Annotated Bibliography

Mitochondrial Encephalopathy Lactic Acidosis and Stroke-Like Symptoms (MELAS)

1962 – 1976

During this period, many case studies were reported of patients reporting neuromuscular disorders and lactic acidosis.

September 1962: Luft, Rolf, Denis Ikkos, Genaro Palmieri, Lars Ernster, and Björn Afzelius. “A Case of Severe Hypermetabolism of Non-Thyroid Origin With a Defect in the Maintenance of Mitochondrial Respiratory Control: A Correlated Clinical, Biochemical, and Morphological Study.” The Journal of Clinical Investigation 41, no. 9 (September 1, 1962): 1776–1804. https://doi.org/10.1172/JCI104637.

Analysis of a hypermetabolic patient indicated increased mitochondria. This is the first case study in the literature and therefore becomes clinically relevant at this time. The authors note an insufficiency of te mitochondria to adjust to this metabolic state that is of non-thyroid origin.

June 1975: Shapira Y, Harel S. The mitochondrial encephalomyopathies: a group of neuromuscular disorders with defects in oxidative pathways of energy production. Child Neurological Society meeting. Abstract 33, 1975

At the first Child Neurological Society meeting, mitochondrial encephalomyopathy was introduced as “a group of neuromuscular disorders with defects in the oxidative pathways of energy production.” It presented with encephalomyopathy accompanied by many other symptoms

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1977-1984

Distinctive mitochondrial deficiency and “ragged-red” muscle fibers identified, but the syndrome remains uncharacterized.

March 1977: Hart, Zwi H., Chung-Ho Chang, Eugene V. D. Perrin, Joseph S. Neerunjun, and Ram Ayyar. “Familial Poliodystrophy, Mitochondrial Myopathy, and Lactate Acidemia.” Archives of Neurology 34, no. 3 (March 1, 1977): 180–85. https://doi.org/10.1001/archneur.1977.00500150066013.

This case reports a 16- year-old boy with progressive dementia and elevated lactic acid levels whose sister died of a similar condition at 18 years old; the lactic acid levels were higher in the CSF, suggesting defective mitochondrial function in the brain cells. Findings of low oxygen consumption indicated a defective of oxidative pathways as the underlying cause of their disease processes. Whether abnormal mitochondria are present in the brain tissue in our case would require a brain biopsy which is highly invasive.

December 1978: Askanas, Valerie, W. King Engel, Daniel E. Britton, Bruce T. Adornato, and Robert M. Eiben. “Reincarnation in Cultured Muscle of Mitochondrial Abnormalities: Two Patients With Epilepsy and Lactic Acidosis.” Archives of Neurology 35, no. 12 (December 1, 1978): 801–9. https://doi.org/10.1001/archneur.1978.00500360025005.

Physicians reported two unrelated 9-year-old boys with lactic acidosis who were short in stature, and experienced focal cerebral seizures followed by transient hemiparesis. Histochemistry analysis of their muscle biopsies showed “ragged-red” fibers, containing clusters of mitochondria having loss of crisp delineation of crista membranes and contained amorphous inclusion material and parallel-packed cristae and sometimes paracrystalline inclusions. Mitochondrial defect was suspected, as abnormalities were able to be recreated in muscle cells cultured from the patients.

July 1980: Fukuhara, Nobuyoshi, Susumu Tokiguchi, Kenichi Shirakawa, and Tadao Tsubaki. “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.” Journal of the Neurological Sciences 47, no. 1 (July 1, 1980): 117–33. https://doi.org/10.1016/0022-510X(80)90031-3.

Two patients, in particular, had clinical features including convulsions, mental deterioration, and muscular atrophy. These case studies of myoclonus epilepsy syndrome were also associated with ragged-red fibres that are known to be related to mitochondrial encephalomyopathies.


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1984-1987

In 1984 MELAS was defined. Genetic patterns are explored, and inheritance is suspected.

October 1984: Pavlakis, Steven G., Peter C. Phillips, Salvatore DiMauro, Darryl C. De Vivo, and Lewis P. Rowland. “Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes: A Distinctive Clinical Syndrome.” Annals of Neurology 16, no. 4 (1984): 481–88. https://doi.org/10.1002/ana.410160409.

The clinical constellation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was first characterized in this report on two patients with the clinical presentations described in the name. In other patients reported in literature, ragged red muscle fibers suggested an abnormality of the electron transport system, but the precise biochemical disorders in these three clinical syndromes remains to be elucidated.

August 1986: Zinn, Arthur B., Douglas S. Kerr, and Charles L. Hoppel. “Fumarase Deficiency: A New Cause of Mitochondrial Encephalomyopathy.” New England Journal of Medicine 315, no. 8 (August 21, 1986): 469–75. https://doi.org/10.1056/NEJM198608213150801.

The authors observed a fumarase deficiency in both the mitochondrial and cytosolic forms. A male infant presented with symptoms of mitochondrial encephalomyopathy at one month of age. His symptoms included failure to thrive, developmental delay, hypotonia, cerebral atrophy, lactic and pyruvic acidemia, and fumaric aciduria.

October 1986: Petty RK, Harding AE, Morgan-Hughes JA. The clinical features of mitochondrial myopathy. Brain. 1986;109:915–38. https://www.ncbi.nlm.nih.gov/pubmed/3779373.

Three subgroups were defined for MELAS: first, chronic progressive external opthalmoplegia (CPEO) and limb weakness, second, proximal weakness with fatigability, and third, predominantly or exclusively central nervous system (CNS) disease.

June 1987: Goda, Satoshi, Shin-ichi Ishimoto, Ikuo Goto, Yoshiyuki Kuroiwa, Kichiko Koike, Masahiko Koike, Masanori Nakagawa, Heinz Reichmann, and Salvatore Dimauro. “Biochemical Studies in Mitochondrial Encephalomyopathy.” Journal of Neurology, Neurosurgery, and Psychiatry 50, no. 10 (1987): 1348–52. https://www.semanticscholar.org/paper/Biochemical-studies-in-mitochondrial-Goda-Ishimoto/42d47239e158cf3a1b7eec5aaa020cf133af1c46

Although the clinical features are relatively distinctive, the biochemical abnormalities reported so far have not been uniform across cases, therefore implying a syndrome. Again, “ragged-red fibres were seen, but biochemical analysis showed increased subsarcolemmal activity in NADH tetrazolium reductase stain. Although this patient lacked muscle symptoms initially, she was diagnosed with MELAS on the basis of her CNS symptomatology; the authors hypothesize that mitochondrial changes in some MELAS patients may be due to chronic hypoxia.

September 1987: Driscoll PF, Larsen PD, Gruber AB. MELAS Syndrome Involving a Mother and Two Children. Arch Neurol. 1987;44(9):971–973. https://jamanetwork.com/journals/jamaneurology/fullarticle/586822

This article discussed potential modes of inheritance and mechanisms of cerebral infarction using a family with four normal sons and an affected mother, son, and daughter. Mitochondrial inheritance has been proposed in the latest pedigree to date, but autosomal and X-linked dominant patterns are also possible. MELAS appears to be familiar, but the mode of inheritance remains uncertain.



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1988-1990

Expanding mitochondrial myopathy to mitochondrial encephalomyopathy and biochemical analysis for potential treatment.

May 1988: Van Erven, P M, F J Gabreëls, W Ruitenbeek, W O Renier, H J Ter Laak, and A M Stadhouders. “A Mitochondrial Encephalomyopathy with a Partial Cytochrome c Oxidase Deficiency of Muscle.” Journal of Neurology, Neurosurgery, and Psychiatry 51, no. 5 (May 1988): 704–8.

This landmark recognizes that CNS disease is a prominent feature in a subgroup of the mitochondrial myopathies, expanding the concept of mitochondrial myopathy to mitochondrial encephalomyopathy.

April 1989: Ogasahara, S, A G Engel, D Frens, and D Mack. “Muscle Coenzyme Q Deficiency in Familial Mitochondrial Encephalomyopathy.” Proceedings of the National Academy of Sciences of the United States of America 86, no. 7 (April 1989): 2379–82.

The activities of complex I-III and of complex II-III were assessed, both of which need coenzyme Q10 (CoQ10), resulting in abnormally low activities. The electron transport system of muscle mitochondria was examined in a familial syndrome of lactacidemia, mitochondrial myopathy, and encephalopathy using a 14-year-old female, and her 12-year-old sister.

June 1989: Seyama, K., K. Suzuki, Y. Mizuno, M. Yoshida, M. Tanaka, and T. Ozawa. “Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes with Special Reference to the Mechanism of Cerebral Manifestations.” Acta Neurologica Scandinavica 80, no. 6 (1989): 561–68. https://doi.org/10.1111/j.1600-0404.1989.tb03927.x.

The researchers suspect that the syndrome could in part be caused by partial deficiency of mitochondrial NADH-ubiquinone oxidoreductase (Complex I), as various defects in the mitochondrial electron transport pathway are found in this syndrome. The mechanism of neurological manifestations remains unknown.

September 1989: Yoneda, Makoto, Masashi Tanaka, Morimitsu Nishikimi, Hiroshi Suzuki, Keiko Tanaka, Masatoyo Nishizawa, Tetsushi Atsumi, et al. “Pleiotropic Molecular Defects in Energy-Transducing Complexes in Mitochondrial Encephalomyopathy (MELAS).” Journal of the Neurological Sciences 92, no. 2 (September 1, 1989): 143–58. https://doi.org/10.1016/0022-510X(89)90132-9.

Enzymic activities of complex I and IV were severely decreased in several patients. These results implicate complexes I, III, IV, and V, containing mitochondrially synthesized subunits. Further, immunoblot analysis demonstrated decreased enzymic activities were based on decreased contents of subunits in these complexes. This is translated into pleiotropic molecular defects in the complexes among the organs of the patient.

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1991-2009

MELAS specific mutations are reported and therapies begin to develop.

December 1990: December 1990: Goto Y, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990; 348: 651– 653. https://www.nature.com/articles/348651a0

This report characterizes the first MELAS specific mutation, an A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR). This paper was the first to observe the association of a heteroplasmic point mutation in the tRNALeu(UUR) gene in association with MELAS syndrome while devising a simple molecular diagnostic test.

January 1994:  “Topical Review: Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes (MELAS): Current Concepts – Michio Hirano, Steven G. Pavlakis, 1994.” Accessed March 13, 2019. https://journals.sagepub.com/doi/abs/10.1177/088307389400900102.

New knowledge leads to rational therapies rather than previous treatments that worked, but were likely only due to the disease resolving over time. This study of mitochondrial diseases furthered understanding of other degenerative disorders.

June 1997: Tanaka, Junko, Toshisaburo Nagai, Hiroshi Arai, Koji Inui, Hideo Yamanouchi, Yu-ichi Goto, Ikuya Nonaka, and Shintaro Okada. “Treatment of Mitochondrial Encephalomyopathy with a Combination of Cytochrome C and Vitamins B1 and B2.” Brain and Development 19, no. 4 (June 1, 1997): 262–67. https://doi.org/10.1016/S0387-7604(97)00573-1.

The efficacy of intravenous injections of Cardiocrome®, was evaluated containing cytochrome c, Favin mononucleotide and thiamine diphosphate for mitochondrial encephalomyopathy (MEM) and it was concluded that this therapy was fairly effective for the management of patients with mitochondrial encephalomyopathy.

February 2001: Wilson, K., Guardino, J. & Shapira, O. M. Pulmonary Tumor Embolism as a Presenting Feature of Cavoatrial Hepatocellular Carcinoma. Chest119, 657–658 (2001).
https://doi.org/10.1378/chest.119.2.657


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2010-2019

Successful therapies are developed and diagnosis is optimized

August 2010: Parsons T, Weimer L, Engelstad K, Linker A, Battista V, Wei Y, et al. Autonomic symptoms in carriers of the m.3243A>G mitochondrial DNA mutation. Arch Neurol. 2010;67:976–979.

Continuing to build off the landmark in 1990, The iPS cells with high heteroplasmy of A3243G mutation showed a deficiency of respiratory complexes I and IV, impairment of respiratory function, attenuated ATP generation, and decreased cell proliferation. These results indicate that fibroblast are the source or defects in the OXPHOS path.

August 2011: Van Erven, P M, F J Gabreëls, W Ruitenbeek, W O Renier, H J Ter Laak, and A M Stadhouders. “A Mitochondrial Encephalomyopathy with a Partial Cytochrome c Oxidase Deficiency of Muscle.” Journal of Neurology, Neurosurgery, and Psychiatry 51, no. 5 (May 1988): 704–8. https://www.fasebj.org/doi/abs/10.1096/fj.10-165340?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=fasebj

This article focuses on how the point mutation in tRNA genes encoded by mtDNA affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS possessing the A3243G mutation. Q10 (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in normal MELAS fibroblasts.

April 2018: Van Erven, P M, F J Gabreëls, W Ruitenbeek, W O Renier, H J Ter Laak, and A M Stadhouders. “A Mitochondrial Encephalomyopathy with a Partial Cytochrome c Oxidase Deficiency of Muscle.” Journal of Neurology, Neurosurgery, and Psychiatry 51, no. 5 (May 1988): 704–8.

This research determined that defective MRM2 causes a MELAS-like phenotype. This information further expands the clinical and genetic knowledge associated with defects of mtDNA metabolism. This discovery suggests that genetic screening of the MRM2 gene could be carried out for diagnostic information in patients with a 3243-negative MELAS-like presentation.

November 2018: Fang, Gao-Li, Yang Zheng, and Yin-Xi Zhang. “Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes in an Older Adult Mimicking Cerebral Infarction: A Chinese Case Report.” Clinical Interventions in Aging, November 27, 2018. https://doi.org/10.2147/CIA.S186636.

January 2019: Baek, Min-Seong, Se Hoon Kim, and Young-Mock Lee. “The Usefulness of Muscle Biopsy in Initial Diagnostic Evaluation of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes.” Yonsei Medical Journal 60, no. 1 (January 1, 2019): 98–105. https://doi.org/10.3349/ymj.2019.60.1.98.

Most of the current diagnostic criteria on the mitochondrial disease was developed prior to the identification of molecular genetic knowledge. Muscle biopsy was the gold standard for obtaining an accurate diagnosis of mitochondrial diseases. Now, the diagnosis of MELAS is often confirmed by the presence of RRF on succinate dehydrogenase histochemical stain, as a result of diseased mitochondrial aggregates in the subsarcolemmal areas of muscle fibers.

January 2019: “Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356288/.

The research indicates that when the mitochondria cause defects in OXPHOS, increasing production of reactive oxygen species (ROS), this triggers the activation of the cell death pathway. Autophagy inpatient-specific induced pluripotent stem (iPS) from fibroblasts of patients with MELAS had well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. An increase in autophagy was observed when compared with its normal counterpart, whereas mitophagy is very scarce contributing to decreased cellular viability.

January 2019: Melas Syndrome – StatPearls – NCBI Bookshelf. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532959/.

January 2019: Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356288/.