MELAS Syndrome Workup
- Author: Fernando Scaglia, MD, FACMG; Chief Editor: Luis O Rohena, MD more...
The following studies are indicated in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome:
Serum lactic acid, serum pyruvic acid, cerebrospinal fluid (CSF) lactic acid, and CSF pyruvic acid
- Lactic acidosis is an important feature of MELAS syndrome. See the image below for the pathophysiologic classification of lactic acidosis.
- In general, lactic acidosis does not lead to systemic metabolic acidosis, and it may be absent in patients with impressive CNS involvement.
- In some individuals with MELAS syndrome, lactic acid levels may be normal in blood but elevated in CSF.
- In respiratory chain defects, the ratio between lactate and pyruvate is high.
Serum creatine kinase levels
- The levels of serum creatine kinase are mildly to moderately increased in some patients with MELAS syndrome.
- Levels tend to increase during and immediately after episodes.
Respiratory chain enzyme activities in skeletal muscle
- If a muscle biopsy is performed to pursue a diagnostic evaluation, then test respiratory chain enzyme activities.
- Patients with MELAS syndrome have been found to have marked deficiency in complex I activity of the respiratory chain.
- Some patients with the disorder have a combined deficiency of complex I and complex IV.
Mitochondrial DNA mutation analysis on blood, skeletal muscle, hair follicles, buccal mucosa, and urinary sediment
- Individuals with more severe clinical manifestations of MELAS syndrome generally have greater than 80% mutant mtDNA in stable tissues such as muscle.
- In rapidly dividing cells, such as the components of the hematopoietic lineages, the m.3243 A → G mutation may segregate to extremely low levels, making genetic diagnosis from blood difficult. The percentage of the mutation decreases progressively in DNA isolated from blood. The mutant load isolated from blood is neither useful for prognosis nor for functional assessment.
- Urinary sediment, followed by skin fibroblasts and buccal mucosa, are the accessible tissues of choice because they are easy to access and the mutation load is higher than that found in blood.
- If the diagnosis is still suspected after normal mtDNA mutation analysis results in these tissues, a skeletal muscle biopsy is required to confirm or rule out the presence of the mutation.
The following imaging studies may be indicated:
CT scan or MRI of the brain
- CT scan or MRI of the brain following a strokelike episode reveals a lucency that is consistent with infarction.
- Later, cerebral atrophy and calcifications may be observed on brain imaging studies.
- Patients with MELAS syndrome who have a presentation similar to Leigh syndrome may have calcifications in the basal ganglia.
Positron emission tomography (PET) studies
- PET studies may reveal a reduced cerebral metabolic rate for oxygen.
- Increased cerebral blood flow in cortical regions may be observed.
- PET may demonstrate preservation of the cerebral metabolic rate for glucose.
Single-photon emission CT studies
- Single-photon emission computed tomography (SPECT) studies can ascertain strokes in individuals with MELAS syndrome using a tracer, N -isopropyl-p-[123-I]-iodoamphetamine.
- The tracer accumulates in the parietooccipital region, and it can delineate the extent of the lesion. SPECT studies are used to monitor the evolution of the disease.
Proton magnetic resonance spectroscopy ( 1 H-MRS): This is used to identify metabolic abnormalities, including the lactate-to-creatine ratio in either muscle or brain and the decreased CNS N -acetylaspartate–to–creatine ratio in regions of stroke. With this technique, elevated regions of lactate have been detected while serum levels are normal.
Echocardiography: This is useful to evaluate for hypertrophic and dilated cardiomyopathy and aortic root dimensions; however, cardiomyopathy is not a common feature in individuals with MELAS syndrome.
EEG findings are usually abnormal. Epileptiform spike discharges are usually present.
ECG is used to look for conduction abnormalities with ventricular arrhythmias. ECG can identify presymptomatic cardiac involvement, preexcitation syndromes, and cardiac conduction block.
Consider performing a muscle biopsy if MELAS syndrome is suspected and if the mtDNA mutation analysis in blood and other accessible tissues provides unremarkable results. In rapidly dividing cell lines, the mutations may segregate to low levels, making genetic diagnosis from blood difficult.
In muscle biopsies stained with hematoxylin and eosin, variation is observed in type 1 and type 2 fiber sizes, representing myopathic changes.
Ragged red fibers are the hallmark of MELAS syndrome. The ragged red fibers stain brilliant red with occasional cytoplasmic bodies with trichrome stain. Ragged red fibers usually stain positive with cytochrome oxydase stain.
Staining with periodic acid-Schiff, nicotinamide adenine dinucleotide (NADH) dehydrogenase tetrazolium reductase, or for succinic dehydrogenase demonstrates increased subsarcolemmal activity. This mitochondrial proliferation has also been observed in blood vessels and is determined using a stain for succinate dehydrogenase.
Electron microscopy demonstrates an increase in number and size of mitochondria, some with paracrystalline bodies.
Seidowsky A, Hoffmann M, Glowacki F, Dhaenens CM, Devaux JP, Lessore de Sainte Foy C, et al. Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. Clin Nephrol. 2012 Aug 21. [Medline].
Meseguer S, Martínez-Zamora A, García-Arumí E, Andreu AL, Armengod ME. The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet. 2014 Aug 22. [Medline].
Mehrazin M, Shanske S, Kaufmann P, Wei Y, Coku J, Engelstad K. Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS. Am J Med Genet A. 2009 Feb 15. 149A(4):584-7. [Medline]. [Full Text].
Liu K, Zhao H, Ji K, Yan C. MERRF/MELAS overlap syndrome due to the m.3291T>C mutation. Metab Brain Dis. 2014 Mar. 29(1):139-44. [Medline].
Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Arch Neurol. 2010 Jan. 67(1):19-24. [Medline].
Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008 Dec 1. 17(23):3697-707. [Medline].
Nemes A, Geleijnse ML, Sluiter W, Vydt TC, Soliman OI, van Dalen BM. Aortic distensibility alterations in adults with m.3243A>G MELAS gene mutation. Swiss Med Wkly. 2009 Feb 21. 139(7-8):117-20. [Medline].
Scarpelli M, Zappini F, Filosto M, Russignan A, Tonin P, Tomelleri G. Mitochondrial Sensorineural Hearing Loss: A Retrospective Study and a Description of Cochlear Implantation in a MELAS Patient. Genet Res Int. 2012. 2012:287432. [Medline]. [Full Text].
[Guideline] International Diabetes Center. Type 2 diabetes practice guidelines. 2003. [Full Text].
Primiano G, Plantone D, Forte F, Sauchelli D, Scaldaferri F, Gasbarrini A, et al. Acute refractory intestinal pseudo-obstruction in MELAS: efficacy of prucalopride. Neurology. 2014 May 27. 82(21):1932-4. [Medline].
Singmaneesakulchai S, Limotai N, Jagota P, Bhidayasiri R. Expanding spectrum of abnormal movements in MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Mov Disord. 2012 Oct. 27(12):1495-7. [Medline].
Fayssoil A. Heart diseases in mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome. Congest Heart Fail. 2009 Nov-Dec. 15(6):284-7. [Medline].
Dindyal S, Mistry K, Angamuthu N, Smith G, Hilton D, Arumugam P, et al. MELAS syndrome presenting as an acute surgical abdomen. Ann R Coll Surg Engl. 2014 Jan. 96(1):101E-103E. [Medline].
Betts J, Jarost E, Perry RH et al. Molecular neuropathology of MELAS; level of heteroplasmy in individual neurons and evidence of extensive vascular involvement. Neuropathology and Applied. Neurobiology. 2006. 32:359-373.
Borner GV, Zeviani M, Tiranti V, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet. 2000 Mar 1. 9(4):467-75. [Medline].
Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992 Apr. 31(4):391-8. [Medline].
Deschauer M, Tennant S, Rokicka A, He L, Kraya T, Turnbull DM. MELAS associated with mutations in the POLG1 gene. Neurology. 2007 May 15. 68(20):1741-2. [Medline].
Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994 Jan. 9(1):4-13. [Medline].
Hirano M, Ricci E, Koenigsberger MR, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992. 2(2):125-35. [Medline].
Jacobs HT, Holt IJ. The np 3243 MELAS mutation: damned if you aminoacylate, damned if you don't. Hum Mol Genet. 2000 Mar 1. 9(4):463-5. [Medline].
Joko T, Iwashige K, Hashimoto T, et al. A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes associated with diabetes mellitus and hypothalamo-pituitary dysfunction. Endocr J. 1997 Dec. 44(6):805-9. [Medline].
Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006 Feb 14. 66(3):324-30. [Medline].
Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005 Feb 22. 64(4):710-2. [Medline].
Matsumoto J, Saver JL, Brennan KC, Ringman JM. Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). Rev Neurol Dis. 2005 Winter. 2(1):30-4. [Medline].
Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol. 1984 Oct. 16(4):481-8. [Medline].
Pons R, Andreu AL, Checcarelli N, Vila MR, Engelstad K, Sue CM. Mitochondrial DNA abnormalities and autistic spectrum disorders. J Pediatr. 2004 Jan. 144(1):81-5. [Medline].
Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options. CNS Drugs. 2006. 20(6):443-64. [Medline].
Shanske S, Coku J, Lu J, Ganesh J, Krishna S, Tanji K. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. Arch Neurol. 2008 Mar. 65(3):368-72. [Medline].
Shimotake T, Furukawa T, Inoue K, Iwai N, Takeuchi Y. Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr Surg. 1998 Dec. 33(12):1837-9. [Medline].
Sue CM, Bruno C, Andreu AL, et al. Infantile encephalopathy associated with the MELAS A3243G mutation. J Pediatr. 1999 Jun. 134(6):696-700. [Medline].
Tanahashi C, Nakayama A, Yoshida M, Ito M, Mori N, Hashizume Y. MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study. Acta Neuropathol. 2000 Jan. 99(1):31-8. [Medline].
Tay SH, Nordli DR Jr, Bonilla E, Null E, Monaco S, Hirano M. Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Arch Neurol. 2006 Feb. 63(2):281-3. [Medline].
Thambisetty M, Newman NJ, Glass JD, Frankel MR. A practical approach to the diagnosis and management of MELAS: case report and review. Neurologist. 2002 Sep. 8(5):302-12. [Medline].