Mitochondrial DNA (mtDNA) Multiple Deletions: mtDNA Analysis by Massively Parallel Sequencing (P07.020)
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Abstract
OBJECTIVE: To search for mtDNA defects in 18 unrelated patients with suspected mitochondrial disorder on the basis of clinical phenotype and/or histological evidence for mitochondrial myopathy.
BACKGROUND: The molecular diagnosis of many patients with mitochondrial disorder remains elusive. Defects in the mtDNA can be easily detected by the recently developed one-step comprehensive massively parallel sequencing (LR-PCR/MPS) based analysis for simultaneous detection of mtDNA point mutations and large mtDNA deletions with heteroplasmy quantification.
DESIGN/METHODS: We tested muscle of 2 groups of patients, age 21-72 years, by LR-PCR/MPS. Group #1 included 11 patients with myopathy alone or associated with progressive external ophthalmoplegia and/or peripheral neuropathy, 10 of whom had histological evidence for mitochondrial myopathy. Group #2 included 7 patients with central and peripheral nervous system involvement, 4 with mitochondrial myopathy on biopsy and 3 with normal muscle biopsy. Two patients from group #1 and 4 patients from group #2 had negative mtDNA common point mutations and deletion screening by traditional PCR/ASO and Southern blot, respectively.
RESULTS: Group #1: All 11 patients showed multiple mtDNA deletions; in addition, 3 patients carried a primary pathogenic mtDNA mutation. Group #2: 3 patients had multiple mtDNA deletions and 2 of them, age 38, carried also pathogenic mtDNA missense mutations; 2 patients harbored pathogenic mtDNA missense mutations associated with a large scale deletion in one; 2 subjects (age 32 and 55 years, respectively) showed normal mtDNA.
CONCLUSIONS: Histological signs of mitochondrial myopathy are likely to be accompanied by mtDNA deletions or point mutations. While the etiology of multiple deletions is indeterminate and requires nuclear genes analysis, mtDNA deletions accompanying pathogenic point mutations, independently from patient's age, may contribute to the phenotypic severity. The increased sensitivity of LR-PCR/MPS might decrease specificity of the mtDNA deletions as finding suggestive of defects in nuclear genes affecting mtDNA maintenance.
Supported by: The Mayo Clinic CTSA through grant number UL1 RR024150 from NIH/NCRR.
Disclosure: Dr. Milone has nothing to disclose. Dr. Li has nothing to disclose. Dr. Tian has nothing to disclose. Dr. Folger has nothing to disclose. Dr. Weinshenker has received personal compensation for activities with Novartis, Biogen Idec, Elan Corporation, GlaxoSmithKline Inc., Asahi Kasei Kuraray Medical Company as a consultant and/or participant on a data safety monitoring board. Dr. Weinshenker has received (royalty or license fee or contractual rights) payments from Mayo Medical Ventures. Dr. Li has nothing to disclose.
Thursday, March 21 2013, 2:00 pm-7:00 pm
- Copyright © 2013 by AAN Enterprises, Inc.
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