Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokehke Episodes: A Distinctive Clinical Syndrome Steven G. Pavlakis, MD,tS Peter C. Phillips, MD,tS Salvatore DiMauro, MD,-F§ Darryl C. De Vivo, MD,"-FS and Lewis P. Rowland, MDtg We report on two patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS).These two and nine other reported patients share the following features: ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Lactic acidemia is a common finding. We believe that MELAS represents a distinctive syndrome and that it can be differentiated from two other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns-Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome. Existing information suggests that MELAS is transmitted by maternal inheritance. The ragged red fibers suggest an abnormality of the electron transport system, but the precise biochemical disorders in these three clinical syndromes remain to be elucidated. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16:481-488, 1984 In the past five years we have evaluated three patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and a strokelike syndrome. One of these patients was reported on separately in abstract form [171. We have identified eight other patients reported on in the medical literature who evidence similar clinical and histopathological features. The cardinal characteristics of these eleven patients include ragged red fibers in skeletal muscle, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Ragged red fibers derive their name from the appearance of the degenerating granular fibers after they have been stained with the modified Gomori trichrome stain. The red staining represents proliferating mitochondrial elements. The presence of ragged red fibers suggests an abnormality of the electron transport system, because these findings are regularly seen in documented biochemical deficiencies that involve the respiratory chain 11, 6, 7, 20, 21, 27-29, 31, 33, 37, 401. Ragged red fibers also have been seen in two other, similar clinical disorders: Kearns-Sayre syndrome [321 and a syndrome characterized by myoclonus epilepsy and ragged red fibers. Fukuhara {lo] has proposed the acronym MERRF for the latter syndrome. The purpose of this report is to review the distinctive characteristics of these three syndromes and to propose the acronym MELAS for this newly described entity. From the College of Physicians and Surgeons of Columbia Universitv. The Neuroloaicd Institute of Presbvterian HosDitd in New York City, the Departments of"Pediatricsand tNeurology, the tDivision of Pediatric Neurology, and the PH. Houston Merrirt Center for Muscular Dystrophy, New York, NY 10032. Received Ocr 31, 1983, and in revised form Feb 3, 1984. Accepted for Dublication Feb 4. 1984. Dr D~ viva, 168th s:, New Address reprint requests York, NY 1o032, , I I Case Reports Patient 1 A boy had a normal prenatal and perinatal history. Polydactyly was noted at birth. By 3 years of age delayed motor and language development were evident; school performance was significantly below grade level by first grade. Short stature was noted at 8 years and sensorineural hearing loss was documented at 14 years. His one sibling was unaffected, and the family history was normal. He was otherwise well until age 15% years when he had two generalized tonic-clonic seizures that lasted 10 minutes, with residual left arm and hand weakness and sensory loss. These abnormalities partially resolved within four weeks. A computed tomographic (CT) scan demonstrated a small right frontoparietal lucency. At age 16 he was admitted to a hospital after the sudden onset of right hand weakness, hyperaggressive behavior, and confusion. There were expressive aphasia and right hemiparesis. Cerebrospinal fluid (CSF) was normal except for a protein concentration of 76 mg/dl. A C T scan showed bilateral nonenhancing parietal lucencies. Cerebral angiography with magnification views showed no abnormalities. The patient was treated with phenytoin and a two-week course of prednisone. The right hemiparesis resolved. , 48 1 A B Two months later, after a febrile illness, he experienced visual and auditory hallucinations with disorientation and slurred speech. At Babies Hospital physical examination showed short stature ( I 64 cm) and small head circumference (52.75 cm), both at the 3rd percentile for age. There were abnormalities of speech with word substitutions, deletions, and anomia. Auditory acuity was diminished bilaterally; there was diffuse limb weakness and drift of the left arm. Tendon reflexes were present. There was no funduscopic abnormality, ophthalmoplegia, tremor, or myoclonus. An electroencephalogram (EEG) showed diffuse slowing without paroxysmal features. Bilateral nonenhancing parietal lucencies were noted on C T scan. Arterial lactate concentration was 2.7 mM/ L and CSF lactate was 4.0 mM/L (normal CSF and serum lactate ranges, 0.5 to 2.2 mM/L). Results of all other serum laboratory studies were normal. Biopsy of the quadriceps muscle showed ragged red fibers on modified Gomori trichrome staining. Activities of pyruvate carboxylase and pyruvate dehydrogenase enzyme complex were normal in cultured skin fibroblasts E4, 51. Several months later the patient had an acute psychotic episode with hyperaggressive behavior and paranoid delusions. Examination showed dysdiadochokinesia of the left hand and mild drift of the left arm as the only abnormalities. All language abnormalities had resolved. CSF lactate concentration during the psychotic behavior was 4.9 mM/L, and arterial lactate level was 4.8 mM/L. Formal psychometric testing demonstrated a Verbal I Q of 57, with Performance and Full Scale IQs below 50. In the ensuing 18 months the patient had no recurrence of seizures, motor deficits, or acute personality disorder. Computed tomographic scam of the head (patient 2), showing multiple nonenhancing lucenciej involving both occipital lobas, (A)the rigbt parietal Lobe and (Bj the right basal ganglion. Patient 2 The second patient, also a boy, had an uneventful prenatal and perinatal history. Early growth and development were 482 Annals of Neurology Vol 16 No 4 October 1984 normal. At age 6 years he experienced intermittent headaches and lethargy. By 9 years school performance deteriorated and short stature was noted. At 5 years his height was at the 50th percentile for age, but 4 years later it was at the 3rd percentile. At 9 years he was hospitalized with fever, vomiting, lethargy, and right hemiparesis. EEG showed left focal slowing. The right hemiparesis gradually resolved over four weeks. Two months later he complained of sudden blindness, which was followed by a generalized clonic seizure. The blindness improved, and a C T scan showed bioccipital lucencies. A regimen of phenobarbital was started. Four-vessel cerebral angiography demonstrated a right extracranial carotid occlusion. In the next twelve hours the patient gradually developed a left hemiparesis and left homonymous hemianopia. C T scanning showed lucencies in the right basal ganglia and both occipital lobes. At age 13 years he was admitted to Babies Hospital for further evaluation. His one sibling was unaffected, and the family history was normal. He was short (128 cm; 3rd percentile for age), and head circumference ( 5 4 cm) was at the 50th percentile. Intellectually he functioned at a 6-year-old level and could recall only one of three objects at five minutes. He had a left homonymous hemianopia, diffuse limb weakness, and left hemiparesis. Tendon reflexes were present. There was no funduscopic abnormality, ophthalmoplegia, tremor, or myoclonus. EEG showed diffuse slowing with right midtemporal and central epileptiform discharges. Bilateral occipital, right parietal, and right basal ganglia lucencies were evident on C T scan (Figure). The arterial lactate concentration was 4 mM/L, CSF lactate level 6.1 rnMIL, and CSF protein concentration 53 mgidl. Results of all other Table 1 . Characterisria of MELAS" Patient No. Author Additional Clinical Features Additional Laboratory Features Koenigsberger et al {I71 6-yr-old girl with periodic loss of consciousness, dementia, hearing loss, transient right hemiparesis; died at 9 yr 9-yr-old boy with deteriorating school performance, focal seizures, alternating hemiparesis, episodic vomiting 9-yr-old boy with episodic vomiting, focal seizures, alternating hemiparesis, single episode of blindness 1 1-yr-old boy with left homonymous hemianopia following right-sided headache; alexia without agraphia 18-yr-old woman with episodic vomiting, headache, left visual field cut and hemiparesis, cortical blindness, dementia I6-yr-old brother of patient 5 with limited extraocular motility and progressive encephalopathy; no strokelike syndrome 16-yr-old girl with episodic vomiting and ataxia, left visual field cut and hemiparesis, deafness, myoclonic seizures, progressive encephalopathy 10-yr-old brother of patient 7 with episodic vomiting, right hemiparesis, blindness, myoclonic seizures, progressive encephalopathy 12-yr-old boy with episodic vomiting, blindness, progressive encephalopathy, coma 16-yr-old boy with alternating hemiparesis, aphasia, decreased hearing, progressive encephalopathy 13-yr-old boy with episodic vomiting, alternating hemiparesis, blindness, progressive encephalopathy ECG showed flattened T waves; C K and L D H elevated; muscle carnitine decreased Askanas et al {2Ib Askanas et al {2}b Skoglund [353 Hart et al El41 Hart et al 1141 Shapira et al {34} 8 Shapira et al {34} 7 Gardner-Medwin et alf121 10 Patient 1 (present report) 11 Patient 2 (present report) Basal ganglia calcification; slow sensory conduction velocities; blunted h G H response to insulin-induced hypoglycemia .. . Basal ganglia calcifications; bilateral parieto-occipital lucencies; elevated SGOT and LDH Alteration of cerebral cortex; microcystic liquefaction; basal ganglia mineralization noted postmortem ... ECG showed flattened T waves; focal microcystic softening of cerebrum and basal ganglia mineralization noted postmortem Elevated CK and LDH; postmortem findings similar to those of sister; muscle not examined Focal lucencies on CT scan Bilateral parietal lucencies on C T scan Bilateral occipital, right parietal, and basal ganglia lucencies "Eleven patients with limb weakness, ragged red fibers, short stature, lactic acidemia, encephalopathy , seizures, and recurrent strokelike syndrome. bWe reexamined patients 2 and 3, reported previously by Askanas et al. CT scan of patient 2 at 10 years of age showed basal ganglia calcifications. ECG = electrocardiogram;CK = creatine kinase; LDH = lactic dehydrogenase;hGH = human growth hormone; SGOT = serum glutamicoxaloacetic transaminase; CT = computed tomographic. blood and CSF studies were normal, and a biopsy of the quadriceps muscle showed ragged red fibers. Methods and Results Mitochondria1 enzymes in skeletal muscle were analyzed in four patients with MELAS. The methods for the determination of cytochrome c oxidase 1427, succinate-cytochrome c reductase 1361, NADHcytochrome c reductase 1361, citrate synthetase [381, carnitine acetyl transferase [23], and carnitine p h i toy1 transferase [2 37 have been previously described. Control muscle was obtained by diagnostic biopsy from patients who were ultimately deemed free of neuromuscular disease. The results of the mitochondrial muscle enzymes are tabulated in Table 5. Discussion These two patients had a mitochondrial myopathy, encephalopathy, lactic acidosis, and a strokelike syndrome (MELAS). These two and nine other patients [2, 12, 14, 17, 34, 357 met the following criteria: normal early development, short stature, seizures, and alternating hemiparesis, hemianopia, or cortical blindness (Table 1). All eleven children were normal at birth Pavlakis et al: MELAS-A Distinct Clinical Entity 483 Table 2. Characteristics of MERRF (Fukuhara Syndromela Patient No. Author Additional Clinical Features Additional Laboratory Features 1 Holliday et a1 [l5] Elevated lactate 2 Holliday et a1 [ 151 3 k g g s et a1 1311 4 Riggs et a1 E311 5 Feit et a1 [S] 28-yr-old man with short stature, seizures, optic atrophy, deafness, dementia; died at 32 yrs 18-yr-old brother of patient 1 with short stature, seizures, optic atrophy, deafness, dementia 9-yr-old girl with short stature, tremor, encephalopathy; no limb weakness 7-yr-old brother of patient 3 with short stature, seizures, tremor; no limb weakness 30-yr-old woman with tremor, progressive encephaiopathy, possible neuropathy Elevated lactate Elevated CK; lactate nor-ma1 Elevated CK; lactate normal Lactate value not reported "Representative patients with limb weakness, ragged red fibers, ataxia, and myoclonus. Sixteen patients are reported in the literature [8, 10, 15, 311. Eleven cases were reviewed by Fukuhara [lo]. W'e have added patients 1 rhrough 5. CK = creatine kinase. and had normal early development, with symptoms of MELAS beginning between ages 3 and 11 years. All were short and had a seizure disorder. The seizures were focal or generalized; two patients had myoclonic seizures. All had either hemiparesis, hemianopia, or cortical blindness, except one 1141 who had the other manifestations and is included in this group because his sister had the full syndrome. Nine developed hemiparesis or hemianopia, and six had episodes of cortical blindness E2, 12, 14, 17, 34, 351. Nine patients became demented {2, 12, 14, 17, 341. Episodic vomiting was prominent in seven patients {2, 12, 34, 351. Three had neurosensory hearing loss {17, 341, and there were two pairs of affected siblings [14, 341. Significant cerebellar dysfunction, interictal myoclonus, heart block, ophthalmoplegia, and retinal pigmentary changes were absent. Fukuhara and associates { 11) described a syndrome that was similar in some respects but differed in others. Fukuhara called the syndrome MERRF (myoclonus epilepsy and ragged red fibers) and cited eleven patients who met the following criteria: normal early development, myoclonus, and a cerebellar syndrome {lo). We have found five other patients reported in the literature [S, 15, 31) (Table 2). Like those with MELAS, these patients had normal early development with symptoms beginning between ages 5 and 42 years; eleven had seizures, eleven became demented, and six had hearing loss [ S , 10, 15, 31). Ten of the sixteen patients had affected family members { 10, 15, 3 I]. Unlike those with MELAS, all had myoclonus and ataxia and none had hemiparesis, hemianopia, or cortical blindness. (We are making a distinction here between myoclonic epilepsy and myoclonus.) All patients with MERRF had interictal myoclonus, not seen in any MELAS patient. In contrast to the findings in those 484 Annals of Neurology Vol 16 No 4 October 1984 with MELAS, intention tremor was prominent in twelve patients with MERRF [S, 10, 311 and deep sensation was impaired in six of the sixteen [lo). In eight, optic nerve atrophy was noted [ l o , IS]. One patient had a menstrual disorder secondary to hypothalamic dysfunction {9].No patient had significant ophthalmoplegia, retinal pigmentary degeneration, or heart block. Kearns-Sayre syndrome, a disease also associated with ragged red fibers, has been defined 1321 as an acquired condition with onset before age 20, ophthalmoplegia, atypical pigmentary degeneration of the retina, and one of the following: heart block, CSF protein level greater than 100 mgldl, or a cerebellar syndrome. Using these criteria Rowland and co-workers [32) identified seventy reported cases of KearnsSayre syndrome. Like those of MELAS and M E W , nearly all cases were associated with growth failure, and neurosensory hearing loss was common. Unlike MELAS and MERRF, few cases were familial. Focal neurological signs, episodic vomiting, cortical blindness, and myoclonus were absent, and seizures occurred only in three patients with concomitant hypoparathyroidism. The neuropathological characteristics of MELAS, MERRF, and Kearns-Sayre syndrome are somewhat similar in that spongy degeneration of the brain has been described in all three syndromes. Three patients with MELAS were studied postmortem (see Table 1). One had a spongy state of the brain with cerebral cortical microcystic liquefaction [ 141. Two siblings showed focal encephalomalacia of the cerebral cortical mantle {343. Our patients and two others 112, 351 had focal lucencies on CT scan. Five patients with MELAS had basal ganglia calcifications evident on CT scan or postmortem, without clinical hypoparathyroidism {2, 14, 341. No spinal cord findings have been reported. Tuble 3.Caes with Charucterirtics of Both MELAS and MERRF” Patient No. Author Clinical Features Laboratory Features 1 Kuriyama et al { 181 14-yr-old boy with short stature, episodic vomiting, myoclonic epilepsy, ataxia, deafness, macuiar degeneration 13-yr-old girl with episodic vomiting, seizures, myoclonus, deafness, Babinski’s signs; no ataxia Multiple “infarcts” of cerebrum and cerebellum; basal ganglia calcification ~ Fukuhara [ 101 Holliday et a1 1.151 ~ ~ ~ ~~~~~ Elevated CK; right occipital lucency on first CT scan; cerebellar atrophy and basal ganglia calcification on second scan; ECG showed ST depression 26-yr-old woman with short stature, seizures, visual field cut and hemiparesis, episodic headaches, myoclonus, optic atrophy, deafness, ataxia; asymptomatic half-sister with elevated lactate ... “All patients had ragged red fibers and lactic acidernia. CK = creatine kinase; CT = computed tomographic; ECG = electrocardiogram Three patients with MERRF were studied postmortem [lo}. Two had a spongy state of the cerebral hemispheres. One of these had spongy degeneration of the subcortical white matter of the cerebellum as well. The third patient was difficult to assess because of antecedent head trauma. All three had degeneration of neurons with glial proliferation in the dentate nuclei and superior cerebellar peduncles. Notably, all three patients had degeneration in the posterior columns and anterior and posterior spinocerebellar tracts of the spinal cord. Thirteen postmortem reports of KearnsSayre syndrome revealed a spongy state of the brain [32]. On CT scan four patients with Kearns-Sayre syndrome had lucencies and two showed calcifications in the presence of hypoparathyroidism r32). The neuropathological findings of these syndromes overlap, but microcystic liquefaction or focal softening and basal ganglia calcification are most prominent in MELAS. Spinal cord degeneration involving posterior columns and spinocerebellar tracts has been seen only in MERRF. Three patients with ragged red fibers had features of both MELAS and M E W [lo, 15, 181. For example, Kuriyama and associates {I81 (Table 3) presented a patient with short stature, episodic vomiting, myoclonic epilepsy, and cerebellar syndrome. The patient had no strokelike episodes. Postmortem examination revealed basal ganglia calcifications and multiple cerebral “infarcts” that were not in the distribution of a specific arterial blood supply. Presumably, the areas of “infarction” were due to some mechanism other than vascular occlusion. The short stature, episodic vomiting, and basal ganglia calcifications were similar to those in patients with MELAS, but the cerebellar syndrome was like that in MERRF. The patient of Kuriyama and co-workers had myoclonic epilepsy but not continuous myoclonus. Fukuhara [lo) (see Table 3) presented a patient with episodic vomiting and myoclonus, as in MERRF, but without ataxia. C T scan showed right occipital lucency and basal ganglia calcifications similar to those in a number of patients with MELAS. Finally, one of three patients reported by Holliday and colleagues { 153 (see Table 3) had intermittent headache, myoclonus, seizures, dementia, and ataxia, as in MERRF, but also had postictal hemiparesis, as in MELAS. These cases illustrate the problem of making clear distinctions between the two syndromes. Ten other patients previously referred to as having “Hackett-Tarlow syndrome” { 10) or “juvenile mitochondrial myopathy” [32} have lactic acidemia and mitochondrial myopathy, often with growth failure [ 13, 19,20, 22,24-26,28, 39,41). This is a heterogeneous group of patients, not easily categorized. One patient { 2 5 ) probably had an incomplete form of Kearns-Sayre syndrome, and another [ 191principally had opthalmoplegia. Limb weakness was the dominant feature in four patients 120, 24, 28, 41). The syndrome in five patients in this group resembles but does not meet the criteria for MELAS C13, 22, 26, 39) (Table 4). All had short stature, two had epilepsy C13, 221, two had episodic vomiting C13, 39}, and four had hearing loss C13, 22, 26). Monnens and colleagues 1261 described a patient without encephalopathy or seizures who had sudden blindness reminiscent of MELAS. Some of these patients may have been in the early stages of MELAS. For instance, Hart and co-workers {14) reported two siblings, one with complete MELAS (see Table 1).The other had only seizures and encephalopathy and would not have met the criteria for MELAS if not for the affected sibling. The transition to MELAS was documented in another family that was first reported as evidencing fascioscapular myopathy with abnormal mitochondria [ 16); lactic acidosis was noted later [3}, and, finally, one sibling developed encephalopathy. It is difficult, therefore, to consider “HackettTarlow” a distinct syndrome. Pavlakis et al: MELAS-A Distinct Clinical Encity 485 Table 4. Cajej with Characteristics Rejembling MELAS" ~ ~ ~ Patient No. Author Clinical Features 1 2 Tarlow et a1 I391 Hackett et a1 [13J 3 Hackett et a1 1131 4 Markesbery [22] 5 Monnens et a1 1267 6-yr-old girl with episodic vomiting 20-yr-old woman with deafness, epilepsy, retarded sexual maturation 11-yr-old sister of patient 2 with deafness, episodic vomiting; severe metabolic acidosis before death 27-yr-old man with seizures, deafness, neurogenic bladder Female with deafness, acute visual loss; cousin with mitochondrial myopathy Laboratory Features ... ... ... Elevated CSF protein; basal ganglia calcification Elevated CK, partial deficiencies of PDH and cytochrome c oxidase "All patients had limb weakness, short stature, ragged red fibers, and lactic acitlemia. CSF = cerebrospinal fluid; CK = creatine kinase; PDH = pyruvate dehydrogenase. Table 5 . Mitochondria/ Enzymes of Muscle in Four Patients with M E L A S and Controls NADH Patient No." Cytochrome ch Oxidase Succinate Cytochrome c'' Reductase Cytochrome ch Reductase Citrate' Synthetase Carnitine" Acetyl Transferase Carnitine" Palmitoyl Transferasr 1 2 3 11 1.23 2.60 1.67 3.24 0.52 0.82 0.86 0.39 3.46 2.5 1 2.96 5.40 10.29 14.71 14.56 17.27 8.37 5.66 8.72 6.04 13.14 13.8 1 Control' Range 2.50 2 0.50(35) 1.76-3.74 1.08 k 0.41 ( 2 6 ) 0.42-1.89 3.38 5 1.33 ( 3 1 ) 1.82-6.22 8.81 r 0.54 ( 2 8 ) 4.12-16.50 1.84 t 0.54 ( 2 8 ) 1.05-2.90 7.45 t 1.44 ( 5 8 ) 4.62-10.49 ... ... "Patients numbered as they appear in Table 1. 'pmol oxldized or reduced per minute per gram. 'p.mol formed per minute per gram. "nmd formed per minute per gram. 'Control values 2 SD with number of conmils in parentheses. The cause of these syndromes is uncertain. All are associated with ragged red fibers, and most include elevated blood lactate concentrations. Presumably there is an underlying biochemical defect in mitochondria. There may be multiple biochemical defects or varied clinical expression of a single defect. The prominence of central nervous system manifestations suggests that nervous system mitochondria are affected. There has been no reported study of brain mitochondria, however. Several biochemical abnormalities have been associated with ragged red fibers 1271, including decreased function of cytochrome c oxidase 173, cytochrome b and aa3 [40], cytochrome b 128, 371, NADH-CoQ reductase complex 120, 291 or ATPase [ 3 3 ) , and loose coupling of oxidative phosphorylation [l, 6, 21). A deficiency of succinate-cytochrome c reductase was found in two siblings with MERRF t 3 1 ) (see Table 2). Monnens and colleagues 126) (see Table 4 ) described a patient who had a syndrome resembling MELAS and also had partial deficiencies of cytochrome c oxidase and pyruvate dehydrogenase. We have studied muscle tissue obtained from four patients with MELAS (patients l, 2 , 3 , and l l, Table l). Enzyme activities re- 486 Annals of Neurology Vol 16 No 4 October 1984 lated to the respiratory chain, as shown in Table 5 , are either normal or partially decreased (cytochrome c oxidase in patients 1 and 3 and succinate-cytochrome c reductase in patient 11). In contrast, citrate synthetase and carnitine acetyl transferase, two enzymes located in the mitochondrial matrix, and carnitine palmitoyl transferase, an enzyme located on the inner mitochondrial membrane, tend to be increased. Although the significance of a partial decrease in respiratory chain enzyme activities in some patients remains uncertain, the general increase in the other enzymes probably reflects the increased number of mitochondria, as shown by morphological study. Thus, no consistent biochemical abnormality has been found in any of these syndromes. We believe that MELAS is a distinctive syndrome manifested by mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent strokelike episodes. MELAS, like M E W , may be familial. Genetic factors, however, are difficult to elucidate, because only two pairs of siblings with MELAS have been reported [ 14, 341. The patient with encephalopathy in the family with fascioscapular myopathy was not reported o n in detail. Each pair of siblings may have had a partially Table 6. Principal Clinical Features of Kearns-Sayre Syndrome, M ERRF, and MELAS Kearns-Sayre Feature Syndrome MERRF MELAS No. of cases 70 70" 70" 56 16 11 0 0 0 Ophthalmoplegia Retinal degeneration Cerebellar syndrome Dementia Myoclonus Seizures Short stature Hearing loss Impaired d e e p sensation (if described) Cortical blindness, hemiparesis, or hemianopia Optic atrophy Positive family history 34 0 3 47 43 ... 0 0 16" 11 16" 11 6 6 6 mitochondria [30}. The finding of ragged red fibers is the hallmark of these various syndromes. Further separation must await elucidation of the inherited biochemical abnormalities. Presented in part ar the Twelfth Annual Meeting of the Child Neurology Society, Williamsburg, VA, Oct 1983. 9 The authors appreciate the excellent secretarial assistance of Alice H . Marti, Hilda D. Diez, and Marcia Villiers. 0 11" 11" References 3 0 0 0 lob ... 2 8 10 4 1 'Feature present in all reported cases. 'Feature absent only in patient 6, Table 1; this boy's sister had the full syndrome. affected mother. One mother had neurosensory hearing loss and diabetes mellitus, and the other had night blindness and ST segment depression on the electrocardiogram. These observations raise the possibility that MELAS is transmitted by non-Mendelian maternal inheritance. Mitochondrial DNA is maternally derived and codes for several subunits contained within the respiratory chain [77. It is tempting to speculate that the relatively low level of respiratory chain enzyme activity noted in Table 5 is the consequence of a generalized defect involving mitochondrial protein synthesis. Wiseman and Attardi {43],in fact, reported a decrease in cytochrome c oxidase and rutamycin-sensitive ATPase in a simian virus 40 transformed human cell line. Studies are in progress to determine whether the genetic aberration presumably associated with MELAS involves mitochondrial DNA. The course of MELAS is variably progressive, punctuated by acute cerebral insults. It can be differentiated from M E W and Kearns-Sayre syndrome as summarized in Table 6. Postmortem studies show focal encephalomalacia, and CT scans show cerebral lucencies or "infarcts," but the focal lucencies may not always correspond to a vascular distribution. Our second patient developed a left hemiparesis immediately after an arteriogram that showed right carotid occlusion. The occlusion may have been a complication of arteriography. Alternately, one could propose that the mitochondrial disturbance involves the endothelium of brain capillaries, contributing to the vascular compromise. It is known that the cerebral microvasculature is rich in 1. Afifi K, Ibrahim MZM, Bergman RA, et al: Morphologic features of hypermetabolic mitochondrial disease: a light microscopic, histochemical, and electron microscopic study. J Neurol Sci 15:271-290, 1972 2. Askanas V, Engel WK, Britton DE, et al: Reincarnation in cultured muscle of mirochondrial abnormalities: two patients with epilepsy and lactic acidosis. Arch Neurol 35:801-809, 1978 3. Bradley WG, Tomlinson BE, Hardy M: Further studies of mitochondrial and lipid storage myopathies. J Neurol Sci 35:200210, 1978 4. D e Vivo DC, Haymond MW, Leckie MP, et al: The clinical and biochemical implications of pyruvate carboxylase deficiency. J Clin Endocrinol Metab 45:1281-1296, 1977 5. De Viva DC, Haymond MW, Obert KA, et al: Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease). Ann Neurol 61483-494, 1979 6. DiMauro S, Bonilla E, Lee CP, et al: Luft's disease: further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27:217-232, 1976 7. DiMauro S, Hays AP, Eastwood AP: Different clinical expressions of cytochrome c oxidase deficiency. In Cerri C, Scarlato G (eds): Mitochondrial Pathology in Muscle Diseases. Padua, Piccin Editore, 1983, pp 111-130 8. Feit H, Kirkpatrick J, Van Woert MH, Pundian G: Myoclonus, ataxia and hypoventilation: response to L-5-hydroxytryptophan. Neurology (NY) 33:109-112, 1983 9. Fitzsimmons RB, Clifton-Bligh F, Wolfenden WH: Mitochondrial myopathy and lactic acidemia with myoclonic epilepsy, ataxia and hypothalamic infertility: a variant of Ramsay Hunr syndrome?J Neurol Neurosurg Psychiatry 44:79-82, 1981 10 Fukuhara N : Myoclonus epilepsy and mitochondrial myopathy. In Cerri C, Scarlato G (eds): Mitochondrial Pathology in Muscle Diseases. Padua, Piccin Editore, 1983, pp 87-1 11 11 Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T Myoclonus epilepsy associated with ragged-red fibers: disease entity or a syndrome? Light and electronmicroscopic studies of two cases and review of the literature. J Neurol Sci 47:117-133, 1980 12 Gardner-Medwin D, Dale G , Parkin JM: Lactic acidosis with mitochondrial myopathy and recurrent coma (abstract). First International Congress on Child Neurology 47, 1975 13. Hackett TN, Bray PF, Ziter FA, et al: A metabolic myopathy with chronic lactic acidemia, growth failure, and nerve deafness. J Pediatr 83:426-431, 1973 14. Hart 2 , Chang C, Perrin E, et al: Familial poliodystrophy, mitochondrial myopathy, and lactic acidemid. Arch Neurol 34:180185, 1977 15. Holliday PL, Climie AR, Gikoy J, Mahmud M: Mitochondrial myopathy and encephalopathy: three cases. A deficiency of NADH-CoQ dehydrogenase? Neurology (Cleveland) 33: 1619-1621, 1983 16. Hudgson P, Bradley WG, Jenkinson M: Familial mitochondrial Pavlakis et al: MELAS-A Distinct Clinical Entity 487 myopathy: a myopathy associated with disordered oxidative metabolism in muscle fibers. J Neurol Sci 16:343-370, 1972 17. Koenigsberger MR, Pellock JM, DiMauro SS, Eastwood AB: Juvenile mitochondrial myopathy, short stature and lactic acidosis: a clinical, biochemical and ultrastructural study (abstract). Fifth National Meeting of the Child Neurology Society, Monterey, CA, Oct 1976 18. Kuriyarna M, Umezaki H , Fukuda Y, et al: Mitochondrial encephalomyopathy with lactate-pyruvate elevation and brain infarctions. Neurology (Cleveland) 34:72-77, 1984 19. Land JM, Hockaday JM, Trevor-Hughes JT, Ross BD: Childhood mitochondrial myopathy with ophthalmoplegia. J Neurol Sci 51:371-382, 1981 20. Land JM, Morgan-Hughes JA, Clark JB: Mitochondrial myopathy: biochemical studies revealing a deficiency of NADHcytochrome b reductase activity. J Neurol Sci 5O:l-13, 1981 21. Luft R, Ikkos D, Palrnieri G, et al: A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical and morphological study. J Clin Invest 41: 17761804, 1962 22. Markesbery WR. Lactic acidemia, mitochondrial myopathy, and basal ganglia calcification. Neurology (NY) 2’91057-1061, 1979 23. Marquis NR, Fritz B: The distribution of carnitine, acetyl carnitine, and carnitine acetyl transferase in rat tissues. J Biol Chem 24012193-2196, 1965 24. Mastaglia FL, Thompson PL, Papadimitrio JM: Mitochondrial myopathy with cardiomyopathy, lactic acidosis and response to prednisone and triamine. Aust N Z J Med 10:660-664, 1980 25. McLeod JG, Baker DC, Shorey CO, Kerr CB: Mitochondrial myopathy with multisystem abnormalities and normal ocular movements. J Neurol Sci 24:29-52, 1975 26. Monnens L, Gabreels F, Willems J: A metabolic myopathy associated with chronic lactic acidemia, growth failure, and nerve deafness. J Pediatr 86:983, 1975 27. Morgan-Hughes JA: Defects of the energy pathways of skeletal muscle. In Matthews OWB, Glaser G H (eds): Recent Advances in Clinical Neurology, Vol 3. Edinburgh, Churchill Livingstone, 1982, pp 1-46 28. Morgan-Hughes JA, Darveniza P, Kahn SN, et al: A mitochondrial myopathy characterized by a deficiency in reducible cytochrome b. Brain 100:617-640, 1977 488 Annals of Neurology Vol 16 No 4 October 1984 29. Morgan-Hughes JA, Darveniza P, Landon D N , et al: A mitochondrial myopathy with a deficiency of respiratory chain NADH-CoQ reductase activity. J Neurol Sci 43:27-46, 1979 30. Oldendorf WH, Cornford ME, Brown WJ: The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1:409-417, 1977 31. Riggs JE, Schochet SS, Fakadej AV, et al: Mitochondrial encephalomyopathy with decreased succinate-cytochrome c reductase activity. Neurology (Cleveland) 34:48-53, 1984 32. Rowland LP, Hays AP, DiMauro S, et al: Diverse clinical disorders associated with morphological abnormalities of mitochondria. In Cerri C, Scarlato G (eds): Mitochondrial Pathology in Muscle Diseases. Padua, Piccin Edirore, 1983, pp 141-158 33. Schotland DL, DiMauro S, Bonilla E, et al: Neuromuscular disorder associated with a defect in mitochondrial energy supply. Arch Neurol 33:475-479, 1976 34. Shapira Y, Cederbaum SD, Cancilla PA, et al: Familial poliodystrophy, mitochondrial myopathy and lactic acidemia. Neurology (NY) 25:614-621, 1979 35. Skoglund R Reversible alexia, mitochondrial myopathy and lactic acidemia. Neurology (NY) 29717-720, 1979 36. Sottocasa GL, Kuylestierna B, Ernster L, Bergstran A: An electron transport system associated with the outer membrane of liver mitochondria. J Cell Biol 32:415-433, 1967 37. Spiro AJ, Moore CL, Prineas JW, et al: A cytochrome related inherited disorder of the nervous system and muscle. Arch Neurol 23:103-112, 1970 38. Srere PA: Citrate synthase. Methods Enzymol 13:3-11, 1969 39. Tarlow MJ, Lake BD, Lloyd JK. Chronic lactic acidosis in association with myopathy. Arch Dis Child 48:489-492, 1973 40. van Biervliet JP, DeBree PK, Bruinvis L, et ak Hereditary mitochondrial myopathy with lactic acidemia, a DeToni-FanconiDebre syndrome and a defective respiratory chain in voluntary striated muscles. Pediatr Res 11:1088-1090, 1977 41. van Wijngaarden GK, Bethlem J, Meijer AE, et al: Skeletal muscle disease with abnormal mitochondria. Brain 90:577-592, 1967 42. Wharton DL, Tzagoloff A: Cytochrome oxidase from beef heart mitochondria. Methods Enzymol 10:245-250, 1967 43. Wiseman A, Artardi G: Cytoplasmically inherited mutations of a human cell line resulting in deficient mitochondrial protein syn. thesis. Somat Cell Genetics 5:241-262, 1979