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MELAS Syndrome Workup

  • Author: Fernando Scaglia, MD, FACMG; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Nov 14, 2014
 

Laboratory Studies

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.
      Pathophysiologic classification of lactic acidosis 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.
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Imaging Studies

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.
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Other Tests

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.

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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.

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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.

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Contributor Information and Disclosures
Author

Fernando Scaglia, MD, FACMG Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital

Fernando Scaglia, MD, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, Society for Inherited Metabolic Disorders, Society for the Study of Inborn Errors of Metabolism, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

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Pathophysiologic classification of lactic acidosis.
 
 
 
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