Oculopharyngodistal myopathy: The recent discovery of an old disease

Oculopharyngodistal myopathy (OPDM) is a group of genetically heterogenous muscle diseases, characterized clinically by onset in adulthood and slowly progressive weakness affecting ocular, bulbar, and distal limb muscles, and pathologically by the presence of rimmed vacuoles and intranuclear inclusions . The disease was first described in four Japanese families more than 4 decades ago, and subsequently was also reported from other countries. It was not until recently that the underlying genetic defects of OPDM were unraveled. To date, the expansion of CGG repeats in the 50 untranslated region (50 UTR) of LRP12 (OPDM1), GIPC1 (OPDM2), NOTCH2NLC (OPDM3), and RILPL1 (OPDM4) have been reported to cause OPDM in Japan and China. Among these 4 OPDM subtypes, OPDM1 is the most common OPDM subtype in Japan, accounting for 31.25% of Japanese OPDM patients, while OPDM2 is the most common OPDM subtype in China, accounting for 37.3% of Chinese OPDM patients. Haplotype analysis in Japanese patients with OPDM1 revealed a shared haplotype, suggesting a founder effect, which explains the high frequency of OPDM1 in Japan. LRP12 encodes low density lipoprotein receptor-related protein 12, a transmembrane protein that is expressed in various organs, including skeletal and cardiac muscle. The normal number of CGG repeats in LRP12 ranges between 13 and 45, whereas affected patients possess more than 50 repeats. The presence of CGG repeat expansions in all four OPDM subtypes suggests that they share a common pathogenic mechanism. The two possible mechanisms are: (1) RNA dependent gain-of function, triggering the formation of cytotoxic RNA foci causing myodegeneration and (2) repeat-associated non-AUG (RAN) translation, producing the toxic protein containing polyglycine stretch. OPDM1 is likely transmitted in an autosomal dominant fashion with incomplete penetrance, as some families had multiple symptomatic individuals in consecutive generations while other families had asymptomatic individuals with disease-range expansions. Repeatinduced transcriptional gene silencing or other epigenetic factors may contribute to the lack of clinical expression in asymptomatic carriers of CGG repeat expansions. Genetic anticipation between generations was reported in one Japanese family. An inverse correlation between the length of CGG repeats and age of onset was observed. Table 1 summarizes clinical features of all reported genetically characterized OPDM1-OPDM4 patients. The characteristic clinical features of OPDM1 are ptosis and pharyngeal and distal muscle weakness, which were found in 97%–98% of patients in case series. The most common initial presenting symptoms of OPDM1 were ptosis (37%) and limb weakness (37%). Asymmetric muscle involvement was seen in about one third of the patients. Respiratory muscle insufficiency may occur in the late stage of the disease. The prominent pharyngeal weakness is associated with frequent aspiration, which can further compromise respiratory function. There is no correlation between OPDM1 and cardiac involvement. In a large Japanese cohort of OPDM1, 7% of patients developed atrial fibrillation, which could be related to their age, while only 3% of the patients had cardiomyopathy. OPDM1 is more common in males, while other OPDM subtypes affect males and females equally. However, the age of disease onset and severity of OPDM1 are similar between both sexes. Muscle imaging reveals the soleus and the medial head of the gastrocnemius to be the most severely affected muscles, whereas rectus femoris and gracilis muscles were relatively well preserved, even at the advanced stage. The serum creatine kinase level is usually normal or mildly elevated. All OPDM subtypes share the pathological hallmarks of chronic myopathic changes with rimmed vacuoles and p62-positive inclusions in myonuclei. A dot-like sarcoplasmic deposition of p62 and small angular fibers are also common. Ultrastructural studies have shown tubulofilamentous intranuclear inclusions of 17.3 nm in diameter in 1 OPDM1 patient, which are larger than those observed in oculopharyngeal muscular dystrophy (OPMD) or OPDM3. In this issue of Muscle & Nerve, Shimizu and colleagues report seven Japanese patients from five families with OPDM1. Six patients experienced limb weakness (five distal and one proximal) at onset without oculopharyngeal involvement. One patient remained asymptomatic even in her 80s, but physical examination revealed mild oculopharyngeal and limb weakness. As the disease progressed, three patients eventually developed all typical clinical features of OPDM, while oculopharyngeal weakness remained absent in two patients and was mild in the remaining patients at 13 to 21 y after the onset of limb weakness. Among six patients with distal lower limb weakness, weakness most severely affected ankle dorsiflexors in five and ankle plantar flexors in one. Of note, the father of two patients without oculopharyngeal LIST OF ABBREVIATIONS: GNE, UDP-N-acetylglucosamine 2-epimerase/Nacetylmannosamine kinase; OPDM, oculopharyngodistal myopathy; OPMD, oculopharyngeal muscular dystrophy; RAN, repeat-associated non-AUG; UTR, untranslated region. Received: 17 September 2022 Revised: 26 September 2022 Accepted: 4 October 2022