Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation
ABSTRACT The authors studied a 47-year-old patient who presented with an association of deafness, acute cerebral stroke-like episode, leukoencephalopathy, and extensive basal ganglia calcifications. Late onset and neuroradiologic findings were atypical for MELAS syndrome (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike episodes). A heteroplasmic G to A transition at nucleotide 4332 in the tRNA glutamine gene was identified in the patient's muscle mitochondrial DNA. The pathogenicity of the mutation was shown in single muscle fibers by the correlation between high mutation load and cytochrome c oxidase defect.
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- "While we have focused on these two disorders, stroke-like episodes are known to occur in other acute, mitochondrial encephalopathies both due to different mitochondrial DNA mutations and to mutations in other nuclear genes. In the mitochondrial genome, this includes mutations in complex I subunits (Horvath et al., 2008) and in other mitochondrial transfer RNA genes (de Coo et al., 1998; Hanna et al., 1998; Bataillard et al., 2001; Jaksch et al., 2001) and large-scale mitochondrial DNA deletions (Yamashita et al., 2008). Mutations in other nuclear-encoded genes causing stroke-like episode include Twinkle (now known as C10orf2) (Lonnqvist et al., 2009) and LRPPRC (Debray et al., 2011). "
ABSTRACT: Mitochondrial dysfunction and disease may arise as a result of mutations in either the mitochondrial genome itself or nuclear encoded genes involved in mitochondrial homeostasis and function. Irrespective of which genome is affected, mitochondrial encephalopathies share clinical and biochemical features suggesting common pathophysiological pathways. Two common paradigms of mitochondrial encephalopathy are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes caused by maternally transmitted mutations of mitochondrial DNA and mitochondrial spinocerebellar ataxia and epilepsy caused by recessively inherited mutations of the nuclear-encoded DNA polymerase gamma, which replicates and repairs the mitochondrial genome. We studied and compared the disease mechanisms involved in these two syndromes. Despite having different genetic origins, their pathophysiological pathways converge on one critical event, damage to the respiratory chain leading to insufficient energy to maintain cellular homeostasis. In the central nervous system, this appears to cause selective neuronal damage leading to the development of lesions that mimic ischaemic damage, but which lack evidence of decreased tissue perfusion. Although these stroke-like lesions may expand or regress dynamically, the critical factor that dictates prognosis is the presence of epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. We believe that it is this cycle of events that determines outcome and which provides us with a mechanistic structure to understand the pathophysiology of acute mitochondrial encephalopathies and plan future treatments.Brain 10/2012; 135. DOI:10.1093/brain/aws223 · 10.23 Impact Factor
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- "Phenotype Mitochondrial gene Mutations References MELAS TRNA Leu(UUR) A3243G, T3271C, A3252G, C3256T, A3260G, T3291C (Goto et al., 1990, 1991, 1994; Morten et al., 1993; Nishino et al., 1996; Sato et al., 1994) tRNA Phe G583A (Hanna et al., 1998) tRNA Val G1642A (Taylor et al., 1996) tRNA Gln G4332A (Bataillard et al., 2001) tRNA Cys A5814G (Manfredi et al., 1995) "
ABSTRACT: Mitochondrial dysfunction has been identified as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Thus, a broad variety of mutation in mitochondrial DNA or nuclear genes leading to the impairment of mitochondrial respiratory chain or of mitochondrial ATP synthesis has been associated with epileptic phenotypes. Additionally, with a variety of different methods impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of animal models of temporal lobe epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca(2+) homeostasis, their dysfunction strongly affects neuronal excitability and synaptic transmission, which is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant temporal lobe epilepsy. Therefore, mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.Experimental Neurology 04/2009; 218(2):326-32. DOI:10.1016/j.expneurol.2009.02.014 · 4.62 Impact Factor
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ABSTRACT: Mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS) is a mitochondrial disorder and an important diagnostic consideration in the young patient with nonhemorrhagic stroke. Its presentation is varied and diagnosis is based on early recognition of the clinical features and correct interpretation of laboratory and radiologic studies. In this article, we report a patient with MELAS and review the clinical, laboratory, and neuroradiologic features of the condition. In the young patient with multiple stroke-like episodes in different vascular territories and neuroradiologic features of transient abnormalities in varying regions, laboratory testing for MELAS must be performed. The presence of ragged red fibers in skeletal muscle and biochemical demonstration of defects in mitochondrial respiratory enzymes strongly support the diagnosis. Molecular genetic testing for abnormalities in mitochondrial DNA will confirm the diagnosis. The importance of a thorough assessment of family history is also emphasized. The basic principles of mitochondrial genetics and the common point mutations and rearrangements of mitochondrial DNA associated with MELAS are reviewed. Although treatment options are limited, several therapeutic agents have been studied. The diagnosis of MELAS should be considered in the young patient with stroke, especially when accompanied by other clinical features such as seizures, encephalopathy, and muscle weakness. Laboratory evaluation can provide an accurate diagnosis, especially when the appropriate mitochondrial DNA studies are performed. Genetic counseling should be provided to patients with MELAS associated with mitochondrial DNA point mutations. Better understanding of the molecular basis of the condition may result in the development of effective treatment strategies.The Neurologist 10/2002; 8(5):302-12. DOI:10.1097/00127893-200209000-00003 · 1.08 Impact Factor