The expanding clinical and pathologic spectrum of mitochondrial DNA Polymerase gamma mutations

• Published in: The FASEB journal 2007-04, Vol.21 (5), p.A76-A76
• Main Authors: Farrell, Michael A, Howley, Rachel, Alderazi, Yazan, Brett, Francesca, Moroney, Joan, Raymond, Murphy
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.5.A76-c

Objective To report the clinicopathologic findings in adult patients with mitochondrial DNA polymerase gamma [POLG] mutations Background Since 2004 when POLG mutations were reported in Alpers' disease over 16 novel mutations have been described but clinicopathologic descriptions are rare. Materials & Methods Two unrelated adults developed intractable fatal status epilepticus [SE] with EEG and imaging evidence for a posterior parieto‐occipital seizure focus. Biochemical evidence of hepatocellular failure developed. Family history was positive for infantile Alpers' in one and negative for mitochondrial disease in the other. The POLG gene was PCR amplified using 15 primer sets spanning exons 3 to 23 of POLG. Analysis of sequence results was carried out using Blast 2 Sequences. A comprehensive autopsy examination was performed in each patient. Results Neuropathologic examination demonstrated parieto‐occipital cortical neuronal loss with gliosis and spongiform change with involvement also of s.nigra and dentate nucleus. Dorsal spino‐cerebellar degeneration was present in both as was liver cell necrosis with fatty change. One patient was homozygous for a mutation in exon 7 of POLG resulting in A467T: A467T and the other had mutations in exons 7 and 13 resulting in A467T: W748S. Conclusions Adult Alpers' should be considered in patients with intractable SE. Sequencing of the POLG gene allows rapid diagnosis. Spongiform change in the parieto‐occipital cortex and selective involvement of S. Nigra and dentate are characteristic. The spectrum of disorders secondary to defective mitochondrial DNA integrity is expanding.