MELAS syndrome

Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes
Classification and external resources
Basal ganglia calcification, cerebellar atrophy, increased lactate; a CT image of a person diagnosed with MELAS
ICD-9	277.87
OMIM	540000
DiseasesDB	8254
eMedicine	ped/1406
MeSH	D017241

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes – abbreviated to MELAS – is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984.^[1] A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent.^[2] The disease can manifest in both sexes.

Presentation

MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development.^[3] Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).

Most people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, Epilepsy, and hormonal imbalances.

The presentation of some cases is similar to that of Kearns-Sayre syndrome.^[4]

Genetics

Muscle biopsy of a person diagnosed with MELAS but carrying no known mutation. (a) Modified Gomori trichrome stain showing several ragged red fibers (arrowhead). (b) Cytochrome c oxidase stain showing Type-1 lightly stained and Type II fibers, darker fibers, and a few fibers with abnormal collections of mitochondria (arrowhead). Note cytochrome c oxidase negative fibers as usually seen in mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). (c) Succinate dehydrogenase staining showing a few ragged blue fibers and intense staining in the mitochondria of the blood vessels (arrow). (d) Electron microscopy showing abnormal collection of mitochondria with paracrystalline inclusions (arrowhead), osmiophilic inclusions (large arrowhead) and mitochondrial vacuoles (small arrowhead). Abu-Amero et al. Journal of Medical Case Reports 2009.^[5]

MELAS is caused by mutations in the genes in mitochondrial DNA.

NADH dehydrogenase

Some of the genes (MT-ND1, MT-ND5) related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex (NADH dehydrogenase, also called complex I) in mitochondria that helps convert oxygen and simple sugars to energy.

Transfer RNAs

Other genes (MT-TH, MT-TL1, and MT-TV) associated with this disorder provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.

Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

Inheritance

This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.

Prognosis

There is no known treatment for the underlying disease, which is progressive and fatal. Patients are managed according to what areas of the body are affected at a particular time. Enzymes, amino acids, antioxidants and vitamins have been used, but there have been no consistent successes reported.

Although there have been no controlled trials on long-term benefits of dietary manipulations, the following supplements have shown promise and given hope to MELAS patients.

• CoQ10 has been helpful for some MELAS patients.^[6] Nicotinamide has been used because complex l accepts electrons from NADH and ultimately transfers electrons to CoQ10.

• Riboflavin has been reported to improve the function of a patient with complex l deficiency and the 3250T-C mutation.^[7]

• The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impaired vasodilation in intracerebral arteries owing to nitric oxide depletion.^[8][9]

• There is evidence from animal studies that resveratrol and other SIRT1 activators may be used to treat MELAS by increasing mitochondrial biogenesis and function. Sirtris Pharmaceuticals, a GlaxoSmithKline company based in Cambridge, MA, is developing a proprietary formulation of resveratrol (called SRT-501) for the treatment of MELAS under Orphan Drug Designation from the U.S. Food and Drug Administration. Results from this phase 1b trial are expected in the first half of 2009.^[10]

• There is also a case report where succinate was successfully used to treat uncontrolled convulsions in MELAS patients, although this treatment modality is yet to be thoroughly investigated or widely recommended.

References

1. ^ Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP (1984). "Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome". Ann Neurol 16 (4): 481–8. doi:10.1002/ana.410160409. PMID 6093682. 
2. ^ Hirano M, Pavlakis SG (1994). "Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts". J Child Neurol 9 (1): 4–13. doi:10.1177/088307389400900102. PMID 8151079. 
3. ^ MELAS syndrome at NLM Genetics Home Reference
4. ^ Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP (1992). "Melas: an original case and clinical criteria for diagnosis". Neuromuscul Disord 2 (2): 125–35. doi:10.1016/0960-8966(92)90045-8. PMID 1422200. 
5. ^ Abu-Amero KK, Al-Dhalaan H, Bohlega S, Hellani A, Taylor RW (2009). "A patient with typical clinical features of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report". J Med Case Reports 3: 77. doi:10.1186/1752-1947-3-77. PMC 2783076. PMID 19946553. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2783076. 
6. ^ Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA (2007). "Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders". Muscle Nerve 35 (2): 235–42. doi:10.1002/mus.20688. PMID 17080429. 
7. ^ Ogle RF, Christodoulou J, Fagan E, et al. (1997). "Mitochondrial myopathy with tRNA(Leu(UUR)) mutation and complex I deficiency responsive to riboflavin". J. Pediatr. 130 (1): 138–45. doi:10.1016/S0022-3476(97)70323-8. PMID 9003864. 
8. ^ Koga Y, Akita Y, Nishioka J, et al. (2007). "MELAS and L-arginine therapy". Mitochondrion 7 (1-2): 133–9. doi:10.1016/j.mito.2006.11.006. PMID 17276739. 
9. ^ Hirata K, Akita Y, Povalko N, et al. (2007). "Effect of l-arginine on synaptosomal mitochondrial function". Brain Dev 30 (4): 238. doi:10.1016/j.braindev.2007.08.007. PMID 17889473. 
10. ^ Sirtris - Investor Relations - News Release

External links

• melas at NIH/UW GeneTests