Theme Page #3: Etiology and Physiology

MELAS is a mitochondrial genetic disorder. Many different transfer RNA (tRNA) mutations in mitochondrial genetic information can cause MELAS .1 The most common mutation is in the MTTL1 mitochondrial gene. A single base pair mutation, m.3243A>G, is found in 80% patients. This point mutation was described in 1990 by Goto et al. and Kobayashi et al., as a mutation in the mtDNA affecting the gene encoding the leucine tRNA (UUR) (tRNALeuUUR) by an exchange at position 3243 of the nucleotide Adenosine to Guanine (A3243G) in the muscle of MELAS patients (Goto et. al, 1990).

The tRNALeuUUR is also known as MT-TL1, located between nucleotides 3230 and 3304 and is responsible for the decoding of UUR codons. The A3243G mutation affects the stability of the structure, methylation, aminoacylation and codon recognition of the tRNALeuUUR, thus reducing the functional level of tRNALeuUUR that participates in the process of mitochondrial protein synthesis.

A second common mutation, m.3271T>C, is found in 10%. MELAS is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000. About 90% of cases present in early childhood or before the age of 40.

MELAS syndrome targets organ systems with high metabolic activity, including the nervous and cardiovascular systems, and clinical onset typically occurs in early adulthood after a seemingly normal childhood with development attributable to cumulative effects of chronic lactic acidosis. Ragged red muscle fibers suggest an abnormality of the electron transport system. Ragged red fibers get their name from the appearance of the degenerating granular fibers following staining with a modified Gomori trichrome stain. The presence of ragged red fibers suggests an abnormality of the electron transport system and these findings are regularly seen in documented biochemical deficiencies that involve the respiratory chain.2

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.1 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.2 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.3

The full history and postmortem findings in one of the first identified cases of mitochondrial encephalomyopathy with stroke-like episodes from 69 reported cases. The syndrome should be suspected by the following three invariant criteria: (1) stroke-like episode before age 40 yr; (2) encephalopathy characterized by seizures, dementia, or both; and (3) lactic acidosis, ragged-red fibers (RRF), or both. The diagnosis may be considered secure if there are also at least two of the following: normal early development, recurrent headache, or recurrent vomiting.3

Although many cases appear in the younger years, there are several reported studies of one patient onset older than 60 years have been reported. Herein, we report a 63-year-old Chinese female initially suspected of ischemic infarction but was ultimately diagnosed with MELAS. This patient had notably short stature, auditory and visual hallucinations, as well as disorganized speech and elevated lactic acid upon resting. Since this was initially misdiagnosed as ischemic infarction, the patient failed to receive prompt treatment. In clinical practice, the diagnosis of MELAS should be considered when encountering elderly patients with recurrent stroke-like episodes, psychotic symptoms, and cognitive dysfunction. To prevent delays in treatment, a detailed medical history should, therefore, be collected before starting with the appropriate laboratory investigations to reach a correct diagnosis.

Figure 1. This image is obtained from : “MELAS Syndrome (JOT107).” Jupiter Orphan Therapeutics.http://www.jupiterorphan.com/melas-syndrome-jot107.html. Signs and symptoms of MELAS can begin at any age, although the most common onset is during childhood.

References

  1. Ogasahara, S., Engel, A. G., Frens, D. & Mack, D. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc. Natl. Acad. Sci. U. S. A. 86, 2379–2382 (1989).
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC286916/
  2. Seyama, K. et al. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with special reference to the mechanism of cerebral manifestations. Acta Neurol. Scand. 80, 561–568 (1989). https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0404.1989.tb03927.x
  3. Yoneda, M. et al. Pleiotropic molecular defects in energy-transducing complexes in mitochondrial encephalomyopathy (MELAS). J. Neurol. Sci. 92, 143–158 (1989).
    https://doi.org/10.1016/0022-510X(89)90132-9
  4. Mitochondrial Disorders Overview – GeneReviews® – NCBI Bookshelf. Available at:
    https://www.ncbi.nlm.nih.gov/books/NBK1224/
  5. Melas Syndrome – StatPearls – NCBI Bookshelf. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532959/.
  6. 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.