title: A new POLG1 mutation with peo and severe axonal and demyelinating sensory-motor neuropathy.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Dipartimento di Scienze Neurologiche, Università degli Studi di Napoli Federico II, via Sergio Pansini 5, 80131, Napoli, Italia. lusantor@unina.it
authors.forename: L
authors.initials: L
authors.lastname: Santoro
authors.forename: F
authors.initials: F
authors.lastname: Manganelli
authors.forename: R
authors.initials: R
authors.lastname: Lanzillo
authors.forename: A
authors.initials: A
authors.lastname: Tessa
authors.forename: F
authors.initials: F
authors.lastname: Barbieri
authors.forename: F
authors.initials: F
authors.lastname: Pierelli
authors.forename: G
authors.initials: G
authors.lastname: Di Giacinto
authors.forename: V
authors.initials: V
authors.lastname: Nigro
authors.forename: F M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D000328:Adult; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D017246:Ophthalmoplegia, Chronic Progressive External / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D011129:Polyradiculoneuropathy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human