Towards a broadening of the phenotype spectrum of the NOTCH2NL gene mutation

Oculopharyngodistal myopathy (OPDM) is a very rare form of myopathy with a late onset, the clinical phenotype of which shares certain traits with oculopharyngeal muscular dystrophy (OPMD). First described in Japan, OPDM has a higher prevalence in Asia than in the rest of the world. The molecular cause was an enigma until 2019, but has now been resolved, with 3 genes identified: LRP12, GIPC1 and NOTCH2NLC, all three of which have pathological nucleotide triplet expansions.

In an article published in June 2021, Chinese researchers reported the involvement of the second of these genes in three unrelated patients, with these patients presenting a broader phenotype spectrum than that of OPDM alone. With two of the families, it was possible to confirm the autosomal dominant nature of the transmission, while in the third family, it was a sporadic case. The clinical picture suggested a motor neuropathy with distal expression and/or a myopathy with rimmed vacuoles. Central nervous system involvement was also noted in several affected individuals. Age of onset seems to be earlier in these broad-spectrum muscular phenotypes. The size of the triplet expansions was similar to that observed in conventional OPDM cases. The NOTCH2NL mutations can, therefore, be considered to be responsible for neurodegenerative processes that extend well beyond the muscle and the lower motor neurons.


GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy. Yu J, Luan XH, Yu M, et al. Ann Clin Transl Neurol. 2021 (Juin).8(6):1330-1342.