Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.
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Abstract:
Multiple deletions of mitochondrial DNA (mtDNA) have recently been reported in familial progressive external ophthalmoplegia (PEO), in a case of progressive encephalomyopathy, and in inherited recurrent myoglobinuria. The inheritance of familial PEO has been autosomal dominant, which indicates that a mutation in an unknown nuclear gene results in several mtDNA deletions of different sizes in these patients. We report a patient with autosomal dominant PEO, whose major clinical symptom, however, was severe retarded depression. The morphological analyses of the tissue samples derived from autopsy showed various abnormalities in the mitochondria in all the tissues studied. The activities of the respiratory chain enzymes encoded by mtDNA were remarkably reduced in the skeletal muscle. The mtDNA analyses confirmed that besides myopathy, this patient had a multisystem disorder with widespread distribution of multiple deletions of mtDNA. The highest percentage of mutated mtDNA was found in the brain, skeletal muscle and the heart, the relative quantity of mutated mtDNA correlating to the severity of the clinical symptoms.Keywords:
External ophthalmoplegia
Mitochondrial encephalomyopathy
Mitochondrial disease
Nuclear DNA
Mitochondrial diseases are characterized by heteroplasmic mitochondrial DNA mutations and multisystemic dysfunction. Base substitutions of mitochondrial DNA have been reported in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), 1,2 myoclonus epilepsy with ragged red fibers (MERRF), 3 and other neuromuscular disorders. 4 Heteroplasmic mitochondrial DNA deletions are usually detected in chronic external ophthalmoplegia, including Kearns-Sayre syndrome, 5 and on rare occasions in Pearson marrow-pancreas syndrome. 6 A few unusual clinical complexes associated with single mitochondrial DNA deletions have been reported, such as maternally transmitted diabetes and deafness, 7 diffuse leukodystrophy, 8 MELAS, Fanconi's syndrome,9 pure myopathy and neuropathy, 10 myopathy with lipomatosis, 11 and Leigh-type neuropathology. 12 We report here a patient with a large-scale mitochondrial DNA deletion, which was located at a novel site and produced an atypical Kearns-Sayre syndrome phenotype. The major clinical sign at the early stage was not ophthalmoplegia, but cerebellar ataxia.
Heteroplasmy
Mitochondrial encephalomyopathy
MELAS syndrome
Lactic acidosis
Mitochondrial disease
External ophthalmoplegia
Cerebellar ataxia
Myoclonic epilepsy
Kearns–Sayre syndrome
Mitochondrial Encephalomyopathies
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Clinical neurology
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Mitochondrial disease
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External ophthalmoplegia
Mitochondrial encephalomyopathy
Kearns–Sayre syndrome
Southern blot
Nuclear DNA
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Neuroradiology
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Multiple deletions of mitochondrial DNA (mtDNA) have recently been reported in familial progressive external ophthalmoplegia (PEO), in a case of progressive encephalomyopathy, and in inherited recurrent myoglobinuria. The inheritance of familial PEO has been autosomal dominant, which indicates that a mutation in an unknown nuclear gene results in several mtDNA deletions of different sizes in these patients. We report a patient with autosomal dominant PEO, whose major clinical symptom, however, was severe retarded depression. The morphological analyses of the tissue samples derived from autopsy showed various abnormalities in the mitochondria in all the tissues studied. The activities of the respiratory chain enzymes encoded by mtDNA were remarkably reduced in the skeletal muscle. The mtDNA analyses confirmed that besides myopathy, this patient had a multisystem disorder with widespread distribution of multiple deletions of mtDNA. The highest percentage of mutated mtDNA was found in the brain, skeletal muscle and the heart, the relative quantity of mutated mtDNA correlating to the severity of the clinical symptoms.
External ophthalmoplegia
Mitochondrial encephalomyopathy
Mitochondrial disease
Nuclear DNA
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Citations (237)
Heteroplasmy
Mitochondrial Encephalomyopathies
Mitochondrial encephalomyopathy
Mitochondrial disease
Human mitochondrial genetics
Kearns–Sayre syndrome
Mitochondrial respiratory chain
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Heteroplasmy
External ophthalmoplegia
Mitochondrial disease
Muscle weakness
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Mitochondrial diseases are a large group of disorders resulting from mutations of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Patients present clinically with multiple manifestations, including myopathies and multiple system disorders. Establishing a specific diagnosis often requires extensive clinical and laboratory evaluation. In this study of 2 adult patients with presumptive mitochondrial disease, the authors have identified distinctive morphological changes in medial rectus muscle biopsies that confirm the diagnosis of chronic progressive external ophthalmoplegia (CPEO). These findings demonstrate the usefulness of electron microscopy using medial rectus muscle in the diagnosis of adult patients with a slowly progressive course of mild skeletal weakness and CPEO.
Mitochondrial disease
External ophthalmoplegia
Muscle weakness
Kearns–Sayre syndrome
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