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.

NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

“…Recently, two studies identified the large GGC repeat expansion in the 5′ UTR of NOTCH2NLC as the third causative factor of OPDM,40 41 which accounts for 16.67% of patients with OPDM in the Chinese population. In addition to the typical OPDM clinical manifestations, patients affected by NOTCH2NLC -OPDM showed leukoencephalopathy, retinal pigmentary degeneration, tremor, ataxia, peripheral neuropathy, increased cerebrospinal fluid (CSF) protein and serum creatine kinase levels, and other abnormalities in the central or peripheral nervous system 40 41. The aberrant findings of DWI, MRI, nerve conduction studies, CSF protein elevation and skin biopsies in some patients with NOTCH2NLC -OPDM highly confused the definitive diagnosis 40 41.…”

“…In addition to the typical OPDM clinical manifestations, patients affected by NOTCH2NLC -OPDM showed leukoencephalopathy, retinal pigmentary degeneration, tremor, ataxia, peripheral neuropathy, increased cerebrospinal fluid (CSF) protein and serum creatine kinase levels, and other abnormalities in the central or peripheral nervous system 40 41. The aberrant findings of DWI, MRI, nerve conduction studies, CSF protein elevation and skin biopsies in some patients with NOTCH2NLC -OPDM highly confused the definitive diagnosis 40 41. In addition, the frequency of non-GGC/GGA/AGC/ACG repeat interruptions in NOTCH2NLC -OPDM was found higher than that in NIID 41.…”

“…Diagnostically, the deposition of ubiquitin-positive and p62-positive intranuclear inclusions in the skin, nervous systems and other organs are pathognomonic of NIID 1. Ogasawara and co-workers40 identified the deposition of p62-positive intranuclear inclusions in 2/7 patients with NOTCH2NLC -OPDM, who would be diagnosed with NIID according to the proposed NIID diagnostic flowchart 1. However, the ubiquitin-positive and p62-positive intramyonuclear inclusions, which essentially are the same as intranuclear inclusions in the neurons, were widely identified in the myonuclear centre of all seven patients with NOTCH2NLC -OPDM 40.…”

Expansion of 5’ UTR CGG repeat in RILPL1 is associated with oculopharyngodistal myopathy

“…Four pair of primers were listed in Supplementary Table. 4. We used a slow-down PCR protocol [19]: initial denaturation at 95 °C for 5 min, followed by 50 cycles of 95 °C for 30 s, 98 °C for 10 s, 62 °C for 30 s and 72 °C for 2 min.…”

“…Meanwhile, the CGG repeat expansion in the 5'UTR of NOTCH2NLC gene is responsible for OPDM type 3(OPDM2; MIM 619473) [4]. Many patients with OPDM phenotype could be classified into one of the three types above, but still some patients and pedigrees with identical manifestations were excluded by genetic tests of the CGG repeat expansions in these three loci.…”