Abstract
Mutations in the gene encoding the catalytic subunit of polymerase γ (POLG1) are a major cause of human mitochondrial disease. More than 150 different point mutations in the gene have been reported to be disease causing, resulting in a large range of clinical symptoms. Depending on the mutation or combination of mutations, disease onset can occur in early infancy or late in adult life. Here, we describe the use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect deletions within POLG1, which could otherwise go undetected by solely sequencing of the gene. We present a case where an entire POLG1 allele is deleted, with a known pathogenic mutation (W748S) on the remaining allele. The deletion was found in a boy with Alpers syndrome, presenting at 18 months of age with slightly retarded motor development, balance problems, and seizures. Administration of valproic acid (VPA) led to rapidly progressive fatal liver failure in our patient, and we would like to highlight the need to carry out complete POLG1 gene analysis before administration of VPA in cases of pediatric seizure disorders of unknown origin. Debut and severity of the disease in this patient was unique when compared to homozygous or heterozygous patients with the W748S mutation, leading to the conclusion that gene dosage plays a role in the clinical phenotype of this disease.
Competing interests: None declared.
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Acknowledgments
The authors acknowledge Dr. Maria Kristoffersen Wiberg for interpretation of MRI, Prof Anna Wedell for helpful discussions, MRC Holland for carrying out the MLPA analysis with the P010 kit, and the excellent technical assistance of Vahid Edrisi.
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Communicated by: Wolfgang Sperl.
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Synopsis
Monoallelic expression of POLG1 with W748S leads to a more severe Alpers disease compared to patients homozygous for the W748S mutation, hence, POLG1 gene dosage appears to be an important determinant of the phenotype in POLG disease.
Author Contributions
Karin Naess: Designing the study, interpretation of data, and writing of article
Michela Barbaro: Analysis and interpretation of data, drafting of article
Helene Bruhn: Analysis and interpretation of data
Rolf Wibom: Analysis and interpretation of data
Inger Nennesmo: Analysis and interpretation of data
Ulrika von Döbeln: Contributed to study design, drafting of article
Nils-Göran Larsson: Revising article critically for important intellectual content
Antal Nemeth: Collection and interpretation of data, drafting of article
Nicole Lesko: Designing the study, analysis and interpretation of data, and writing of article
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Nicole Lesko
The authors declare no conflict of interest.
Financial support was given through the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet.
The study was approved by the regional ethics committee in Stockholm, Sweden.
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Naess, K. et al. (2011). Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome. In: JIMD Reports - Case and Research Reports, 2012/1. JIMD Reports, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_73
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DOI: https://doi.org/10.1007/8904_2011_73
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