A new POLG1 mutation with peo and severe axonal and demyelinating sensory-motor neuropathy

L. Santoro, F. Manganelli, R. Lanzillo, A. Tessa, F. Barbieri, F. Pierelli, G. Di Giacinto, V. Nigro, F. M. Santorelli

Research output: Contribution to journalArticlepeer-review


Background: Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with defective enzymatic activities of oxidative phosphorylation (OXPHOS), depletion of mitochondrial DNA (mtDNA) and/or accumulation of mtDNA mutations and deletions. Recent positional cloning studies have linked the disease to four different chromosomal loci. Mutations in POLG1 are a frequent cause of this disorder. Methods: We describe two first-cousins: the propositus presented with PEO,mitochondrial myopathy and neuropathy, whereas his cousin showed a Charcot- Marie-Tooth phenotype. Neurophysiological studies, peroneal muscle and sural nerve biopsies, and molecular studies of mtDNA maintenance genes (ANT1, Twinkle, POLG1, TP) and non dominant CMT-related genes (GDAP1, LMNA, GJB1) were performed. A severe axonal degeneration was found in both patients whereas hypomyelination was observed only in the patient with PEO whose muscle biopsy specimen also showed defective OXPHOS and multiple mtDNA deletions. While no pathogenetic mutations in GDAP1, LMNA, and GJB1 were found, we identified a novel homozygous POLG1 mutation (G763R) in the PEO patient. The mutation was heterozygous in his healthy relatives and in his affected cousin. Conclusions: A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory-motor neuropathy. Most likely, his cousin had an axonal polyneuropathy with CMT phenotype of still unknown etiology.

Original languageEnglish
Pages (from-to)869-874
Number of pages6
JournalJournal of Neurology
Issue number7
Publication statusPublished - Jul 2006


  • Mitochondrial disorders
  • Neuropathy
  • PEO
  • POLG1

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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