DP - Unbound Medicine ER -