Clinicopathologic Features of Oculopharyngodistal Myopathy WithLRP12CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes

Abstract

and the OPDM_LRP12 Study Group IMPORTANCE Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown.OBJECTIVE To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. DESIGN, SETTING, AND PARTICIPANTSThis case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot.MAIN OUTCOMES AND MEASURES Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics.RESULTS Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r 2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. CONCLUSIONS AND RELEVANCEThis study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

“…Serum creatine kinase levels are usually normal or mildly increased in individuals with OPDM, and skeletal muscles shows moderate fibrosis and small angular fibers. Besides these non-specific myopathic changes, OPDM histopathology is characterized by the presence of cytoplasmic rimmed vacuoles (RVs) and typical eosinophilic nuclear inclusions (NIs), which are both p62-and ubiquitin-positive ( Zhao et al, 2015 ; Deng et al, 2020 ; Saito et al, 2020 ; Kumutpongpanich et al, 2021 ; Matsubara et al, 2021 ; Xi et al, 2021 ). Of interest, these intranuclear inclusions are also observed in skin sections of individuals with OPDM cases ( Ogasawara et al, 2021 ), and are reminiscent of the typical inclusions observed in FXTAS and NIID.…”

“…Of interest, these intranuclear inclusions are also observed in skin sections of individuals with OPDM cases ( Ogasawara et al, 2021 ), and are reminiscent of the typical inclusions observed in FXTAS and NIID. Importantly, the mutations causing OPDM were recently identified as similar expansions of ∼70 to 200–300 CGG repeats located within the 5′UTR of two different genes, LRP12 and GIPC1 ( Ishiura et al, 2019 ; Deng et al, 2020 ; Kumutpongpanich et al, 2021 ; Xi et al, 2021 ). Furthermore, an expansion of CGG repeats in the 5′UTR of the NOTCH2NLC gene was identified in OPDM cases with variable neurological manifestations ( Ogasawara et al, 2020 ; Yu et al, 2021 ), and an expansion of CGG repeats within the 5′UTR of the RILPL1 gene was recently reported in medRxiv in affected individuals of a large Chinese family with OPDM ( Yang et al, 2021 ).…”

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder

“…Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological diseases 15 . Large GGC expansions are strictly linked to neurological disorders of predominant neurocognitive impairment, such as fragile X-associated tremor and ataxia syndrome, NIID, and oculopharyngeal muscular dystrophy 16 – 21 .…”

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

“…In a global perspective, abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological diseases 12 . Large GGC expansions are strictly linked to neurological disorders of predominant neurocognitive impairment, such as fragile X-associated tremor and ataxia syndrome, NIID, and oculopharyngeal muscular dystrophy [13][14][15][16][17][18] .…”