syndromes in the neonatal period and are unlikely diag- noses in an ..... Gardner-Medwin D, Dale G, Parkin JM: Lactic acidosis with mitochon- drial myopathy ...
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Genetic defects involving enzymes of the urea cycle, such as ornithine transcarbamoylase or carbamoylphosphate synthetase, are possible causes of hyperammonemia.3 These defects, however, present distinctive clinical syndromes in the neonatal period and are unlikely diagnoses in an otherwise healthy 16-year-old. Interestingly, hyperammonemia with normal liver function is a frequent feature of several genetic syndromes involving errors of amino acid metabolism, grouped under the heading of "organic acidemias."3'7 Examples include propionic, isovaleric, and methylmalonic acidemias. Hyperammonemia develops in these patients with organic acidemias even though all the enzymes of the urea cycle are present in normal amounts and function normally in vitro. There is experimental evidence that high levels of these organic acids,8' or their coenzyme A esters,'0 can severely inhibit the conversion of ammonia into urea. Specifically, there is a decrease in the production of N-acetylglutamate, an allosteric activator of carbamoylphosphate synthetase. Carbamoylphosphate synthetase catalyzes the crucial reaction by which ammonia enters the urea cycle; a decrease in the amount of its activator (N-acetylglutamate) leads to a buildup of ammonia. Because methanol toxicity can be regarded as an acquired organic acidemia (that is, formic acidemia), we speculate that formic acid may exert an indirect effect on ammonia clearance similar to that of the organic acids mentioned earlier. We further suggest that hyperammonemia may be an important and hitherto unappreciated contributor to the profound impairment of the central nervous system seen in patients with methanol poisoning. We encourage the early measurement of serum ammonia levels in suspected or confirmed cases of methanol toxicity, to help determine if this represents an isolated incident or a consistent feature of this disorder. REFERENCES 1. Kruse JA: Methanol poisoning. Intensive Care Med 1992; 18:391-397 2. Agency for Toxic Substances and Disease Registry: Methanol toxicity. Am Fam Phys 1993; 47:163-171 3. Rezvani I, Auerbach VH: Urea cycle and hyperammonemia, In Behrman RE, Vaughan VC, Nelson WE (Eds): Nelson Textbook of Pediatrics, 13th edition. Philadelphia, Pa, WB Saunders, 1987, pp 297-301 4. Balistreri WF: Reye syndrome, In Behrman RE, Vaughan VC, Nelson WE (Eds): Nelson Textbook of Pediatrics, 13th edition. Philadelphia, Pa, WB Saunders, 1987, pp 840-842 5. Grufferman S, Morris D, Alvarez J: Methanol poisoning complicated by
myoglobinuric renal failure. Am J Emerg Med 1985; 3:24-26 6. Rosenberg LE, Fenton WA: Disorders of propionate and methylmalonate metabolism, In Scriver CR, Beaudet AL, Sly WS, Valle D (Eds): The Metabolic Basis of Inherited Disease. New York, NY, Health Professions Division, McGraw-Hill, 1989, pp 821-845 7. Sweetman L: Branched chain organic acidurias, In Scriver CR, Beaudet AL, Sly WS, Valle D (Eds): The Metabolic Basis of Inherited Disease. New York, NY, Health Professions Division, McGraw-Hill, 1989, pp 791-821 8. Stewart PM, Walser M: Failure of the nornal ureagenic response to amino acids in organic acid-loaded rats. J Clin Invest 1980; 66:484-492 9. Glasgow AM, Chase HP: Effect of propionic acid on fatty acid oxidation and ureagenesis. Pediatr Res 1976; 10:683-686 10. Coude FX, Sweetman L, Nyhan WL: Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria-A possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest 1979; 64:1544-1551
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MELAS Syndrome STEVEN J. KOGA, MD MARIAN HODGES, MD, MPH CATHERINE MARKIN, MD PAUL GORMAN, MD Portland, Oregon
MELAS IS THE SYNDROME OF mitochondrial encephalopathy, lactic acidosis, and strokelike episodes.' It is one of a number of mitochondrial syndromes that share the common characteristics of encephalopathy and myopathy. Other mitochondrial diseases include myoclonus and epilepsy with ragged redfibers (MERRF),2 Kearns-Sayre syndrome,34 and progressive external ophthalmoplegia.5 In recent years these syndromes have been shown to be associated with specific mutations of mitochondrial DNA (mtDNA).'-" At the same time, more common conditions such as cardiomyopathy, aminoglycoside-induced ototoxicity, and some forms of diabetes mellitus also have been shown to be associated with mitochondrial DNA mutations."-" These associations, and the recognition of "incomplete" forms of the above encephalopathic and myopathic syndromes, indicate that mitochondrial dysfunction may be underrecognized in the pathogenesis of a number of diseases. We report the case of a patient with the MELAS syndrome. We use the case as a basis for discussing the current clinical and molecular understanding of the syndrome and to explore the probable role of mitochondrial mutations in other diseases. Report of a Case A 43-year-old woman presented to the emergency department in respiratory arrest after five tonic-clonic seizures. She had had lethargy with nausea, vomiting, and diarrhea for a week and slurred speech for two days before admission. The patient's husband reported that she had been healthy with the exception of exercise intolerance and hearing loss since childhood. Her family history was relevant for at least ten maternally related family members with some combination of hearing loss, small stature, and adult-onset diabetes mellitus. On physical examination she appeared ill, was of slight build, and was being sustained by mechanical ventilation. Her blood pressure was 80/50 mm of mercury, her heart rate 100 beats per minute, respiratory rate 24 breaths per minute, and temperature 38. 1°C (100.6°F). She was unresponsive even to deep pain, and her lungs had bibasilar crackles. Laboratory evaluation showed an arterial pH of 7.20;
(Koga SJ, Hodges M, Markin C, Gorman P: MELAS syndrome. West J Med 1995; 163:379-381) From the Department of Medical Education, Providence Medical Center (Drs Koga and Markin), and the Division of General Internal Medicine (Dr Hodges) and the Biomedical Information Communication Center (Dr Gorman), Oregon Health Sciences University, Portland. Reprint requests to Steven J. Koga, MD, Caldwell Internal Medicine PA, 1818 S 10th St, Caldwell, ID 83605.
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a serum lactate level of 0.62 mmol per liter (0.62 mEq per liter; normal, 0.5 to 2.2 mmol per liter); serum bicarbonate, 12 mmol per liter (12 mEq per liter; normal, 23 to 29); and serum glucose, 10.0 mmol per liter (180 mg per dl; normal, 3.8 to 6.4 mmol per liter). An echocardiogram showed global hypokinesis with an ejection fraction estimated at 20%, and magnetic resonance imaging of the brain showed a left parietotemporal infarct, diffuse cerebral atrophy, and bilateral basal ganglial calcifications. The patient was suffering from multisystem failure, the cause of which was not clear. A MEDLINE search was done using the keywords "deafness," "diabetes mellitus," and "myocardial disease." A single reference was recovered implicating mitochondrial disease as the basis for such a syndrome.'3 This led to a presumptive diagnosis of the MELAS syndrome, which was later confirmed by a muscle biopsy showing ragged red fibers and DNA testing that revealed the characteristic mitochondrial DNA mutation of the MELAS syndrome.
Discussion In 1975 a syndrome consisting of lactic acidosis and mitochondrial myopathy was described in two separate reports.202' The acronym MELAS was proposed for the syndrome in 1984.' In a review in 1992, the diagnostic criteria were clarified using 69 cases.22 It was proposed that the syndrome should be suspected by the presence of three invariant criteria: strokelike episodes before age 40; encephalopathy characterized by seizures, dementia, or both; and either ragged red fibers on muscle biopsy or the presence of lactic acidosis, or both. It was further proposed that the diagnosis could be considered secure if any two of normal early development, recurrent headache, and recurrent vomiting also were present. The same year, 40 different cases of MELAS were reported.23 Both studies noted the presence of the above-named characteristics plus exercise intolerance, muscle weakness, and computed tomographic scan abnormalities-low-density areas, cortical atrophy, basal ganglia calcifications-in greater than 80% of cases. Other clinical signs have been noted, including short stature, hearing loss, positive family history, and cardiomyopathy. More than 80% of the patients with the MELAS syndrome who have undergone genetic testing have been shown to carry a specific point mutation of mtDNA-an adenine to guanine transition at position 3243 of the mitochondrial genome.23Y4 This mutation lies within the DNA coding for the transfer RNA specific for leucine.'It is hypothesized that the mtDNA mutation causes a generalized impairment of protein translation that leads to defects of multiple respiratory chain enzymes. This disruption of aerobic metabolism would result in the clinical manifestations of the syndrome." The MELAS syndrome is acquired only through maternal transmission because the ovum supplies close to 100% of the mitochondria to the zygote. This pattern of inheritance can be confused with autosomal dominant inheritance, but is distinguished by the lack of paternal transmission of the trait. A thorough family history of our
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patient revealed a pattern of maternal inheritance for at least four preceding generations. Affected family members possessed any number of the following characteristics: deafness, small stature, diabetes mellitus, and exercise intolerance. Of these characteristics, deafness was the most pervasive and a critical clinical feature in reaching a unifying diagnosis. Our patient did have one child, a 14-year-old son, who was noted to be of small stature but had yet to demonstrate any other signs or symptoms of MELAS. It should be noted that the mtDNA mutation is not found in all the mitochondria of an afflicted person. There exists a mixture of normal and mutant mtDNAs within a single cell-a condition called heteroplasmy.6'4 The percentage of mutant mtDNA within different tissues also varies.2", These findings might account for the variety of clinical manifestations seen in persons with the MELAS syndrome. Furthermore, asymptomatic or oligosymptomatic relatives of MELAS patients have been shown to have mutant mtDNA, but in levels proportional to the severity of their disease.2' This adds to the evidence that the mutation plays a direct role in the pathogenesis of the syndrome. Overall morbidity and mortality data for the MELAS syndrome are not known. Likewise, there is no known definitive therapy for the syndrome. A case has been reported of a MELAS patient who was successfully treated with riboflavin and niacinamide (nicotinamide)-precursors of coenzymes in the mitochondrial electron transport chain.26 The patient presented here was treated supportively during her prolonged hospital stay, as well as empirically with the administration of niacinamide and riboflavin. She had a slow but progressive return to her previous functional status, and after nine months her symptoms had not recurred. The MELAS syndrome is one of a number of known mitochondrial syndromes. As with MELAS, most of these syndromes are associated with specific nucleic acid mutations. MERRF is a syndrome characterized by myoclonus, epilepsy, ataxia, and ragged red fibers on muscle biopsy. It is associated with a specific transfer RNA point mutation.7 Similarly, Leber's hereditary optic neuropathy-a syndrome of central optic nerve death, blindness, and cardiac dysrhythmia-and a syndrome of ataxia, retinitis pigmentosa, and peripheral neuropathy are associated with point mutations within respiratory complex genes of mitochondria."1 Two other syndromes, progressive external ophthalmoplegia and a syndrome of ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia known as Keams-Sayre syndrome, have been associated with large deletions in mtDNA.10 These mitochondrial syndromes illustrate the broad spectrum of disease caused by mutations in mtDNA. There is a relationship between mtDNA abnormalities and disease states other than encephalomyopathies (such as MELAS). A report in 1992 demonstrated an excess of maternal transmission of non-insulin-dependent diabetes mellitus, whereas several other studies have associated
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some forms of diabetes with specific mtDNA mutations.'2'3"8 Furthermore, an mtDNA point mutation has been associated with a syndrome of adult-onset myopathy and cardiomyopathy," and recent data have demonstrated an mtDNA mutation that confers susceptibility to aminoglycoside ototoxicity.Y4"6 This information represents a rapid increase in the recognition and understanding of mitochondrial disease and should serve to sensitize clinicians to patterns of maternal inheritance,
particularly in patients with multisystem disease. Furthermore, they suggest a role for mtDNA defects in more common disorders. The current understanding of the MELAS syndrome and other diseases related to mtDNA mutations is a result of recent advances in molecular biology and molecular diagnostic techniques. A number of diseases were discussed in a recent editorial-including those caused by mutations in mtDNA-that now have been introduced into the realm of adult medicine as a result of advances in medical science.2" These range from conditions such as
cystic fibrosis and phenylketonuria, in which early recognition and management have allowed survival well into adulthood, to adult-onset genetic disorders such as the mitochondrial encephalomyopathies. The editorial writers called for internists-and we would include all practitioners of adult medicine-to assume increased responsibility for the diagnosis and management of this expanding number of disorders. This case report serves to emphasize the need for greater recognition and understanding of disorders related to mitochondrial dysfunction (as well as the growing number of "new" adult diseases) and illustrates one strategy for dealing with the need for an ever-expanding knowledge base-the use of computer-based information systems. REFERENCES 1. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Ann Neurol 1984; 16:481-488 2. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T: Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): Disease entity or a syndrome?-Light- and electron-microscopic studies of two cases and review of literature. J Neurol Sci 1980; 47:117-133 3. Kearns TP, Sayre GP: Retinitis pigmentosa, extemal ophthalmoplegia, and complete heart block. Arch Ophthalmol 1958; 60:280-289 4. Shy GM, Silberberg DH, Appel SH, Mishkin MM, Godfrey EH: A generalized disorder of nervous system, skeletal muscle and heart resembling Refsum's disease and Hurler's syndrome: Clinical, pathologic and biochemical characteristics. Am J Med 1967; 42:163-168 5. Morgan-Hughes JA: Mitochondrial myopathies, In Mastaglia FL, Walton J (Eds): Skeletal Muscle Pathology. Edinburgh, Scotland, Churchill Livingstone, 1982, pp 309-339 6. Goto Y, Nonaka I, Horai S: A mutation in the tRNA (Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990; 348:651-653
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7. Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC: Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990; 61:931-937 8. Holt IJ, Harding AE, Morgan-Hughes JA: Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331:717-719 9. Zeviani M, Moraes CT, DiMauro S, et al: Deletion of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346 10. Moraes CT, DiMauro S, Zeviani M, et al: Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989; 320:1293-1299 11. Zeviani M, Gellera C, Antozzi C, et al: Maternally inherited myopathy and cardiomegaly: Association with mutation in mitochondrial DNA tRNA(Leu)(UUR). Lancet 1991; 338:143-147 12. Reardon W, Ross RJM, Sweeney MG, et al: Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 1992; 340:13761379 13. Gerbitz KD, Paprotta A, Jaksch M, Zierz S, Drechsel J: Diabetes mellitus is one of the heterogeneous phenotypic features of a mitochondrial DNA point mutation within the tRNA(Leu)(UUR) gene. Fed Eur Biochem Soc 1993; 321:194196 14. Hutchin T, Haworth I, Higashi K, et al: A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Res 1993; 21:41744179 15. Hu DN, Qui WQ, Wu BT, et al: Genetic aspects of antibiotic induced deafness: Mitochondrial inheritance. J Med Genet 1991; 28:79-83 16. Prezant TR, Agapian JV, Bohlman MC, et al: Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and nonsyndromic deafness. Nat Genet 1993; 4:289-294 17. Fischel-Ghodsian N, Prezant TR, Bu X, Oztas S: Mitochondrial ribosomal RNA gene mutation in a patient with sporadic aminoglycoside ototoxicity. Am J Otolaryngol 1993; 14:399-403 18. Kadowaki T, Kadowaki H, Mori Y, et al: A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330:962968 19. Ballinger SW, Shoffner JM, Hedaya EV, et al: Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet 1992; 1:1 1- 1 5 20. Gardner-Medwin D, Dale G, Parkin JM: Lactic acidosis with mitochondrial myopathy and recurrent coma (Abstr). First International Congress on Child Neurology 1975, No. 47 21. Koenigsberger MR, Pellock JM, DiMauro SS, Eastwood AB: Juvenile mitochondrial myopathy, short stature and lactic acidosis: A clinical, biochemical and ultrastructural study (Abstr). Fifth National Meeting of the Child Neurology Society, 1976 22. Hirano M, Ricci E, Koenigsberger MR, et al: MELAS: An original case and clinical criteria for diagnosis. Neuromuscul Disord 1992; 2:125-135 23. Goto Y, Horai S, Matsuoka T, et al: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): A correlative study of the clinical features and mitochondrial DNA mutation. Neurology 1992; 42:545-550 24. Ciafaloni E, Ricci E, Shanske S, et al: MELAS: Clinical features, biochemistry, and molecular genetics. Ann Neurol 1992; 31:391-398 25. Mosewich RK, Donat JR, DiMauro S, et al: The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes presenting without stroke. Arch Neurol 1993; 50:275-278 26. Penn AMW, Lee JWK, Thuillier P, et al: MELAS syndrome with mitochondrial tRNA(Leu)(UUR) mutation: Correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 1992; 42:2147-2152 27. Segal S, Roth KS: Inborn errors of metabolism: A new purview of internal medicine (Editorial). Ann Intern Med 1994; 120:245-246
