Progressive carotid artery stenosis with a novel tRNA phenylalanine mitochondrial DNA mutation

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Abstract

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a distinct clinical syndrome caused by mutations in the mitochondrial DNA. The pathogenesis of stroke-like episodes remains unknown but major vessels stenosis is not a cause of stroke-like episodes. We describe a novel heteroplasmic G617A transition in the mitochondrial transfer RNA phenylalanine gene in a patient with encephalomyopathy who presented with recurrent embolic ischemic strokes accompanied by transient occlusion of middle cerebral, anterior cerebral and internal carotid arteries. These ischemic strokes were presumed to be artery-to artery embolisms associated with carotid artery stenosis. Single muscle fiber analysis revealed the pathogenicity of the mutation although its causative role on carotid artery stenosis remains to be elucidated. This case expands phenotypic spectrum of mitochondrial disorders in terms of macroangiopathy, but macroangiopathy-related ischemic strokes should be distinguished from classic stroke-like episodes of MELAS that are speculated to be microangioapthy-related or non-ischemic neurovascular events.

Introduction

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a distinct clinical syndrome of respiratory-chain disorder caused by mutations in the mitochondrial DNA (mtDNA) [1]. Most of the mutations are located in the mitochondrial transfer RNA (tRNA)LEU(UUR) gene, but mutations in other tRNA genes or polypeptide-coding genes have been identified in MELAS or MELAS overlapping syndrome. Phenotypic–genotypic variation is emphasized accordingly, but the original definition of MELAS becomes blurred [2]. “Stroke-like episode” is a distinct feature of MELAS but it has never been clearly defined yet [3]. Thus, “stroke-like episode” or “ischemic stroke” may have been used ambiguously without clear distinction in mitochondrial disorders [4], [5]. We previously reported that stroke-like episodes of MELAS are non-ischemic neurovascular cellular events presumably associated with neuronal hyperexcitability, which is a different pathophysiology from ischemic stroke [2], [6], [7].

We now report on a case of mitochondrial encephalomyopathy with a novel mtDNA mutation, who presented with ischemic stroke accompanied by recurrent occlusion of major cervicocerebral arteries.

Section snippets

Case report

This 40-year-old left-handed Japanese man began to have brain infarction since the age of 35 years. He was the second son of unrelated parents. His mother and elder brother had no significant medical history including diabetes, hearing loss, headache or other symptoms associated with mitochondrial disorders. His farther had a history of ischemic heart disease. His psychomotor development appeared normal until 8 years when mental retardation and hearing impairment were noticed. He developed

Histopathological analysis

A biopsy specimen obtained from the left biceps brachii was processed for routine histochemical staining and immunostainings, including dsytrophin, sarcoglycan, dysferlin, caveolin 3, merosin, and collagen VI. Muscle biopsy showed myopathic changes with a few cytochrome c oxidase-negative ragged-red fibers (RRF), but strongly succinate dehydrogenase-reactive vessels were absent (Fig. 4). Some necrotic fibers were seen, but immunostainings were normal.

Genetic study

After informed consent from his family, genetic study was performed in this patient. DNA was isolated from blood by standard procedure, and direct sequencing of total mtDNA was performed. We applied the long PCR-based sequencing method to avoid nuclear pseudogene amplification. With 96 primer sets designed for sequencing, we obtained the reaction products using a big dye terminator cycle sequencing ready reaction kit (PE Applied Biosystems, USA), which were then analyzed with an ABI 3700

Discussion

This study provides three important implications in mitochondrial disorders. First, a novel G617A transition in the tRNA phenylalanine gene was identified in three members of this family examined and shown to be pathogenic in at least muscle pathology in this patient. Second, recurrent embolic strokes occur in mitochondrial disorders as macroangiopathy-related ischemic events. Third, progressive carotid artery stenosis could develop in mitochondrial disorders.

Regarding genetic study, at least 9

Acknowledgments

The authors have nothing to disclose regarding funding, conflicts of interest or commercial relationships including grants, honoraria, speaker's lists, significant ownership, or financial support from pharmaceutical or other companies.

A part of this study was presented at the 5th International Congress on vascular dementia, held in Budapest, Hungary, November 8–11, 2007.

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