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Biochemical Studies in Mitochondrial Encephalomyopathy J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.10.1348 on 1 October 1987. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1987;50:1348-1352 Biochemical studies in mitochondrial encephalomyopathy SHUICHIRO GODA,* SHINJI ISHIMOTO,* IKUO GOTO,* YOSHIGORO KUROIWA,* KICHIKO KOIKE,f MASAHIKO KOIKE,t MASANORI NAKAGAWA,4 HEINZ REICHMANN,t SALVATORE DIMAURO,4 From the Department ofNeurology,* Neurological Institute, Faculty ofMedicine, Kyushu University; Department ofPathological Biochemistry, Atomic Disease Institute,t Nagasaki University School ofMedicine, Japan; and H Houston Merritt Clinical Research Centerfor Muscular Dystrophy and Related Diseases,$ The College ofPhysicians and Surgeons ofColumbia University, USA SUMMARY The alpha-keto acid dehydrogenase complex and its component enzymes, lactate dehy- drogenase, pyruvate carboxylase, cytochrome c oxidase, succinate-cytochrome c reductase, NADH- cytochrome c reductase, and the concentration of cytochromes and enzymes of beta-oxidation in muscle from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke- like were episodes studied and no specific defect was found. These results raise the possibility thatguest. Protected by copyright. the mitochondrial changes in the patient may be secondary. A syndrome which has been labelled formances gradually deteriorated. She became nauseated MELAS '(mitochondrial myopathy, encephalopathy, during exercise without pain or weakness. At age 14 she had lactic acidosis and stroke-like episodes) is character- two generalised seizures. Five months after the first attack ised by seizures and stroke-like symptoms as well as she suddenly developed right hemiparesis, numbness of the lactic acidosis, ragged-red fibres and dementia. tongue and speech disturbances, followed by several attacks Although the clinical features are of jerky involuntary movements of the right arm and relatively dis- in calculation. Her tinctive, the biochemical abnormalities reported so difficulty family history was far have not been unremarkable. uniform. We studied several On admission her was 38 enzymes and the weight kg (- 16 SD) and her concentration of cytochromes in iso- height 151 cm (- 10 SD). She was alert, but showed mild lated muscle mitochondria from a patient with the memory disturbances, paraphasia, agraphia, acalculia and syndrome, and found no specific defect of the respira- constructional apraxia. She had right homonymous hemi- tory chain. anopia with concentric constriction of the visual field. Optic fundi and external ocular movement were normal and there Case report was no ptosis. Auditory acuity was normal. There was mod- erate weakness of the right limbs. Deep tendon reflexes were A girl, the second child of unconsanguineous healthy par- moderately hyperactive in both legs. Muscle tone was nor- ents had mal. She had mild of the normal growth and development until age 10 years impairment light touch and joint http://jnnp.bmj.com/ but she could never run as fast as her peers. At age 11, she position sense on the right half of the body. No cerebellar began to complain of nausea and headache during swim- ataxia was found. ming and had recurrent febrile illnesses. She also had visual Normal laboratory tests included: complete blood count, problems and concentric field constriction was found by an blood coagulation and platelet function tests, serum electro- ophthalmologist. CT scan at that time was normal but EEG lyte, cholesterol, triglyceride and free fatty acids, serological showed bilateral synchronous spike and wave bursts. At age tests including viral studies, thyroid and adrenal function 12 febrile episodes spontaneously subsided but school per- tests, serum copper, ceruloplasmin, thiamine, ammonia and galactose, basal metabolic rate, CSF protein concentration, echocardiogram. The following tests gave abnormal results on September 27, 2021 by Address for reprint requests: Dr S of (normal values in parentheses): urinalysis showed ketonuria, Goda, Department Neurology, serum Neurological Institute, Faculty of Medicine, Kyushu University 60, creatine kinase (CK) was 400 IU/I (15-60), lactate 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan. dehydrogenase (LDH) was 984 IU/l (120-250), and glutamic-oxaloacetic transaminase (GOT) was 127 IU/I (less Received 3 April 1986 and in revised form 6 August 1986. than 40); serum lactate varied between 40 2 and 83-7 mg/dl Accepted 23 October 1986 (4-16), and serum pyruvate between 0-82 and 1 89 mg/dl 1348 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.10.1348 on 1 October 1987. Downloaded from l U .9-I fh r~~~~~~~~r A. i F.- ~ ~ F wS z O, * V7.3 Jftt guest. Protected by copyright. _~~~~~~~~~~~~~~~~~~~~~~~~,J A ~ ~~~~ a http://jnnp.bmj.com/ on September 27, 2021 by Fig 11a-t4i ?iclt l iil-Cof9vizlalZiH. 25")/. A.l.sZc.t ni-sl<' an.f va'ablfz ' in .;7cs_'ttztnconlSf'/leI vC' Is71si7x'sK% Basf¢/ph I b/rt-'I (...Itt N. ; l- /. i /i' t)Rl Xltsf. !) ol:< I.J(})o. ..I tl 1) t't? Il t?iff'I ch n riaI 11fX/I Ip//rzZ;)(tI inclld vif zE)ti.il ith-,lz8 E cir !11t'0 0.COOs f x 4 Tle' upperlfirct contalZItE.( MWIV1-AaiI J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.50.10.1348 on 1 October 1987. Downloaded from 1350 Goda, Ishimoto, Goto, Kuroiwa, Koike, Koike, Nakagawa, Reichmann, DiMauro (0 3-0 9); arterial blood showed pH 7 37, PO2 105 mm Hg, Results pCO2 32 mm Hg, base excess 5 4 mmoles/l; CSF lactate was 76-9 mg/dl (mean: 19 0) and pyruvate was 3 0 mg/dl Morphology With the haematoxylin-eosin stain, (mean: 1-02). EEG showed marked slowing of the back- muscle fibres ranged 20-60 pm (mainly 40-50 pm) in ground activity, irregular slow waves at the left temporal diameter and a slight increase in endomysial con- area and bilateral synchronous spike and wave bursts. Peri- nective tissue was seen. With the modified trichrome odic sharp waves were transiently seen at the left temporal 5 to 10% of fibres were so-called area. A high-amplitude somatosensory evoked potential stain approximately (SEP) was evoked bilaterally by median nerve stimulation "ragged-red" fibres, which showed increased sub- with a wave form abnormality similar to that of myoclonic sarcolemmal activity in NADH tetrazolium reductase epilepsy. A giant SEP with C response was evoked by the left stain. Increased subsarcolemmal activities in scat- median nerve stimulation. No visual evoked potential was tered fibres were also seen in succinic dehydrogenase evoked by stimulation of the right hemifield in checkerboard and PAS stain. But Sudan III stain did not show pattern reversal, but normal P100 was evoked by stimulation apparent lipid deposits. Acid phosphatase was nega- of the left hemifield. Auditory brainstem responses were nor- tive. With the myosin ATPase normal checkerboard mal. Needle EMG revealed low amplitude polyphasic motor pattern was preserved. With ubiquinone and cyto- unit potentials in the muscles of the right arm; no abnormal- sub- ities were noted in the other muscles. Nerve conduction chrome oxidase stain 5-10% of fibres with dense velocities were normal in the right median, sural and tibial sarcolemmal staining were seen scattered respectively nerves. and no apparent decrease in overall activity com- Brain CT scan on admission showed a low density area pared with the controls was observed. With mito- with irregular enhancement in the left temporo-parietal lobe, chondrial ATPase there was no difference between the which disappeared 2 weeks later when another low density case and the control. Electron microscopy showed area was found in the left occipital lobe. Cerebral angio- increased number and size of the mitochondria, graphy showed hypervascularity at the left occipital lobe, packed cristae and peculiar inclusion bodies (fig). which was considered to reflect hyperaemia after infarction. was stored atguest. Protected by copyright. elevation of blood lactate and pyruvate was Biochemistry The muscle biopsy Marked - noted after slight exercise. No hypoglycaemia was found 80°C until use. Alpha-keto acid dehydrogenase during 36 hours of fasting. Blood glucose increased normally complex and component enzymes, pyruvate carboxy- after glucagon injection and venous lactate increased nor- lase and lactate dehydrogenase were assayed by the mally after forearm ischaemic exercise. Glucose, alanine and methods of Koike et al,2 Atkin et al3 and Okabe et galactose tolerance tests caused elevation of lactate. Hypo- Table 1 Enzymes concerned with pyruvate metabolism glycaemia was not induced by fructose, glycerol or alanine loads. Patient Control The patient's clinical state and blood lactate and pyruvate levels were not influenced by high-fat or high-carbohydrate Pyruvate dehydrogenase diets or by intravenous fat infusion. complex 35-1 1-15 Paraphasia and memory disturbances disappeared soon Pyruvate dehydrogenase 3-1 1-2-3 The worsened during the Lipoate acetyl after admission. reading difficulty transferase 106 100-400 first month of admission, then improved and reading was Lipoamide dehydrogenase 3600 1000-3000 normal by the tenth week. Agraphia also improved but Pyruvate carboxylase 3 9 1-18 incompletely. Serum enzymes returned to normal values Lactate dehydrogenase 69-7 x 03 50-250 x 2-oxoglutarate within 2 weeks. She had an episode of status epilepticus after dehydrogenase complex 44-7 2-20 intense exercise, followed by postictal stupor. This episode 2-oxoglutarate dehydrogenase 13 8 2-24 was accompanied by marked elevation of serum lactate and pyruvate
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