The G13513A Mutation in the ND5 Gene of Mitochondrial DNA as a Common Cause of MELAS or Leigh Syndrome

Abstract

Background: The number of molecular causes of MELAS (a syndrome consisting of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) and Leigh syndrome (LS) has steadily increased. Among these, mutations in the ND5 gene (OMIM 516005) of mitochondrial DNA are important, and the A13513A change has emerged as a hotspot. Objective: To describe the clinical features, muscle pathological and biochemical characteristics, and molecular study findings of 12 patients harboring the G13513A mutation in the ND5 gene of mitochondrial DNA compared with 14 previously described patients with the same mutation. Design: Clinical examinations and morphological, biochemical, and molecular analyses. Setting: Tertiary care university hospital and molecular diagnostic laboratory. Patients: Three patients had the typical syndrome features of MELAS; the other 9 had typical clinical and radiological features of LS. Results: Family history suggested maternal inheritance in a few cases; morphological studies of muscle samples rarely showed typical ragged-red fibers and more often exhibited strongly succinate dehydrogenasereactive blood vessels. Biochemically, complex I deficiency was inconsistent and generally mild. The mutation load was relatively high in the muscle and blood specimens. Conclusion: The G13513A mutation is a common cause of MELAS and LS, even in the absence of obvious maternal inheritance, pathological findings in muscle, or severe complex I deficiency.

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

“…All these three patients manifested late-onset stroke-like episodes, similar to those G13513A causing MELAS patients reported by others. 23,24,37,38 In addition, a novel missense mutation, A11470C of complex I, was identified in an adult-onset MELAS patient (patient 10), in agreement with the notion that mutations of mitochondrial complex I genes have an important role in late-onset MELAS. Several aspects of the evidence can support etiologic role of the A11470C mutation.…”

“…Recently, an increasing number of cases with oxidative phosphorylation disease have been reported with MTND mutations, and among them, the G13513A mutation in MTND5 is the most frequently reported. 22,23 Three cases with MELAS/LS overlap syndrome carrying the G13513A mutation have been reported previously. 24,25 Four cases with childhood/juvenile onset MELAS/LS overlap syndrome (patients 4-7) reported in this study again stress that the G13513A mutation should be screened preferentially in patients with MELAS/LS overlap syndrome.…”

Molecular base of biochemical complex I deficiency

“…Three common mutations, m.3460G>A in ND1, m.11778G>A in ND4, and m.14484T>C in ND6 have been described, with the mutations in ND1 and ND6 being the hotspots for LHON (Chinnery et al, 2001;Valentino et al, 2004). Mutations in ND5, like m.13513G>A may cause mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (Santorelli et al, 1997;Shanske et al, 2008). However, the hotspot for MELAS is m.3243A>G in the tRNA leucine 1 gene.…”

Respiratory chain complex I deficiency caused by mitochondrial DNA mutations

“…Indeed, it was previously believed that complex I deficiency due to mtDNA mutations accounted for only 5-10% of paediatric complex I deficiency cases. 18,19 Recent screening of mitochondrial complex I subunit genes has shown mutations in mtDNA accounting for a much higher number of cases, [20][21][22][23][24][25][26][27] and therefore, its screening is an essential step in the genetic diagnosis of complex I deficiency. Previous studies assessing the prevalence of nuclear gene mutations in complex Ideficient paediatric cases have found the prevalence of these to also be high.…”