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

[Guest guest]

J Neurol. 2006 May 24

A new POLG1 mutation with peo and severe axonal and demyelinating

sensory-motor neuropathy.

Santoro L, Manganelli F, Lanzillo R, Tessa A, Barbieri F, Pierelli F,

Di Giacinto G, Nigro V, Santorelli FM.

Dipartimento di Scienze Neurologiche, Universita degli Studi di

Napoli " Federico II " , via Pansini 5, 80131, Napoli, Italia.

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.