Kearns-Sayre syndrome

Autopsy reports of patients with mitochondrial encephalopathy with lactic acidosis and strokelike episode (MELAS) are rare. This report documents the clinical and autopsy findings of a 47-year-old woman with MELAS syndrome. The diagnosis was corroborated by documenting a mitochondrial DNA mutation tRNA-Leu (UUR) at position 3243. The patient's clinical history was marked by schizophrenia, peptic ulcer disease, constipation requiring hemicolectomy, migraine headaches, deafness, and a left temporal lobe infarct. At autopsy, a muscle biopsy demonstrated numerous ragged red fibers and a partial cytochrome C oxidase deficiency. By electron microscopy, increased numbers of slightly hypertrophic mitochondria were observed focally within myocytes and vessel walls; paracrystalline mitochondrial inclusions were not seen. The brain at autopsy showed mild cerebral atrophy and diffuse cortical gliosis. Prominent bilateral basal ganglia calcifications and vascular sclerosis were present, and a small remote left temporal lobe infarct was seen.

(Arch Pathol Lab Med. 1998;122:978-981)

The mitochondrial encephalomyopathies are a group of varied disorders frequently characterized by an underlying defect in mitochondrial DNA. Most of these syndromes are characterized by skeletal muscle and cerebral symptomatology and pathology.1 A number of syndromes have fallen under the general term of mitochondrial encephalomyopathy, including Kearns-Sayre syndrome,2 myoclonic epilepsy with ragged red fibers (MERRF),3 and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS).4

Relatively few complete autopsy reports on patients with MELAS syndrome have appeared in the literature. This report summarizes the autopsy results of a 47-yearold woman with MELAS syndrome confirmed by mitochondrial DNA analysis. The pathologic findings in this case are compared with previous cases reported in the literature.

REPORT OF A CASE

The patient was a 47-year-old woman who presented approximately 3 months prior to her death with symptoms of increased confusion. The patient's medical history was significant for a 20year history of paranoid schizophrenia, protein calorie malnutrition, peptic ulcer disease requiring partial gastrectomy, constipation and obstruction requiring a hemicolectomy, migraine headaches, deafness, and a left temporal lobe infarct. At the time of presentation, the patient experienced a generalized tonic clonic seizure. Magnetic resonance imaging showed bilateral calcifications of the basal ganglia (Figure 1) and a small left temporal lobe infarct. Previous lactic acid levels were reported to have been elevated, and a pyruvate level of 193 (mu)mol/L (normal 34 to 102 (mu)mol/L) was noted. An electroencephalographic study showed severe generalized disorganization, indicating a diffuse encephalopathy. Urine toxicology was negative. The patient subsequently developed upper quadrant pain, and an abdominal computed tomographic scan (CT scan) showed an inferior vena cava thrombus with extension into the right femoral veins. Heparin therapy was started and upper gastrointestinal hemorrhage ensued. A Greenfield filter was placed. The patient subsequently became septic with blood cultures positive for Staphylococcus aureus. Approximately 3 months after presentation, the patient died and a complete autopsy was performed.

AUTOPSY FINDINGS

The left iliopsoas muscle was examined. Routine formalin-fixed, paraffin-embedded cross and longitudinally oriented sections of skeletal muscle showed no evidence of inflammation, vasculitis, or granulomas. No significant increase in endomysial fat or fibrous tissue was evident. There was a mild variation in muscle fiber size. Enzyme histochemistry and special stains, including acid and alkaline phosphatase, esterase, nicotinomide-adenine dinucleotide (reduced form), cytochrome C oxidase, periodic acid-Schiff, oil red O, modified Gomori's trichrome, sulfonated Alcan blue, and adenosine triphosphatase at pH 4.6 and 9.8, were performed on frozen muscle material. The trichrome stain showed increased numbers of ragged red fibers (approximately 1% of muscle fibers examined) (Figure 2). Scattered muscle fibers showed an absence of staining with cytochrome C oxidase (

Examination of the brain and spinal cord included histologic sections from each level of the spinal cord, medulla, pons, midbrain, cerebellum including dentate nucleus, bilateral hippocampus, bilateral basal ganglia, and mamillary bodies, and representative sections from the frontal lobe, parietal lobe, and occipital lobe. Gross examination of the brain showed mild cerebral atrophy (brain weight 1120 g). A small hematoma was noted in the right temporal horn, and a small remote infarct was seen in the left temporal lobe region, measuring 0.7 cm in greatest dimension. Prominent mineralization of both basal ganglia was also present. Examination of histologic sections confirmed the presence of prominent basal ganglia calcification, most notably in the gray matter parenchyma and in a perivascular distribution in both gray and white matter (Figure 5). Staining of mineralized concretions was positive with a von Kossa stain and focally positive with Prussian blue. A small remote infarct was noted in the gray matter of the left temporal lobe. Widespread mild gliosis was seen throughout the cerebral cortices and cerebellum. Vessels in the basal ganglia and temporal lobe regions showed moderate vascular thickening and focal calcifications. Ultrastructural examination of tissue from the frontal lobe region was performed. Specific abnormalities, including increased or abnormal mitochondria, were not identified in this evaluation. In addition, a mild focal loss of cerebellar Purkinje cells accompanied by a mild gliosis was present.

Other pathologic findings at the time of the autopsy included a panlobar pneumonia, which was felt to be secondary to aspiration. The patient was severely cachectic overall and had brown atrophy of the heart (150 g) as well as atrophy of the liver, pancreas, and spleen. Organized thrombi were noted in the inferior vena cava and right femoral vein. There was a small acute pulmonary thromboembolism in the left lower lobe of lung. Multiple acute gastric erosions with evidence of gastric hemorrhage were also noted. A congenital right hydronephrosis and bilateral pyelonephritis were seen.

COMMENT

In 1994, Hirano and Pavlakis6 reviewed 110 previously reported cases of MELAS and noted that more than 90% of patients presented prior to the age of 40 years with exercise intolerance, strokes, seizures, ragged red fibers on muscle biopsy, and lactic acidosis. The patient in this report demonstrated all of these clinical features with the exception of a lack of documentation with regard to exercise intolerance. Our patient also demonstrated a number of other features encountered somewhat less frequently in patients with MELAS, including headaches, hearing loss, and evidence of prominent basal ganglia calcification radiographically.6,7 Somewhat unique in our patient was a long history of schizophrenia, a feature that to our knowledge has not been previously associated with MELAS. Whether this feature represented part of this patient's disease process or was a coincidental occurrence is not known. Basal ganglia calcification was noted in 24 (45%) of 53 patients with MELAS in one review of the literature.6

The pathologic findings in muscle biopsies of patients with MELAS have been well documented and include the presence of ragged red fibers, which are best seen on a trichrome stain. These fibers are somewhat nonspecific, however, in that they can be present in any of the mitochondrial myopathies or encephalomyopathies, as well as in a wide variety of other conditions, including polymyositis, inclusion body myositis, dermatomyositis, with certain drugs, and in normal elderly individuals.8-10 It has been suggested that ragged red fibers are present in conditions associated with an impairment of mitochondrial protein synthesis as opposed to conditions resulting from point mutations in structural genes.11 This process ultimately results in disruption of oxidative phosphorylation and subsequent decreased protein synthesis, which may act as an induction for mitochondrial proliferation.12 In addition, a partial cytochrome C oxidase deficiency has also been described in some cases of MELAS.13,14 However, it appears that although cytochrome C oxidase may be decreased, the most significantly deficient enzyme of oxidative phosphorylation in patients with MELAS involves complex I.15

Another interesting finding in this case, which has rarely been previously reported, is the presence of increased numbers of mitochondria within endothelial and smooth muscle cells comprising small vessel walls.16,17 Similar cases have been documented that rarely involve small vessels in the brain.13,18,19 Various hypotheses have been advanced to explain these findings. Ohama et al18 suggested that the strokes encountered in the setting of MELAS are most likely due to vascular changes caused by primary mitochondrial dysfunction in vascular wall smooth muscle and endothelial cells within the brain. They further conjectured that the mitochondrial accumulation seen within vessel walls may be induced by a chronic ischemic condition, perhaps secondary to impaired cardiac function, which has been described in a subset of patients with MELAS.18 It may be that the prominent mineralization that is seen in many patients with MELAS likewise represents the effects of localized ischemia related to vascular disease. Kishi et al13 suggested that the strokelike changes may be related to vasculopathy. More recently, mitochondrial RNA was assessed in vessels near infarcts as compared with vessels distant to the infarcts using in situ hybridization.20 This study noted increased hybridization signal with mitochondrial probes in blood vessels adjacent to the infarcts, suggesting that the mitochondria may accumulate in response to cerebral infarction or ischemia.20 Alternately, DiTrapani and colleagues21 hypothesized that the disruption of mitochondrial metabolism may be the underlying factor in the development of cerebral ischemic lesions.

Autopsy findings in the brains of patients with MELAS have been documented in slightly more than a dozen cases in the literature.13,14,18,19,22-28 In the majority of these cases, cerebral atrophy and foci of necrosis/infarct were documented at autopsy, similar to our case. Likewise, basal ganglia calcification was found in the vast majority of cases, particularly in a perivascular distribution. Energydispersive x-ray analysis of the mineralized deposits have shown an accumulation of calcium, phosphorous, iron, and sulfur.13 Many of the other findings that have been rarely reported, including Purkinje cell loss, loss of neurons in certain brainstem locations, and posterior column degeneration, appear to be less specific.

Two main mitochondrial DNA point mutations have been described in association with MELAS: 80% to 90% of patients have an A to G transition at nucleotide 3243 of tRNA-Leu (UUR) and, less commonly, patients have a T to C transition at nucleotide 3271.(6,29,30) Recently, a third uncommonly encountered mutation at nucleotide 3291 has been described.31 In a subset of patients, specific molecular abnormalities have not been demonstrable.32 Although it appears that these mutations, particularly the nucleotide 3243 mutation, are associated with MELAS, their presence may also be found in patients who do not have clinical evidence of MELAS. In general, there appears to be a correlation quantitatively between the clinical severity and the amount of mutation present in that clinically symptomatic individuals have higher percentages of mutant genomes in skeletal muscle as compared with asymptomatic individuals.33 It has been established that different mutations may result in the same clinical phenotype and that the same mutation may result in considerable phenotypic variability. It has also been noted that ragged red fibers seen in muscle biopsies histologically have higher levels of mutant genome as compared with nonragged red fibers.34

Special thanks go to Denise Egleton for her assistance in the preparation of this report.

References

1. Shapira Y, Harel S, Russell A. Mitochondrial encephalopathy: a group of neuromuscular disorders with defects in oxidative metabolism. Isr J Med Sci. 1977;13:161-164.

2. Kearns TP, Sayre GP. Retinitis pigmentosa, external ophthalmoplegia and complete heart block. Arch Ophthalmol.1958;60:280-287. 3. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibers (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.

4. Pavlakis SG, Phillips PC, DiMauro S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a distinctive clinical syndrome. Ann Neurol.1984;16:481-488.

5. Johnston W, Karpati G, Carpenter S, Arnold D, Shoubridge EA. Late-onset mitochondrial myopathy. Ann Neurol.1995;37:16-23. 6. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol.1994; 9:4-13.

7. Hirano M, Ricci E, Koenigsberger M, et al. MELAS: an original case and clinical criteria for diagnosis. Neuromusc Disord. 1992;2:125-135.

8. Rifai Z, Welle S, Kamp C, Thornton CA. Ragged red fibers in normal aging and inflammatory myopathy. Ann Neurol.1995;337:24-29. 9. Nelson RL, Prayson RA. Mitochondrial abnormalities and inclusion body myositis: a histopathologic and ultrastructural study of 36 patients. J Surg Pathol. 1997;2:63-68.

10. oh SJ, Thomas TD, Kuruoglu HR. Ragged red fibers and aging. Ann Neurol. 1992;32:253A.

11. DiMauro S, Moraes CT. Mitochondrial encephalomyopathies. Arch Neurol 1993;50:1197-1208.

12. Moraes CT, Ricci E, Petruzzella V, et al. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nat Genet.1991;1359367.

13. Kishi M, Yamamura Y, Kurihara T, et al. An autopsy case of mitochondrial encephalomyopathy: biochemical and electron microscopic studies of the brain. J Neurol Sci. 1988;86:31-40.

14. Nishizawa M, Tanaka K, Shinozawa K, et al. A mitochondrial encephalomyopathy with cardiomyopathy. J Neurol Sci. 1987;78:189-201. 15. Miyaboyashi S, Hanamizu H, Nakamura R, Hayashi J-I, Tada K. Clinical and biochemical phenotype of the MELAS mutation. J Inherit Metab Dis. 1993; 16:886-892.

16. Sakuta R, Nonaka I. Vascular involvement in mitochondrial myopathy. Ann Neurol. 1989;25:594-601.

17. Hasegawa H, Matusoka T, Goto Y-I, Nanoka I. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Ann Neurol. 1991;29:610-615.

18. Ohama E, Ohara S, Ikuta F, et al. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol (Berl). 1987;74:226-233.

19. Ihara Y, Namba R, Kuroda S, et al. Mitochondrial encephalomyopathy(MELAS): pathological study and successful therapy with coenzyme Q^sub 10^ and idebenone. J Neurol Sci. 1989;90:263-271.

20. Love S, Hilton DA. Assessment of the distribution of mitochondrial ribosomal RNA in MELAS and in thrombotic cerebral infarcts by in situ hybridization. J Pathol.1996;178:182-189.

21. DiTrapani G, Gregori B, Servidei S, Ricci E, Sabatelli M, Tonali P. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Clin Neuropathol. 1997;16:195-200.

22. Shapira Y, Cederbaum SC, Cancilla PA, et al. Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia. Neurology. 1975;25:614-621. 23. Hart Z, Chang C-H, Perrin E, et al. Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia. Arch Neurol. 1977;34:180-185.

24. Bogousslavsky , Perentes E, Deruaz , Regli F. Mitochondrial myopathy and cardiomyopathy with neurodegenerative features and multiple brain infarcts.

J Neurol Sci. 1982;55:351-357.

25. Mukoyama M, Kazui H, Sunohara N, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with acanthocytosis: a clinicopathological study of a unique case. J Neurol. 1986;233:228-232.

26. Hasuo K, Tamura S, Yasumori K, et al. Computed tomography and angiography in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes): report of 3 cases. Neuroradiology. 1987;29:393-397.

27. Oldfors A, Tulinius M, Holme E, et al. Mitochondrial encephalomyopathy: a variant with heart failure and liver steatosis. Acta Neuropathol (Berl). 1987;74: 287-293.

28. Hamazaki S, Okada S, Kusaka H, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: report of an autopsy. Acta Pathol Jpn. 1989;39:599-606.

29. Goto Y-1I, Nonaka I, Horai S. A mutation in the tRNALeu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348:651-653.

30. Goto Y-l, Nonaka I, Horai S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochem Biophys Acta. 1991;1097-328-240.

31. Goto Y-1, Tsugane K, Tanabe Y, Nonaka I, Horai S. A point mutation at nucleotide pair 3291 of the mitochondrial tRNA Leu (UUR) gene in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochem Biophys Res Comm.1994;202:1624-1630.

32. Goto Y-l. Clinical features of MELAS and mitochondrial DNA mutations. Muscle Nerve. 1995;suppl 3:5107-S112.

33. Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry and molecular genetics. Ann Neurol. 1992;31:391-398.

34. Moraes CT, Ricci E, Bonilla E, et al. The mitochondrial tRNA Leu (UUR) mutation in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscles. Am J Hum Genet. 1992;50:934-939.

Accepted for publication June 4, 1998.

From the Department of Anatomic Pathology, Cleveland (Ohio) Clinic Foundation.

Reprints: Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.

Copyright College of American Pathologists Nov 1998
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