LAUSR

Oculopharyngodistal myopathy (OPDM) is a slowly progressive adult-onset muscle disease characterized by ptosis, ophthalmoparesis, dysphagia, and weakness of the facial, masseter, bulbar, and distal limbs muscles [1]. Ishiura et al. revealed that OPDM is caused by noncoding CGG repeat expansions in the low-density lipoprotein receptor-related protein 12 gene (LRP12) [2]. Ishiura et al. also found similar noncoding CGG repeat expansions in two clinically similar conditions: neuronal intranuclear inclusion disease (NIID) and oculopharyngeal myopathy with leukoencephalopathy (OPML), in the NBPF19 (NOTCH2NLC) and LOC642361/NUTM2B-AS1 genes, respectively [2]. As is the case between NIID and OPML as well as between OPML and OPDM, clinical or pathological similarities between OPDM and NIID are also expected. In fact, the presence of neuronal intranuclear inclusions in OPDM patients has been demonstrated [3,4]. However, the findings in neuromuscular tissues, such as the sural nerve, where biopsies are often performed, are not yet established. Here, we report a genetically confirmed case of OPDM that shared clinicopathological neuromuscular characteristics with NIID (Fig. 1A). A 70-year-old man without a family history of neuromuscular disease presented with an eight-year history of hoarseness and dysphagia, followed by bilateral ptosis and weakness and atrophy of the muscle of the distal upper limb, as well as paresthesia in the toes of both feet. His past medical history included juvenile baldness, sick sinus syndrome with atrial fibrillation, and bilateral cataracts. Neurological examination revealed limited horizontal eye movements. Further examination revealed a myopathic face with facial muscle atrophy and bilateral ptosis, bilateral muscle weakness in the distal upper extremities, atrophic thenar and hypothenar muscles, and absent deep tendon reflexes in all four extremities. The other examinations revealed normal findings. Laboratory study results were normal, except for an elevated serum creatine kinase level of 339 IU/L. Brain magnetic resonance imaging did not reveal leukoencephalopathy. Computed tomography revealed bilateral partial adipose tissue replacement of the paraspinal and gastrocnemius muscles. The patient underwent a biopsy of the biceps brachii muscle, which revealed variation in the fiber size, increased number of internalized nuclei, scattered pyknotic nuclear clumps, and occasional atrophic fibers with rimmed vacuoles. No necrotic or inflammatory changes or ragged red fibers were observed. At age 80 years, he was admitted for heart failure, which improved after diuretic therapy. At this time, he exhibited evident limited eye movements in all directions, bulbar weakness, and distal-predominant muscle atrophy as well as distal paresthesia. The patient had daytime hypercapnia, with a pCO2 of 52 mmHg on arterial blood gas analysis. His vital capacity by spirometry was 40.1% of the predicted value. Nerve conduction studies disclosed mixed axonal and demyelinating features characterized by reduction of amplitude of motor and sensory action potentials and conduction slowing, which were more prominent in his lower extremities. Needle electromyography disclosed fibrillation potentials and positive sharp waves in the biceps brachii and tibialis anterior muscles. Blood tests did not identify an underlying cause for the neuropathy. To examine the cause of the unexpected symptoms and findings suggesting neuropathy, biopsies of the biceps brachii muscle and sural nerve were performed. The histopathological findings of the muscle were similar to those of his first biopsy (Fig. 1B). Immunohistochemistry revealed a few p62and ubiquitinimmunoreactive intramyonuclear inclusions. The sural nerve showed severe axonal loss (Fig. 1C). Even here, p62-immunoreactive intranuclear inclusions in fibroblasts were observed (Fig. 1D). Further, electron microscopy demonstrated intranuclear aggregations consisting of haphazardly arranged filaments of 10to 15-nm diameter, admixed with granular substances, in the fibroblasts of both biceps brachii muscle and sural nerve. (Fig. 1E–F). Subsequently, genetic analysis using repeat-primed polymerase chain reaction and Southern blot demonstrated CGG repeat expansion (106 CGG repeats) in the LRP12 gene (Fig. 1A). CTG repeat expansion in the DMPK gene was 12 and 13, thus, within the normal range. The patient followed a clinical course typical of OPDM, and