Introduction 336Clinical abnormalities 336Genetics and pathogenesis 340Treatment 34152Mitochondrial encephalomyelopathy, lactic acidosisand stroke-like episodes (MELAS)MAJOR PHENOTYPIC EXPRESSIONMitochondrial myopathy, shortness of stature, stroke-like episodes, seizures, encephalopathy progressive to dementia,migraine,diabetes mellitus,lactic acidemia,ragged red muscle fibers and mutations in the mitochondrial tRNA leucine gene.INTRODUCTIONThis syndrome was first defined as such by Pavlakis andcolleagues  in 1984, although patients have doubtless beenreported earlier. Among the mitochondrial myopathies this isone of the more common .The typical clinical presentation includes all of the featuresthat make up the name of the syndrome, but there is enor-mous variability. Some affected individuals have only diabetes,or only migraine. Others have only hearing loss, or hearingloss and diabetes . The disease is inherited in a maternalpattern, and the gene is on the mitochondrial genome(Figure 52.1). Most of the patients have had one of two pointmutations in the mitochondrial gene for the leucine (UUR)tRNA (A3243G and T3271C) [4–7] (Figure 52.2).CLINICAL ABNORMALITIESThere is a considerable variety of expression consistent withthe varying heteroplasmy of mitochondrial inheritance. Thetypical picture is of normal development followed by a severe,progressive encephalomyopathy. Onset may be myopathicwith exercise intolerance or weakness (Figure 52.3). Manypatients have shortness of stature, and this may be the firstmanifestation of disease (Figure 52.4). One of our patientshad been treated unsuccessfully with human growth hor-mone by a pediatric endocrinologist; this has also beenreported by others. In many patients the onset of symptomsis with the first stroke-like episode, usually between 4 andND5QMELAS 3243G, 3271CLHON 3460ALHON 14448CLHON 14449ALHON 11778ANARP 8993G/CMERRF 8344GDEAF 1555GCYND6Cyt bTF PE12s16sPHPLQLOHND1WD KGRND2ANCOICOIICOIIIATP8ATP6ND3ND4LSHND4LIMLUURSUCNVCommon54kbdeletion–KSSFigure 52.1 The circular DNA of the human mitochondrial genome.Shown are the sites of the genes for the mitochondrial genes, as wellas the sites for the most common mutations, including the A3243Gand T3271C mutations associated with MELAS syndrome.
Clinical abnormalities 33715 years-of-age [1,4,8–14]. Less commonly, the onset of dis-ease may be in infancy , often with delayed developmentalmilestones or learning disability.The myopathy may be present before the first stroke. Atone extreme is a floppy infant at 4 months-of-age . Morecommonly, there is exercise intolerance, easy fatigability orfrank weakness. Patients may have difficulty going up stairs.Myopathy may be progressive. Proximal muscles tend to bemore involved than the distal . Musculature is generallythin.The facial appearance may be myopathic .The creatinephosphokinase activity in the blood may be elevated [13,16].Some patients have been diagnosed as having polymyositis .The electromyogram (EMG) may demonstrate a myopathicpattern.The stroke-like episode is the hallmark feature of this syn-drome. At the same time, these episodes may occur in only afew members of a pedigree, in which a much larger numberhas the same mutation [15,16]. In one series of four families stroke-like episodes occurred only in the probands. Twoof the affected mothers were clinically entirely normal. Inother pedigrees no member may have had this defining man-ifestation. The episode may initially be manifest by vomitingand headache, convulsions or visual abnormalities . Lesscommonly, there may be numbness, hemiplegia or aphasia.There may be recurrent episodes of headache or vomitinglasting a few hours to several days. The episode may be fol-lowed by transient hemiplegia or hemianopia lasting a fewhours to several weeks. Computed tomography (CT) or mag-netic resonance imaging (MRI) scan of the brain followingsuch an episode reveals lucency consistent with infarction AT AT AT AA TA TA TA TA TAAAAAAAA AAAAA AAA TT TTTTTTTTTTTGGG GGGGGGGGGGG CCCCCCCCCCCC CCCC5Ј-G C3Ј-OHMELASnp3243Mitochondrialencephalomyopathyor MELASnp3252MELASnp3271AnticodonFigure 52.2 The tRNA for leucine, the site of the defect in theMELAS syndrome. In addition to the point mutation at npA3243G,the common mutation in MELAS, and npT3271C and npA3252G theother MELAS mutations, there are a number of other known mutationsin the tRNA leucine which cause mitochondrial diseases. Theseinclude: npT3250C, mitochondrial myopathy; npA3751G chronicprogressive external ophthalmoplegia (CPEO) proximal weakness,sudden death; npA3260G, adult onset hypertrophic cardiomyopathyand myopathy; npA3302G, mitochondrial myopathy; and npC3303T,adult onset hypertrophic cardiomyopathy and myopathy.Figure 52.3 K.S., a boy with MELAS illustrating his lordotic,myopathic posture. He presented at 4 years-of-age with weaknessand exercise intolerance. He also had insulin-dependent diabetesmellitus. Blood concentration of CPK was 462IU/L. Plasmalactate was 93.1mg/dL. (This illustration was kindly providedby Dr. Richard Haas of UCSD.)Figure 52.4 N.F., a boy with MELAS who had strokes on threeoccasions and had become demented. Stature was very short.(This illustration was kindly provided by Dr. Richard Haas of UCSD.)
(Figures 52.5 and 52.6). This picture may resolve over hoursor days, but later there may be cerebral atrophy and calcifica-tions, especially in the basal ganglia [17–24] (Figure 52.6).Infarcts are most common in the posterior temporal, pari-etal or occipital lobes, but histologic examination may revealclear-cut infarcts widely scattered in the cerebrum, cerebel-lum or basal ganglia [18,20,25,26]. So these episodes are infact strokes. The term ‘stroke-like’may be appropriate in thatno vascular changes of inflammation or atherosclerosis arefound in the brain. We have tended to refer to this type oflesion as metabolic stroke in other diseases, such as propionicacidemia (Chapter 2) or methylmalonic acidemia (Chapter 3).In MELAS mitochondrial angiopathy is evident in contrastenhancement in affected areas [21,27–29], and even in the skinas purpuric lesions.The migraine or migraine-like headaches seen in thesepatients may reflect the same process. Headache may be hemi-cranial. In pedigrees of patients with classic MELAS there aremany members whose only manifestation is migraine [8,15](Figure 52.7). Developmental delay, or learning disability or attention deficit disorder , is mainly found in patientsprior to the development of the first stroke. This was the his-tory of the patient illustrated in Figure 52.4 who did not havehis first stroke until the age of 8, but had been in a specialeducation program for years. On the other hand, somepatients with considerable myopathy and/or other sympto-matology may be intellectually normal (Figure 52.3). Theencephalopathy when it develops may be progressive todementia (Figure 52.4). The patient may be apathetic andcachectic .Additional neurologic features include ataxia, tremor, dysto-nia, visual disturbances and cortical blindness. Some have hadmyoclonus. Convulsive seizures may be focal or generalizedtonic-clonic, but may also be myoclonic . The electroen-cephalogram (EEG) is usually abnormal, and there are usu-ally epileptiform spike discharges.Some patients have had ophthalmoplegia or ptosis .Others have had pigmentary degeneration of the retina like those with the neurodegeneration, ataxia and retinitispigmentosa (NARP) mutation (Chapter 54). Patients havebeen referred to as having the Kearns-Shy syndrome .Others have presented with the picture of Leigh syndrome(Chapter 47), in which patients have recurrent attacks of338 MELASFigure 52.5 CT of the brain of M.R., a boy with the A3243 Gmutation, illustrating the posterior infarct and the extensivecalcifications in the basal ganglia, including the caudate, putamenand globus pallidus. (Illustration kindly provided by Dr. Richard Haasof UCSD.)ABFigure 52.6 MRI of the brain of N.F. illustrating widespreadcortical atrophy, residual at a right parieto-occipital infarct withventriculomegaly and increased T2 signal representing preinfarctionstate in left temporoparieto-occipital cortex. (This illustration kindlyprovided by Dr. Richard Haas of UCSD.)
Clinical abnormalities 339neurologic regression, pyramidal and extrapyramidal signs,brainstem abnormalities and leukodystrophy [31,32].An interesting consequence of the MELAS mutation isthe occurrence of diabetes mellitus  (Figure 52.7). Thisappears to be the most common manifestation of MELAS. Itis usually type II diabetes ,but the boy shown in Figure 52.3had insulin-dependent diabetes mellitus.Sensorineural hearing loss is another common manifesta-tion, and it may be seen in individuals with or without diabetesand no other manifestations of disease . It may also be seenin patients with the classic syndrome. Deafness has beenreported in about 25 percent of patients . The disease is amajor cause of aminoglycoside-induced hearing loss . Thisprovides an argument for screening for the MELAS mutationin patients with antibiotic-induced deafness, in order to testaffected relatives and avoid aminoglycosides in them.Cardiomyopathy is a less common feature, but may befound in about 10 percent of patients. It is usually hyper-trophic cardiomyopathy, but it may be dilated . Patientswith the MELAS mutations have been found to have MELASand cardiomyopathy, but others have had isolated cardio-myopathy and no neurologic disease. There may be conduc-tion abnormalities – for instance, Wolff-Parkinson-Whitesyndrome  – and often an abnormal electrocardiogram. Huge accumulation of mitochondria has been observedin myocardial fibers .Renal involvement may take the form of renal tubular aci-dosis, and there may be a typical renal Fanconi syndrome. One patient developed a nephrotic syndrome and hadfocal glomerulosclerosis . A variety of other organs hasbeen involved in individual patients. One had pancreatitisfollowing valproate administration . Others have hadperipheral neuropathy with or without rhabdomyolysis [38,39].One had ischemic colitis . Pigmentary abnormalities ofthe skin have been reported .The histologic signature of the MELAS syndrome is theappearance of ragged red fibers in the muscle (Figure 52.8)[1,12,13,36]. These are best seen in the trichrome stain. InH and E there may be variation in fiber size and increase in con-nective tissue. Staining with periodic acid Schiff (PAS), NADHtetrazolium reductase or for succinic dehydrogenase may showincreased subsarcolemmal activity. Electron microscopy revealsan increase in number and size of mitochondria (Figure 52.9),some with paracrystalline inclusion bodies [13,36].The lactic acidosis is an important feature of this disorder. Itdoes not usually lead to systemic acidosis, and it may even beabsent in patients with impressive involvement of the centralnervous system. The levels may be elevated in cerebrospinalfluid (CSF) and normal in blood .The patient in Figure 52.4had repeated determinations of lactate in the blood in thenormal 20mg/dL range; his CSF lactate was 56.3mg/dL. TheCSF concentration of protein may be mildly elevated.75ϩ688333 38 4314 1312417 mo414755637660’s MId57in 197780ϩI.II.III.IV.Developmental delayedseizuresParkinson’sDepressionMELASMigraineDiabetesFigure 52.7 Pedigree of the family ofN.F. illustrating the occurrence of diabetes,migraine, seizures and other problems.Analysis of the blood revealed thenpA3243G mutation.Figure 52.8 Ragged red fibers of the muscle of a patient withMELAS. (Illustration kindly provided by Dr. Richard Haas of UCSD.)
GENETICS AND PATHOGENESISThe MELAS syndrome is the result of mutation in mitochondr-ial genes for tRNA .The most common is A-to-G transitionat position 3243 of the tRNALeu(UUR) [4,5] (Figure 52.1).Approximately 80 percent of affected individuals have thismutation in the dihydrouridine loop of the gene [8,16,42–44].The other common mutation, occurring in about 8.5 percentof individuals, is also in the tRNALeu(UUR) at 3271 in theanticodon,where there is a T-to-C transversion .The G-to-Atransversion at 3252 of the same gene has been reported inmitochondrial encephalopathy . Another mutation in thedihydrouridine loop at nucleotide 3250 is a T-to-C transition.Another mutation in this gene is an A-to-T change at posi-tion 3256 .A 5814G in the tRNACys gene was reported in apatient with cardiomyopathy and myopathy .A quite distinct mutation,an A-to-G transition at nucleotide11084 in the ND4 gene for the subunit of Complex I of the res-piratory chain, was reported by Letrit et al.  in a Caucasianpatient. This same mutation was later reported by Sakuta andcolleagues  in 10–14 percent of Japanese studied, bothpatients with mitochondrial myopathy and normal controls,suggesting that it might be a polymorphism. On the otherhand, this mutation was not found in 109 normal or patientCaucasians nor in American blacks, nor in a considerablenumber of patients with other mitochondrial diseases. So theissue on this transition is unresolved. A large (10.5kg) dele-tion was reported in a MELAS patient with a renal Fanconisyndrome .The common mutation creates a new site for Hae III lead-ing to a 169bp fragment in controls after electrophoresis andfragments of 97 and 72bp in patients with MELAS .Sequencing (Figure 52.10) reveals the G in MELAS wherethere is an A in control.Varying heteroplasmy among affectedindividuals appears to reflect variable segregation in theovum. On the other hand, study of the proportion of mutantDNA in various tissues obtained from a woman and hertwo daughters revealed similar proportions in tissues derivedfrom ectodermal, endodermal and mesodermal germ layers,indicating little mitotic segregation after early embryogenesis. The issue of heteroplasmy, which can vary from tis-sue to tissue making detection difficult has been addressedin MELAS A3243G by the design of peptide nucleic acidswhich bond to the wild type mtDNA at 3243 preventingPCR amplification and making the mutant the dominantproduct .Mutations in the tRNA for leucine might be expected tohave an important effect on translation and hence proteinsynthesis in mitochondria. This has been demonstrated instudies of cybrids  by fusing human cell lines lackingmitochondrial DNA with exogenous mitochondria contain-ing 0 to 100 percent of the common 3243 mutant DNA.Cybrids containing more than 95 percent mutant DNA haddecreased rates of synthesis and steady state levels of mito-chondrial proteins leading to respiratory chain deficiency.Patients with the MELAS syndrome have been found tohave marked deficiency in the activity of complex I of therespiratory chain . In mitochondria from muscle,rotenone-sensitive NADH-cytochrome reductase activity was0–27 percent of control value, and immunochemical studyrevealed a general decrease in complex I subunits. In a patientwith the T-to-C 3250 mutation, complex I activity in musclewas six percent of control and that of complex IV was 47 per-cent of control . The productions of CO2 from labeledpyruvate, malate and 2-oxoglutarate were all reduced . Ina study of four patients with the 3243 mutation, the activityof complexes I and IV were reduced in muscle and other340 MELASFigure 52.9 Electronmicroscopy of the muscle of the mother ofK.S. She had diabetes, but no symptoms of myopathy. Illustrated aremany pleomorphic mitochondria, abnormal concentric lamellar cristaeand electron-dense bodies. There is also glycogen accumulation.(Illustration kindly provided by Dr. Richard Haas of UCSD.)Figure 52.10 Sequencing gel of the MELAS region of the leucineTRNA of muscle. The npA3243G mutation in K.S.; BB was a normalcontrol. (Illustration kindly provided by Dr. Richard Haas of UCSD.)
References 341tissues, but there was no correlation between the proportionof mutant DNA in a tissue and the activity of the respiratorychain complexes .TREATMENTA variety of supportive measures is helpful in this disorder, asin other mitochondrial diseases. Riboflavin therapy has beenreported to be of benefit in a patient with complex I defi-ciency and the T-to-C 3250 mutation . A dose of 20mgtwice a day was employed in a 2-year-old patient with myopa-thy who could not ascend stairs and was reluctant to walk.Improvement in muscle strength occurred, and there was nofurther deterioration over three years of observation.Coenzyme Q has been helpful in a number of patients .Some amelioration of muscle weakness has been observed, aswell as some decrease in plasma levels of lactate. CSF lactatedid not improve. Doses of 30–90mg per day were reported. 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