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

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.