MELAS: Clinical features, biochemistry, and molecular genetics

H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia-Presbyterian Medical Center, New York, NY.
Annals of Neurology (Impact Factor: 9.98). 04/1992; 31(4). DOI: 10.1002/ana.410310408


We studied 23 patients with clinically defined mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), 25 oligosymptomatic or asymptomatic maternal relatives, and 50 mitochondrial disease control subjects for the presence of a previously reported heteroplasmic point mutation at nt 3,243 in the transfer RNALeu(UUR) gene of mitochondrial DNA. We found a high concordance between clinical diagnosis of MELAS and transfer RNALeu(UUR) mutation, which was present in 21 of the 23 patients with MELAS, all 11 oligosymptomatic and 12 of 14 asymptomatic relatives, but in only five of 50 patients without MELAS. The proportion of mutant genomes in muscle ranged from 56 to 95% and was significantly higher in the patients with MELAS than in their oligosymptomatic or asymptomatic relatives. In subjects in whom both muscle and blood were studied, the percentage of mutations was significantly lower in blood and was not detected in three of 12 asymptomatic relatives. The activities of complexes I + III, II + III, and IV were decreased in muscle biopsies harboring the mutation, but there was no clear correlation between percentage of mutant mitochondrial DNAs and severity of the biochemical defect.

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    • "The key parameters of the Kimura distribution during transmission were determined by studying 87 human mother–offspring pairs transmitting a known pathogenic mtDNA mutation (Wonnapinij et al., 2010). This parameter value was set at b = 0.66 based on 87 human mother–offspring pairs (Lott et al., 1990; Ciafaloni et al., 1992; Larsson et al., 1992; Martinuzzi et al., 1992; Tatuch et al., 1992; Zhu et al., 1992; Hammans et al., 1993, 1995; Piccolo et al., 1993; Howell et al., 1994; Santorelli et al., 1994; Harding et al., 1995; Houstek et al., 1995; Makelabengs et al., 1995; Black et al., 1996; Mak et al., 1996; Carelli et al., 1997; Uziel et al., 1997; Olsson et al., 1998; Onishi et al., 1998; Tanaka et al., 1998; Chinnery et al., 1999; White et al., 1999; Lien et al., 2001; Porto et al., 2001; Hurvitz et al., 2002; Wong et al., 2002; Kaplanova et al., 2004; Enns et al., 2006; Phasukkijwatana et al., 2006), including the following mutations: m.3243A>G (15 pairs), m.83446A>G (10 pairs), m.11778G>A (23 pairs), m.3460G>A (15 pairs), m.9883T>C (10 pairs) and m.8993T>G (14 pairs). Data from the A3243G mutation taken from blood samples were adjusted to correct for the known decrease in the A3243G mutation level in blood with age (Rajasimha et al., 2008). "
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    ABSTRACT: Mitochondrial medicine is one of the few areas of genetic disease where germ-line transfer is being actively pursued as a treatment option. All of the germ-line transfer methods currently under development involve some carry-over of the maternal mitochondrial DNA (mtDNA) heteroplasmy, potentially delivering the pathogenic mutation to the offspring. Rapid changes in mtDNA heteroplasmy have been observed within a single generation, and so any 'leakage' of mutant mtDNA could lead to mtDNA disease in future generations, compromising the reproductive health of the first generation, and leading to repeated interventions in subsequent generations. To determine whether this is a real concern, we developed a model of mtDNA heteroplasmy inheritance by studying 87 mother-child pairs, and predicted the likely outcome of different levels of 'mutant mtDNA leakage' on subsequent maternal generations. This showed that, for a clinical threshold of 60%, reducing the proportion of mutant mtDNA to <5% dramatically reduces the chance of disease recurrence in subsequent generations, but transmitting >5% mutant mtDNA was associated with a significant chance of disease recurrence. Mutations with a lower clinical threshold were associated with a higher risk of recurrence. Our findings provide reassurance that, at least from an mtDNA perspective, methods currently under development have the potential to effectively eradicate pathogenic mtDNA mutations from subsequent generations.
    Human Reproduction 01/2013; 28(3). DOI:10.1093/humrep/des439 · 4.57 Impact Factor
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    • "The most common point mutations related to MELAS A3243G, T3271C, G13513A were tested as previously described [21] [22] [2]. The PCR products were digested using HaeIII, DraI and BpuAI, respectively. "
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    ABSTRACT: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes is a mitochondrial multisystem disorder. This disease has mainly been associated to the mitochondrial DNA mutation A3243G located in the tRNA Leucine gene. In this article, we report the clinical, radiological and molecular results of a 10 years old Child with the classical Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes phenotype. A 10 years old male Japanese child presented with recurrent episodes of headache, nausea and vomiting of 5 years duration and hyperlactic acidemia. These episodes were associated with motor weakness on the right side, with difficulties in language and memory and visual disturbance. Neurological examination revealed generalized muscle weakness with mild right sided hemiparesis. The Magnetic Resonance Imaging revealed infarct like lesions in the left occipital regions and the left medial temporal. The mitochondrial DNA mutations A3243G, T3271C and G13513A were tested using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism analysis and direct sequencing. The heteroplasmic A3243G mutation was detected in the blood of the patient and his mother. l-Arginine is reported to be beneficial for the patients and a preventive treatment was given in the form of arginine 500 mg twice per day.
    Mitochondrion 09/2012; 12(5):569–570. DOI:10.1016/j.mito.2012.07.051 · 3.25 Impact Factor
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    • "The disorder is characterized by symptoms and signs of central nervous system involvement, including seizures, migraine, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting. Other common symptoms are: hearing loss, reduced statural growth, diabetes (Ciafaloni et al, 1992). MELAS syndrome can be caused by mutation in several genes of the mtDNA coding for tRNA or polypeptides, including MTTL1, MTTQ, MTTH, MTTK, MTTS1, MTND1, MTND5, MTND6, and MTTS2. "
    Novel Aspects on Epilepsy, 10/2011; , ISBN: 978-953-307-678-2
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