Jiaxi Yu1,2, Xing-Hua Luan3, Meng Yu1,2, Wei Zhang1,2, He Lv1,2, Li Cao3, Lingchao Meng1,2, Min Zhu4, Binbin Zhou4, Xiao-Rong Wu4, Pidong Li5, Qiang Gang1,2, Jing Liu1,2, Xin Shi1,2, Wei Liang1,2, Zhirong Jia1,2, Sheng Yao6, Yun Yuan1,2, Jianwen Deng1,2, Daojun Hong4, Zhaoxia Wang1,2. 1. Department of Neurology, Peking University First Hospital, Beijing, 100034, China. 2. Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, 100034, China. 3. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200030, China. 4. Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China. 5. Grandomics Biosciences, Beijing, 100176, China. 6. Department of Neurology, Sixth Medical Center of PLA General Hospital, Beijing, 100853, China.
Abstract
BACKGROUND: The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. METHODS: Whole-exome sequencing (WES) and long-read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. RESULTS: We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. INTERPRETATION: These phenotypes enrich the class of features associated with NOTCH2NLC-related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.
BACKGROUND: The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. METHODS: Whole-exome sequencing (WES) and long-read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. RESULTS: We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. INTERPRETATION: These phenotypes enrich the class of features associated with NOTCH2NLC-related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.