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Original Contribution
January 2006

Association of Novel POLGMutations and Multiple Mitochondrial DNA Deletions With Variable Clinical Phenotypes in a Spanish Population

Author Affiliations

Authors Affiliations: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Facultad de Medicina, Universidad Autónoma de Madrid (Mr González-Vioque and Drs Bornstein, Fernández-Moreno, and Garesse), Centro de Investigación, Hospital Universitario 12 de Octubre (Messrs Blázquez and Fernández-Moreira and Drs Campos, Arenas, and Martín), and Servicio de Neurología, Hospital Universitario La Paz (Dr Arpa), Madrid, Spain; Servicio de Neurología, Hospital Virgen del Rocío, Sevilla, Spain (Dr Bautista); Servicio de Anatomía Patológica, Hospital Do Meixoeiro, Vigo, Spain (Dr Navarro).

Arch Neurol. 2006;63(1):107-111. doi:10.1001/archneur.63.1.107

Background  Both dominant and recessive mutations were reported in the gene encoding the mitochondrial (mt) DNA polymerase γ (POLG) in patients with progressive external ophthalmoplegia (PEO). Phenotypes other than PEO were recently documented in patients with mutations in the POLG gene.

Objective  To screen patients with mitochondrial disease and multiple mtDNA deletions in muscle for mutations in the coding regions of the POLG, PEO1, and SLC25A4genes.

Design  To identify the underlying molecular defect in a group of patients with multiple mtDNA deletions comparing their molecular genetic findings with those of healthy controls.

Patients  Twenty-four patients (16 men and 8 women) diagnosed with mitochondrial disease and having multiple mtDNA deletions in muscle by Southern blot analysis. Thirteen patients had PEO; 2 had PEO alone, 4 had PEO and myopathy, and 5 had PEO and multisystem involvement. Four patients had multisystem disease without PEO. The remaining 9 patients had isolated myopathy. DNA from 100 healthy individuals was also studied.

Results  No mutation was identified in the PEO1 or SLC25A4 genes. Nine POLG mutations were observed in 6 of 24 patients. Four novel mutations were detected and mapped in the linker region (M603L) and in the pol domain of the enzyme (R853W; D1184N; R1146C). Five patients with PEO had mutations: 2 were compound heterozygotes, 1 was homozygous, and another showed a mutation in a single allele. The remaining patient also showed a sole mutation and had an unusual phenotype lacking ocular involvement.

Conclusions  POLG molecular defects were found in 25% of our patients with multiple mtDNA deletions and mitochondrial disease. The uncommon phenotype found in 1 of these patients stresses the clinical variability of patients harboring POLG mutations. Molecular studies in the POLG gene should be addressed in patients with mitochondrial disease, particularly in those with PEO, and multiple mtDNA deletions.