POLG-Related Disorders: Muscle Biopsy Findings, Mitochondrial DNA Content and Deletions (P07.206)

Abstract

Objective: To correlate clinical findings with muscle histological and molecular data in 19 patients with POLG-related disorder. Background POLG encodes for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma. Mutations in POLG result in a spectrum of clinical phenotypes varying from Alpers syndrome to ataxia-peripheral neuropathy (PN) syndrome to progressive external ophthalmoplegia (PEO). Design/Methods: Review of clinical and muscle histological findings, quantitation of mtDNA in blood and/or muscle by qPCR, search for mtDNA multiple deletions in muscle and/or blood by Southern blot and/or PCR. Results: 1. Four patients with Alpers syndrome had normal muscle biopsy. All had normal mtDNA content in blood; 1/4 had mtDNA depletion in muscle; none of them had mtDNA deletions in muscle. All 4 patients were compound heterozygous for two missense mutations. 2. Twelve patients with PEO and myopathy accompanied by PN in 9 and stroke and epilepsy in 2, had normal mtDNA content in blood. Eleven patients had muscle biopsy showing mitochondrial myopathy only in 9. One patient had mtDNA depletion and deletions in muscle; another had multiple deletions in both muscle and blood, and 3 others had multiple mtDNA deletions in muscle but not in blood. Two patients were homozygous for missense mutations and 10 were compound heterozygous for missense or splice-site mutations. 3. Two patients with PN and ataxia had no histological signs of mitochondrial myopathy. One patient was homozygous for p.A467T and the other was a compound heterozygous for two missense mutations. 4. A patient with intractable epilepsy and stroke-like events had COX (-) fibers, no mtDNA deletions in blood and normal muscle mtDNA. This patient carried two missense mutations. Conclusions: Sequencing of POLG was the most reliable diagnostic test in Alpers syndrome. Histological signs of mitochondrial dysfunction did not correlate with mtDNA depletion or deletions. Supported by: Mayo Clinic CTSA through grant number UL1 RR024150 from NIH/NCRR. Disclosure: Dr. Milone has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Sorenson has nothing to disclose. Dr. Zhiyv has nothing to disclose. Dr. Wong has nothing to disclose.