Oculopharyngodistal myopathy-2 (OPDM2) is an autosomal dominant muscle disorder characterized by onset of distal muscle weakness, mainly of the lower limbs, and/...
Oculopharyngodistal myopathy-2 (OPDM2) is an autosomal dominant muscle disorder characterized by onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. The disorder is slowly progressive, and patients develop facial weakness, bulbar weakness, and difficulty walking or climbing stairs. Some patients may have upper limb involvement and subclinical respiratory insufficiency. Laboratory studies show increased serum creatine kinase; skeletal muscle biopsy shows myopathic changes with abnormal cytoplasmic and intranuclear inclusions (summary by Deng et al., 2020).
For a discussion of genetic heterogeneity of OPDM, see OPDM1 (164310).
▼ Clinical Features
Lu et al. (2008) reported a multigenerational Chinese family in which 6 individuals had OPDM. The proband was a 24-year-old woman who had insidious onset of distal muscle weakness at age 22. The disorder was progressive, and she developed external ophthalmoplegia, dysphagia, dysarthria, bulbar muscle weakness, facial muscle weakness, and distal muscle weakness and atrophy of all 4 limbs, resulting in poor grasp and walking difficulties. Serum creatine kinase was increased, and EMG showed a myopathic pattern. Skeletal muscle biopsy showed rimmed vacuoles with tubulofilamentous inclusions in both the sarcoplasm and nucleus, as well as connective tissue proliferation. The other affected family members had a similar phenotype.
Deng et al. (2020) reported OPDM2 in multiple affected members of 3 unrelated Chinese families and 7 unrelated Japanese families, as well as in 9 Chinese patients with sporadic disease. Family 1 had previously been reported by Lu et al. (2008) and Zhao et al. (2015), and 3 patients with sporadic disease had been reported by Zhao et al. (2015). Clinical details were provided for 12 probands reported by Deng et al. (2020). The patients presented at a mean age of 27 years (range 14 to 38) with distal muscle weakness, ptosis, or eye muscle weakness. The disorder was slowly progressive, and all patients eventually developed the full phenotype, which included ophthalmoparesis, facial and bulbar muscle weakness, dysphagia, nasal voice, and distal limb muscle weakness and atrophy resulting in gait difficulties. Both upper and lower limbs could be affected; at least 1 patient was wheelchair-bound at age 35. Laboratory studies showed increased serum creatine kinase and myopathic changes on EMG. Muscle imaging of affected muscles showed fatty replacement. Skeletal muscle biopsy showed a myopathic pattern with fiber size variation, endomysial fibrosis, and rimmed vacuoles containing p62 (SQSTM1; 601530)-positive inclusions. Electron microscopic studies showed that the rimmed vacuoles contained myeloid bodies and tubulofilamentous inclusions; intranuclear inclusions containing filamentous aggregates were also observed.
Xi et al. (2021) reported 28 patients with OPDM2, including 18 patients from 4 unrelated families and 10 patients with sporadic disease. Sixteen of the 28 patients had initial symptoms of lower limb weakness. Eighteen patients had ptosis, 19 had ophthalmoparesis, 24 had facial palsy or atrophy, 22 had bulbar symptoms, 18 had proximal weakness, and 14 had joint contractures. Three patients had cardiac involvement. All 28 patients had distal weakness. Of 21 patients who had EMGs, 7 had myotonic changes and 3 had neurogenic changes. Rimmed vacuoles were seen on muscle biopsy in 14 of 17 patients. Xi et al. (2021) compared clinical features in the 28 patients with OPDM2 and GPC1 repeat expansions to 13 patients with OPDM without GPC1 repeat expansions and found no difference between gender, age at onset, disease duration, initial symptoms, and weakness distribution. However, none of the patients without GPC1 repeat expansions had cardiac involvement.
The transmission pattern of OPDM2 in the families reported by Deng et al. (2020) was consistent with autosomal dominant inheritance. There was no evidence of genetic anticipation, although there was some suggestion of incomplete penetrance.
▼ Molecular Genetics
In affected members of 3 unrelated Chinese families (families 1, 7, and 8) with OPDM2, Deng et al. (2020) identified a heterozygous trinucleotide repeat expansion in the 5-prime untranslated region of the GIPC1 gene (GGC(n); 605072.0001). The expansion, which was found by a combination of linkage analysis, long-range sequencing, and PCR analysis, segregated with the disorder in the families. Further analysis of patient cohorts identified the same heterozygous repeat expansion in 9 additional Chinese patients with sporadic disease and in 7 Japanese OPDM probands. RNA sequencing of patient cells showed differential regulation of several genes. Deng et al. (2020) hypothesized that elevated GIPC1 mRNA levels with the transcribed expanded GGC repeats may result in RNA toxicity, although they suggested that it may not matter which gene is involved.
Xi et al. (2021) identified a heterozygous trinucleotide repeat in noncoding exon 1 of the GIPC1 gene (CGG(n)) in 28 patients with OPDM2, including 18 patients from 4 unrelated families and 10 patients with sporadic disease. The expansion, which was found by a combination of linkage analysis, long-range sequencing, whole-exome sequencing, and PCR analysis in family 1, segregated with the disorder in the family. The additional patients were identified by direct analysis of the CGG repeat length in the GIPC1 gene. Repeat lengths in the patients ranged from 70 to 138. Both repeat size expansion and retraction were observed in parent-to-offspring transmission.
▼ Genotype/Phenotype Correlations
Xi et al. (2021) identified a slight correlation between the age of onset of OPDM2 and size of a CGG triplet repeat (605072.0001) in noncoding exon 1 of the GIPC1 gene.