Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases

Byung-Ok Choi,Ki Wha Chung,Jung Hee Hwang,Eun Hye Jeong,Nam Soo Cho,Eun Min Cho,Young Se Hyun,Hyeon Jeong Jeon,Ki Min Seong

doi:10.3858/emm.2010.42.6.046

Abstract

Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make the exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mtDNA mutations in 61 Korean unrelated families (or isolated patients) with MELAS or MERRF. In particular, the mtDNA sequences were completely determined for 49 patients. From the mutational analysis of mtDNA obtained from blood, 5 confirmed pathogenic mutations were identified in 17 families, and 4 unreported pathogenically suspected mutations were identified in 4 families. The m.3243A>G in the tRNA(Leu(UUR))was predominantly observed in 10 MELAS families, and followed by m.8344A>G in the tRNA(Lys) of 4 MERRF families. Most pathogenic mutations showed heteroplasmy, and the rates were considerably different within the familial members. Patients with a higher rate of mutations showed a tendency of having more severe clinical phenotypes, but not in all cases. This study will be helpful for the molecular diagnosis of mitochondrial diseases, as well as establishment of mtDNA database in Koreans.

Highlights

Mitochondrial diseases are clinically and genetically a very heterogeneous disorder group
The frequent mitochondrial disorders caused by the point mutations of mitochondrial DNA (mtDNA) are mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS, MIM# 540000), and myclonus epilepsy with ragged-red fibers (MERRF, MIM# 545000)
The m.3243A>G in the tRNALeu(UUR) (21.3%) and the m.8344A>G in the tRNALys (33.3%) were the most frequently identified in Korean MELAS and myoclonus epilepsy with ragged-red fibers (MERRF) patients, respectively

Summary

Introduction

Mitochondrial diseases are clinically and genetically a very heterogeneous disorder group. Some mitochondrial disorders only affect a single organ, such as the eye in Leber hereditary optic neuropathy (LHON), but most diseases involve multiple organ systems and often typically manifest in tissues with high-energy demand, e.g., nerve and muscle. The multi-organ involvement and overlapping of symptoms among mitochondrial disorders make the exact diagnosis and classification difficult. The second group is composed of the rearrangements of mtDNA, such as duplication or large deletion, which are usually either maternally inherited or sporadic (Schmiedel et al, 2003). The frequent mitochondrial disorders caused by the point mutations of mtDNA are mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS, MIM# 540000), and myclonus epilepsy with ragged-red fibers (MERRF, MIM# 545000)

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