Clinical Endocrinology (1995) 43, 235-239 Case report MELAS syndrome associated with diabetes mellitus and hyperthyroidism: a case report from Taiwan Chwen-YI Yang, Hlng-Chung Lam, Hsln-Chen Lee., Yau-Hue1 Wel*, Chih-Chen Lu, Tlan-Mu Han, Jln-Llan Tsalt, Yen-Hwang ChuangS and Jenn-Kuen Lee Division of Endocrinology and Metabolism, Department of Medicine, National Yang-Ming University and Veterans General Hospital-Kaohsiung, Kaohsiung *Department of Biochemistry, National Yang-Ming University, tSchoo1 of Technology for Medical Science, Kaohsiung Medical College, and $Department of Neurology, Kaohsiung Medical College, Taiwan, Republic of China (Received 79 May 1994; returned for revision 8 August 7994; finally revised 20 January 1995; accepted 17 February 7995) Summary MELAS syndrome Is a form of mitochondria1 myopathy with manifestations of seizure, stroke-like syndrome, lactic acidosis, ragged red muscle fibres and mltochondrial encephaiopathy. The syndrome has been reported in association with a variety of endocrine and metabolic disorders Including diabetes mellltus (DM), hypothalamo-pituitary hypofunction, hypothalamic growth hormone deficiency and delayed puberty. MitocCIondriai DNA (mtDNA) point mutation may be the malor pathological defect. However, association of MELAS syndrome with hyperthyroidlsm has not previously been reported. A case Is reported from Taiwan of a 32-year-old woman suffering from MELAS syndrome with associated DM and hyperthyroldlsm. When the latter was dlagnosed In Aprll 1988, the patient underwent subtotal thyroldectomy. There was no family history of thyroid disease. Because of repeated seizures, she had computed tomography (CT) and magnetic resonance imaging (MRI) of the brain which showed focal, iow-denslty leslons over the cerebral hemispheres. Both serum and cerebral spinal fluid lactic acid levels were elevated. Mild elevations of serum T4 and T3 and a high titre of TSH receptor antibody were still present. Hyperglycaemla was noted during hospltallzatlon and DM confirmed by oral glucose tolerance test. Muscle biopsy showed ragged red fibres. DNA analysis showed an A-to-G transitlon at the 3243rd nucieotlde position of the tRNALeufUURi gene of the mtDNA from the patient. Quantltatlve polymerase chain reaction (PCR) and restrlctlon analysis revealed that about 60% of the blood mtDNA was of mutant type. The patient received antlthyrold drugs for hyperthyroidism, diet control for DM and anti-epiieptlc drugs for seizure. The mitochondrial encephalomyopathies are hereditary neurodegenerative disorders characterized by multiple features and are usually divided into three clinical subgroups: (1) chronic progressive external ophthatmoplegia (CPEO) including Kearns-Sayre syndrome: (2) myoclonic epilepsy associated with ragged red muscle fibres (MERRF); and (3) MELAS syndrome (Rowland et al., 1983). MELAS syndrome is an unusual form of mitochondrial disorder with manifestations of mitochondrial myopathy, encephalopathy, ragged red fibres, lactic acidosis and stroke-like syndrome (Pavlakis et al., 1984). Children and young adults are most often affected. Patients are usually asymptomatic in infancy and have normal early development. Most patients are short and have recurrent epileptic seizures which are partial or generalized. Headache, vomiting, hemiplegia or hemianopia may also be present. Maternal inheritance has been found because human sperm contain only few mitochondria which do not penetrate the egg (Maertens & Dyken, 1992). The major defect is point mutation of the tRNALeU("uR'R) gene in the mitochondrial DNA (mtDNA) with heteroplasmic A-toG transition at nucleotide position 3243 (80%) and T-to-C mutation at nucleotide position 3271 (10%) (Goto et al., 1990). MELAS syndrome has been reported to be associated with a variety of endocrine and metabolic disorders, including diabetes mellitus (Onishi et ul., 1993), hypothalamo-pituitary hypofunction (Ishii et al., 1991), hypothalamic growth hormone deficiency (Matsuzaki et al., 1991) and short stature (Pavlakis et ul., 1984). However, the association of MELAS syndrome with hyperthyroidism has not previously been reported. We describe a case of MELAS syndrome associated with Graves' hyperthyroidism and DM. Case report Correspondence: Dr Chwen-Yi Y ang, Division of Endocrinology and Metabolism, Department of Medicine, Veterans General Hospital-Kaohsiung, 386 Ta-Chung 1st Road, Kaohsiung, Taiwan 813, ROC. 0 1995 Blackwell Science Ltd A 32-year-old Chinese woman presented with frequent episodes of facial jerking. Her family history was unremarkable, apart from the death of a younger brother at age 26 235 236 Chwen-Yi Yang et al. Flg. 1 Brain CT showing a, in Dec. 1992, low-density lesions over the postero-temporal regions bilaterally and right frontal region, with gyral enhancement and mild mass effect; b, in June 1993, prominence of a left-sided frontal sulcus with gyral enhancement. Resolution of the lesions in the postero-temporal regions can be seen. following several episodes of cerebral idarction. Her birth and developmental histories were unremarkable. Graves' disease with hyperthyroidism had been diagnosed in April 1988, and subtotal thyroidectomy was performed in another medical centre. There was no family history of thyroid disease. During the previous 4 years, her condition had been stable. In April 1992, she began to suffer from seizures and was admitted to a local hospital, but a specific diagnosis was not made. In December 1992, the patient was admitted to our unit because of focal motor seizures and bizarre behaviour of one week duration. Brain CT showed lowdensity areas over the postero-temporal and right frontal regions (Fig. 1a). Carotid angiography revealed hyperaemic changes in the right frontal region. 9 9 m THMPAO ~ brain SPECT showed decreased uptake in the left occipital region, and marked uptake in the right frontal and left temporoparietal-occipital regions. IQ testing (Wechsler Adult Intelligence scale) showed moderate mental subnormality (Verbal IQ 48, Performance IQ 46, Full IQ 44). She was discharged in a stable condition after 24 days of hospitalization. However, 6 months later, the patient was re-admitted because of persistent facial jerking. On examination, the patient was obtunded, and under weight (30.5kg, height 155cm). Her intelligence was impaired. Reduced muscle power and mutism were noted. Frequent twitching of the right side of her face and trunk was noted during the fist few days of hospitalization. Laboratory tests revealed ~'~ormalhaematoh3Y and biochemistry profiles except for elevated CSF lactate Flg. 2 Brain MRI, axial section: proton density image (FSE 2100/ 17) showing high signals over both frontal and left temporoparietal regions. 0 1995 Blackwell Science Ltd, Clinical Endocrinology,43, 235-239 MELAS syndrome, diabetes mellitus and hyperthyroidism 1 Flg. 3 Restriction analysis of mtDNA from the blood cells of the patient with MELAS. Lane 1 shows Apa I-digested PCR fragments amplified from the patient’s blood cell mtDNA, lane 2 is a negative normal control. For restriction analysis with Apa I, a 1159-base-pair DNA fragment encompassing the putative mutation site (nucleotide position 3243) was amplified by PCR using a pair of primers L2678-2696 and H3817-3836, and then digested with 10 units of Apa I overnight under the conditions recommended by the manufacturers. The digest was subjected to electrophoresis on 1.5% agarose at 100V for 40 min. The DNA bands were visualized under UV light illumination after staining with ethidium bromide for 20min at 25°C. The only possibility for a new Apa I restriction site was the G-to-A transition at nucleotide 3243. (llOmmol/l (normal <25)) and serum lactate (33mmol/l (normal 5-19)) concentrations. Brain CT showed focal low density over the left frontal region with partial recovery of the previously noted low-density areas (Fig. lb). MRI showed diffuse, high-signal cerebral lesions over both frontal and left temporo-parietal regions (Fig. 2). A muscle biopsy from the right vastus lateralis muscle was stained with modified Gomori-trichrome and showed ragged red fibres. DNA analysis was performed as previously described (Chen et d., 1993). Restriction analysis of muscle and blood DNA showed an A-to-G transition at the 3243rd nucleotide position in the mtDNA, and about 60% mutant type mtDNA was present in the blood cells of the patient as estimated by scanning densitometry of the DNA bands in the agarose gel (Fig. 3). Endocrine studies revealed mild hyperthyroidism (T3 3.6 nmol/l, normal range 1.3-2.3; T4 166nmol/l, normal range 77-154; FT4 52pmol/l, normal range 12-22, measured by radioimmunoassay; TSH O, 30, 60, 90 and 120min, respectively). The patient was treated with a simple diabetic diet and received propylthiouracil for recurrent hyperthyroidism, diphenylhydantoin and phenobarbitone for seizure control, and a-tocopherol and ubiquinone for the mitochondria1 respiration defect. After 30 days in hospital, she was discharged in a stable condition. Discussion MELAS syndrome was first describedin 1984 (Pavlakiset al., 1984), but the clinical criteria for diagnosis have recently been revised (Hirano et al., 1992). A point mutation at nucleotide position 3243 within the tRNALeUluuR)gene of mtDNA was found in 80% of MELAS patients and another mutation at nucleotide position 3271 in 10% (Goto et al., 1990; Goto, 1993). It has been shown recently that such mutations may cause progressive inhibition of the 238 Chwen-Yi Yang et al. mitochondrial respiratory function (Hayashi et al., 1993). The defects in oxidative phosphorylation and respiratory chain function may result from a deficiency of the electron transport protein cytochrome C oxidase (Haginoya et al., 1993; Muller-Hocker et al., 1993), and deficiencies of NADH dehydrogenase (Muller-Hocker el al., 1993), NADH coenzyme Q reductase (Kobayashi et al., 1987) and pyruvate dehydrogenase (Nagai et al., 1992). The proportion of mutant mtDNA varied between different tissues and organs (Hamazaki et al., 1993; Love et al., 1993). MELAS syndrome is therefore a multisystem disease that involves multiple organs, including non-endocrine and endocrine (Hirano et al., 1992). Hence it is not surprising to find that MELAS syndrome has been reported to be associated with both type 1 and type 2 DM since DM may be one of the heterogeneous features of a mtDNA point mutation (Gerbitz, 1992; Reardon et al., 1992; Gerbitz et al., 1993). Some patients with diabetes and the MELAS mutation have been reported t o have negative islet cell antibodies which supports the hypothesis that the DM is related to mitochondrial defects (Reardon et al., 1992; Onishi et al., 1993), but serum islet cell antibodies in our patient were not checked. The association of MELAS syndrome with hyperthyroidism and DM has not been reported before. However, Kearns-Sayre syndrome (KSS) has been reported in association with thyroid disease and DM (Harvey & Barnen, 1992). Since KSS and MELAS syndrome belong to the same group of mitochondrial defects, it is not surprising to find a patient suffering from both MELAS syndrome and hyperthyroidism. Gerbitz (1992) has proposed that mtDNA mutation may lead to an abnormality in MHC-restricted immune response, resulting in a pathogenetic mechanism similar to that found in autoimmune type I DM. Since Graves’ hyperthyroidism is also an autoimmune disease, the same mechanism may be responsible for the pathogenesis of hyperthyroidism in this patient. Acknowledgements We are indebted to Professor Shun-Sheng Chen of Kaohsiung Medical College for microscopic examination of the muscle biopsy. One of the authors, Yau-Huei Wei, would like to express his sincere appreciation to the National Science Council for the Outstanding Research Award received in the course of this study. References Chen, R.S., Huang, C.C., Lee, C.C., Wei, Y.Y., Hsi, M.S., Pang, C.Y. & Wei, Y.H. (1993) Overlapping syndrome of MERRF and MELAS: molecular and neuroradiological studies. Acta NeuroIogica Scandinavica, 87,494-498. Gerbitz, K.D. (1992) Does the mitochondrial DNA play a role in the pathogenesis of diabetes. Diabetologia, 35, 1181- 1186. Gerbitz, K.D., Paprotta, A., Jaksch, M., Zierz, S.& Drechsel, J. (1993) Diabetes mellitus is one of the heterogeneous phenotype features of a mitochondrial DNA point mutation within the tRNALeU(uuR)gene. FEBS Letters, 321, 194-196. Goto, Y. (1993) MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes): Clinical features and mitochondrial DNA mutations. Nippon Rinsho. Japanese Journal of Clinical Medicine, 51,2313-2318. Goto, Y., Nonaka, I. & Horai, S. (1990) A mutation in the tRNALeulUuR)gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature, 348,65 1-653. Haginoya, K., Miyabayashi, S., Iinuma, K. & Tada, K. (1993) Quantitative evaluation of electron transport system proteins in mitochondrial encephalomyopathy. Acta Neuropathologica, 85, 370-317. Hamazaki, S., Koshiba, M. & Sugiyama, T. (1993) Organ distribution of mutant mitochondrial tRNALeu(u”R’gene in a MELAS patient. Acta Pathologica Japonica, 43, 187-191. Harvey, J.N. & Barnen, D. (1992) Endocrine dysfunction in Kearns-Sayre syndrome. Clinical Endocrinology, 37,91- 104. Hayashi, J.I., Ohta, S., Takai, D., Miyabayashi, S., Sakuta, R., Goto, Y. & Nonaka, I. (1993) Accumulation of mtDNA with a mutation at position 3211 in tRNAhfUuR’ gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function. Biochemical and Biophysical Research Communications, 197, 1049-1055. Hirano, M., Ricci, E., Koenigsberger, M.R., Defendini, R., Pavlakis, S.G., DeVivo, D.C., Dimauro, S. & Rowland, L.P. (1992) MELAS: an original case and clinical criteria for diagnosis. Neuromuscular Disorders, 2, 125- 135. Ishii, A., Watanabe, S.,Ohkoshi,N., Mizusawa, H. & Kanazawa, I. (1991) Mitochondria1 encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) associated with hypothalamopituitary hypofunction: a case report. Rinsho ShinkeigakuClinical Neurology, 31, 179-183. Kobayashi, M., Morishita, H., Sugiyama, N., Yokochi, K., Nakano, M. & Wada, Y. (1987) Two cases of NADH-coenzyme Q reductase deficiency: relationship to MELAS syndrome. Journal of Pediatrics, 110, 223-221. Love, S., Nicoll, J.A.R. & Kinrade, E. (1993) Sequencing and quantitative assessment of mutant and wild-type mitochondrial DNA in p a r a m sections from cases of MELAS. Journal of Pathology, 170, 9-14. Maertens, P. & Dyken, P.R. (1992) Inborn errors of metabolism I: Neurologic degenerative diseases. In Pediatric Neurology for the Clinician (ed. Ronald B. David),pp. 353-359. Appleton & Lange, Connecticut. Matsuzaki, M., I d , T., Ebato, K.,Suzuki, H., Shishikura, K., Osawa, M. & Fukuyama, Y. (1991) HypothalamicGH deficiency and gelastic seizures in a 10-year-old girl with MELAS. No To Huttatsu, 23,411-416 (In Japanese; English abstract). Muller-Hocker, J., Hubner, G., Bise, K., Forster, C., Hauck, S., Paetzke, I., Pongratz, D. & Kadenbach, B. (1993) Generalized mitochondrial microangiopathy and vascular cytochrome c oxidase deficiency. Occurrence in a case of MELAS syndrome with mitochondrial cardiomyopathy-myopathy and combined 0 1995 Blackwell Science Ltd, Clinical Endocrinology, 43,235-239 MELAS syndrome, diabetes mellitus and hyperthyroidism complex I/IV deficiency. Archives of Pathology and Laborarory Medicine, 117, 202-210. Nagai, T., Goto, Y., Matsuoka, T., Sakuta, R., Naito, E., Kuroda, Y. & Nonaka, I. (1992) Leigh encephalopathy: histologic and biochemical analyses of muscle biopsies. Pediatric Neurology, 8, 328-332. Onishi, H., Inoue, K., Osaka, H., Kimura, S., Nagatomo, H., Hanihara, T., Kawamoto, S., Okuda, K., Yamada, Y.& Kosaka, K. (1993) Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and diabetes mellitus: molecular genetic analysis and family study. Journal of the Neurological Sciences, 144, 205-208. Pavlakis, S.G., Phillips, P.C., DiMauro, S., DeVivo, D.C. & 0 1995 Blackwell Science Ltd, Clinical Endocrinology, 43,235-239 239 Rowland, L.P. (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: A distinctive clinical syndrome. Annals of Neurology, 16,481-488. Reardon, W., Ross, R.J.M., Sweeney, M.G., Luxon, L.M., Pembery, M.E., Harding, A.E. & Trembath, R.C. (1992) Diabetes mellitus associated with a pathogenic point mutation in mitochondria1 DNA. Lancer, 340, 1376-1379. Rowland, L.P., Hays, A.P., Dimaura, S., De Vivo, D.C. & Behrens, M. (1983) Diverse clinical disorders associated with morphological abnormalities of mitochondria. In Mitochondrial Pathology in Muscle Diseases (eds. Cerri C. & Scarlato G.), pp. 141-158. Piccin Editore, Padua.