P.79 Late onset oculopharyngeal muscular dystrophy in a POLG1-related progressive external ophthalmoplegia (PEO), a diagnostic challenge

Abstract

POLG1, a nuclear gene, encodes the catalytic subunit of mitochondrial DNA polymerase γ involved in mtDNA maintenance. Autosomal dominant or recessive inherited phenotypes related to POLG1 mutations display clinical variability, including isolated or syndromic progressive external ophthalmoplegia (PEO). Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy characterized by progressive ptosis, dysphagia, and limb weakness. In OPMD patients, the 5’ (GCN)10 repeat region of the PABPN1 gene is abnormally expanded up to 17 repeats. The (GCN)11 enlarged repeat allele is described as a polymorphism or a recessive allele. However, rare cases of patients with a single (GCN)11 heterozygous allele are known to express a late-onset OPMD phenotype. Reporting a patient associating POLG1 compound heterozygous mutations and a PABPN1 (GCN)11 heterozygous expansion with mixed phenotype, we aim to point out the potential clinical overlap and diagnostic challenge linked to these entities. A 74-year-old male patient presented with progressive bilateral ptosis and mild dysphagia at the age of 70. CK and lactate levels were normal. Electrodiagnostic tests demonstrated a mild sensory neuropathy and muscle biopsy showed atrophic and necrotic fibers, increased internal nuclei and twelve COX-negative fibers. Electron microscopy identified electrodense deposits in mitochondria but no intranuclear inclusions. Muscle oxidative phosphorylation analyses demonstrated complexes I and II diminished activities. POLG1 sequencing revealed the previously described c.1760C>T, p.(Pro587Leu) pathogenic variant and the c.233T>A, p.(Met78Lys) novel variant. Segregation study allowed to conclude a trans conformation in the proband. We report a patient presenting with progressive ptosis associated with two potential coexisting etiologies ascertained by polemic evidence. On one hand, biallelic variants were found on his POLG1 gene, associated with features of mitochondrial defects on muscle biopsy. On the other hand, the phenotype also fits with OPMD and is associated with a PABPN1 (GCN)11 heterozygous expansion allele. This peculiar observation illustrates the potential diagnostic challenge that may represent a progressive ptosis, especially in elderly patients. POLG1, a nuclear gene, encodes the catalytic subunit of mitochondrial DNA polymerase γ involved in mtDNA maintenance. Autosomal dominant or recessive inherited phenotypes related to POLG1 mutations display clinical variability, including isolated or syndromic progressive external ophthalmoplegia (PEO). Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy characterized by progressive ptosis, dysphagia, and limb weakness. In OPMD patients, the 5’ (GCN)10 repeat region of the PABPN1 gene is abnormally expanded up to 17 repeats. The (GCN)11 enlarged repeat allele is described as a polymorphism or a recessive allele. However, rare cases of patients with a single (GCN)11 heterozygous allele are known to express a late-onset OPMD phenotype. Reporting a patient associating POLG1 compound heterozygous mutations and a PABPN1 (GCN)11 heterozygous expansion with mixed phenotype, we aim to point out the potential clinical overlap and diagnostic challenge linked to these entities. A 74-year-old male patient presented with progressive bilateral ptosis and mild dysphagia at the age of 70. CK and lactate levels were normal. Electrodiagnostic tests demonstrated a mild sensory neuropathy and muscle biopsy showed atrophic and necrotic fibers, increased internal nuclei and twelve COX-negative fibers. Electron microscopy identified electrodense deposits in mitochondria but no intranuclear inclusions. Muscle oxidative phosphorylation analyses demonstrated complexes I and II diminished activities. POLG1 sequencing revealed the previously described c.1760C>T, p.(Pro587Leu) pathogenic variant and the c.233T>A, p.(Met78Lys) novel variant. Segregation study allowed to conclude a trans conformation in the proband. We report a patient presenting with progressive ptosis associated with two potential coexisting etiologies ascertained by polemic evidence. On one hand, biallelic variants were found on his POLG1 gene, associated with features of mitochondrial defects on muscle biopsy. On the other hand, the phenotype also fits with OPMD and is associated with a PABPN1 (GCN)11 heterozygous expansion allele. This peculiar observation illustrates the potential diagnostic challenge that may represent a progressive ptosis, especially in elderly patients.