Identification of novel mutations in five patients with mitochondrial encephalomyopathy

Abstract

MELAS, MERRF, LHON and NARP, are well-established mitochondrial syndromes associated with specific point mutations of mitochondrial DNA (mtDNA). However, these recurrent mtDNA mutations account for only a minority of mitochondrial disease cases. To evaluate the impact of novel mtDNA mutations, we performed mtDNA sequence analysis in muscle and other tissues of 240 patients with different mitochondrial neuromuscular syndromes. We identified a total of 33 subjects with novel, private or uncommon mutations. Among these, five novel mutations were found in both paediatric and adult cases. We here report on the clinical description of these patients, as well as the biochemical and molecular genetic characterization of the corresponding mutations. Patients 1 and 2 showed changes in ND genes, patient 3 carried a heteroplasmic deletion in the COI gene, patients 4 and 5 carried heteroplasmic mutations in tRNA(Trp) and tRNA(Phe), respectively. Altogether, these data indicate that mtDNA analysis must become part of the routine screening for mitochondrial disorders.

Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

“…The T10191C mutation, detected in patient 2 in this study, was first reported in a patient that presented with a progressive Leigh-like clinical picture of epilepsy, strokes, optic atrophy and cognitive decline by Taylor et al 32 Subsequently, several MELAS or LS patients were reported carrying the T10191C mutation. 31,[33][34][35] The clinical features of patient 2 in the present study conformed with typical MELAS but her brain MRI showed lesions in both cerebral cortex and midbrain, suggesting that a diagnosis of MELAS/LS overlap syndrome was more appropriate. Patient 3 presented a similar clinical picture as patient 2, with a final diagnosis of MELAS/LS overlap syndrome based on the combination of clinical manifestations and brain MRI findings.…”

Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine

“…Recombination of the iron-coordinated sulfur leads to formation of a cyclic-peroxo intermediate [5]. Homolytic cleavage of the O-O bond results in a sulfoxy-cation and an Fe(II)-activated oxygen [6]. Recombination [7] followed by hydrolysis yields the products, sulfite and GSH [8], and restore the enzyme to its resting state [1].…”

“…The latter, via resonance, gives a radical cation character to the coordinated sulfane sulfur on the substrate [4]. Recombination of the superoxo and sulfur radical species yields a cyclic peroxo intermediate [5], followed by homolytic cleavage of the O-O bond resulting in a sulfoxy-cation intermediate and an Fe(II)-bound activated oxygen [6]. Recombination of the activated oxygen and the sulfoxy-cation yields the GSSO 2 -intermediate [7], which is hydrolyzed to give the products, sulfite and GSH [8].…”

“…EE is caused by mutations in the ethe1 gene that encodes persulfide dioxygenase (PDO or ETHE1). Over 20 mutations have been described in the ethe1 gene, of which a subset represents missense mutations (3,4,6).…”

“…EE is caused by mutations in the ethe1 gene that encodes persulfide dioxygenase (PDO or ETHE1). Over 20 mutations have been described in the ethe1 gene, of which a subset represents missense mutations (3,4,6).PDO is a mitochondrial matrix protein that participates in the mitochondrial sulfide oxidation pathway, which converts H 2 S to the end products, thiosulfate and sulfate (7,8). In addition to PDO, the other enzymes involved in the mitochondrial sulfur oxidation pathway are sulfide quinone oxidoreductase (9), rhodanese (10), and sulfite oxidase (11).…”