CGG expansion inNOTCH2NLCis associated with oculopharyngodistal myopathy with neurological manifestations

ABSTRACT Background Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1 , have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC . Objectives To identify and to clinicopathologically characterize OPDM patients who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Methods Two hundred eleven patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of the identified OPDM_NOTCH2NLC patients were re-reviewed. Intra-myonuclear inclusions were further evaluated by immunohistochemistry and electron microscopy. Results Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC . All seven patients clinically had ptosis, ophthalmoplegia, dysarthria, and muscle weakness, and myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which are diagnostic of NIID typically on skin biopsy, in addition to rimmed vacuoles. Sample for electron microscopy was available only from one patient, which showed intranuclear inclusions of 12.6 ± 1.6 nm in diameter. Conclusions We identified seven OPDM_NOTCH2NLC patients. Our patients had various additional central and/or peripheral nervous system involvement, albeit all being clinicopathologically compatible; thus, diagnosed as having OPDM, expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC .