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

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.

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

“…In this study, we screened the STR variants in dHMN patients, and identified GGC expansion in NOTCH2NLC in two autosomal dominant families and CAG expansion in ATNX2 in a patient with dHMN‐plus cerebellar ataxia. As we discussed in a previous study, 11 the GGC repeat expansion in the NOTCH2NLC has been associated with a new type of hereditary distal neuromyopathy based on a common pathological basis of widespread eosinophilic intranuclear inclusions in both nerves and muscles. Herein, we found that the GGC expansion in NOTCH2NLC can be responsible to a part of patients with dHMN with minor subclinical sensory abnormalities, of which the electrophysiological changes indicated both axonal and demyelinating involvements, and the clinical features showed some extra‐motor neuropathy symptoms such as tremor, dry cough, urinary incontinence, or headache.…”

“…Nevertheless, it still remains difficult and elusive to genetic diagnosis of dHMN, because the causative variants have been identified in only 20.0–47.8% of affected index patients with different ethnic origins 6–10 . Recently, GGC repeat expansion in the 5′ untranslated region (5’UTR) of the NOTCH2NLC gene has been associated with distal motor neuropathy and rimmed vacuolar myopathy 11 . Additionally, some patients with CAG repeat expansion in the Ataxin‐2 (ATXN2) gene also can affect motor neuropathy independently 12 .…”

“… 6 , 7 , 8 , 9 , 10 Recently, GGC repeat expansion in the 5′ untranslated region (5’UTR) of the NOTCH2NLC gene has been associated with distal motor neuropathy and rimmed vacuolar myopathy. 11 Additionally, some patients with CAG repeat expansion in the Ataxin‐2 (ATXN2) gene also can affect motor neuropathy independently. 12 Therefore, it is necessary to further conduct the genetic studies on short tandem repeat (STR) in some genetically unsolved patients with dHMN.…”

GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies

“…17 Another Chinese study reported 3 unrelated patients with NOTCH2NLC GGC repeat expansions manifesting with distal motor neuropathy and rimmed vacuolar myopathy. 16 All patients presented with progressive weakness affecting predominantly distal lower limb muscles. In the present study, the 7 patients with NOTCH2NLC GGC repeat expansions had very mild or absent motor symptoms.…”

“…The GGC repeat expansion in the 59 untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), [5][6][7] a sporadic or autosomal-dominantly inherited neurodegenerative disease characterized by the eosinophilic, ubiquitin-and p62-positive intranuclear inclusions in cells of the CNS, peripheral nervous system, skin, and visceral organs. 8 There is a broad spectrum of clinical manifestations of NIID, including a diverse combination of cognitive impairment, 7,8 parkinsonism, 7,9 cerebellar ataxia, 10,11 encephalitis-like episodes, 8,12 tremor, 13,14 myopathy, 15,16 and peripheral neuropathy. 16,17 However, peripheral neuropathy was rarely reported as the main presentation of NIID.…”