eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
MELAS Syndrome: Differential Diagnoses & Workup
Updated: Jul 23, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Other Problems to Be Considered
Sensorineural hearing loss
Peripheral neuropathy
Rhabdomyolysis
Intestinal pseudoobstruction
Myoclonic epilepsy and ragged red fiber disease
Neurodegeneration, ataxia, and retinitis pigmentosa
Primary mtDNA depletion syndrome
Disorders of pyruvate metabolism
Workup
Laboratory Studies
- Serum lactic acid, serum pyruvic acid, cerebrospinal fluid (CSF) lactic acid, and CSF pyruvic acid
- Lactic acidosis is an important feature of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome.
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.
- Lactic acidosis is an important feature of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome.
- 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.
Imaging Studies
- 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.
Other Tests
- EEG
- EEG findings are usually abnormal.
- Epileptiform spike discharges are usually present.
- ECG
- ECG is used to look for conduction abnormalities with ventricular arrhythmias.
- ECG can identify presymptomatic cardiac involvement, preexcitation syndromes, and cardiac conduction block.
Procedures
- 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.
Histologic Findings
- 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.
More on MELAS Syndrome |
| Overview: MELAS Syndrome |
 Differential Diagnoses & Workup: MELAS Syndrome |
| Treatment & Medication: MELAS Syndrome |
| Follow-up: MELAS Syndrome |
| Multimedia: MELAS Syndrome |
| References |
| « Previous Page | Next Page » |
References
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. Feb 15 2009;149A(4):584-7. [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. Dec 1 2008;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. Feb 21 2009;139(7-8):117-20. [Medline].
[Guideline] International Diabetes Center. Type 2 diabetes practice guidelines. 2003;[Full Text].
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. Mar 1 2000;9(4):467-75. [Medline].
Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. Apr 1992;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. May 15 2007;68(20):1741-2. [Medline].
Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. Jan 1994;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. Mar 1 2000;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. Dec 1997;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. Feb 14 2006;66(3):324-30. [Medline].
Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. Feb 22 2005;64(4):710-2. [Medline].
Matsumoto J, Saver JL, Brennan KC, Ringman JM. Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). Rev Neurol Dis. Winter 2005;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. Oct 1984;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. Jan 2004;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. Mar 2008;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. Dec 1998;33(12):1837-9. [Medline].
Sue CM, Bruno C, Andreu AL, et al. Infantile encephalopathy associated with the MELAS A3243G mutation. J Pediatr. Jun 1999;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. Jan 2000;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. Feb 2006;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. Sep 2002;8(5):302-12. [Medline].
Further Reading
Keywords
MELAS syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke, oxidative phosphorylation, OXPHOS disorder, strokelike episode, seizures, diabetes mellitus, hearing loss, cardiac disease, short stature, endocrinopathies, exercise intolerance, neuropsychiatric dysfunction, hemiplegia, hemianopia, schizophrenia, bipolar disorder, autism spectrum disorders, ASD, hypertrophic cardiomyopathy, hypertension, atrioventricular blocks, long QT syndrome, Wolff-Parkinson-White syndrome, Leigh syndrome, subacute necrotizing encephalopathy, hypothyroidism, hyperthyroidism, developmental delay, learning disability, attention deficit disorder, polydipsia, polyuria, nephrotic syndrome, treatment, diagnosis
