CASE REPORT

MELAS Masquerading as a Systemic Vasculitis
Matthew B. Carroll, MD, FACP

Abstract: Mitochondrial encephalomyopathy, lactic acidosis, and
stroke (MELAS) is a mitochondrial genetic disorder caused by a
point mutation, resulting in the substitution of guanine for adenine at
nucleotide 3243 (A3243G). It is a multisystem disorder with variable manifestations and typically presents between the first and third
decades of life. It should be suspected if a patient exhibits stroke-like
episodes before age 40, encephalopathy characterized by seizures,
dementia, or both, and lactic acidosis, ragged-red fibers in muscle, or
both.
We present the case of a 26-year-old white man suspected with
primary central nervous system vasculitis admitted to our facility
with profound constipation from severe intestinal dysmotility. Although his gastrointestinal and neurologic symptoms did not meet
criteria for a specific vasculitic syndrome, his symptoms and blood
test abnormalities were concerning for such a process. MELAS was
included in our differential diagnosis because his symptoms failed to
fit a defined vasculitic process. When genetic testing documented the
presence of the point mutation A3243G, his diagnosis was changed.
This case illustrates the importance of considering a mitochondrial
genetic disorder in the differential diagnosis of patients who present
to Rheumatologists with suspected unusual or atypical vasculitic
symptoms.
Key Words: MELAS, systemic vasculitis, stroke-like events,
encephalopathy, ragged red fibers, headache, lactic acidosis
(J Clin Rheumatol 2007;13: 334 –337)

M

itochondria are subcellular organelles on which all
mammalian cells are dependent for the production of
energy. Mitochondrial dysfunction can have a tremendous
impact on cellular function. We present the case of a patient
with MELAS, or mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like events, a clinical syndrome caused
by a mitochondrial DNA (mtDNA) point mutation whose
initial presentation mimicked a vasculitis. Deficient adeno-

From the Wilford Hall Medical Center, Lackland AFB, TX.
The author has not received any support from any public or private firms,
corporations, pharmaceutical companies, or industries.
The views expressed in this article are those of the author and do not reflect
the policy of the Department of Defense or other departments of the
United States government.
Reprints: Matthew B. Carroll, MD, FACP, Keesler Medical Center, 301
Fisher Street, Keesler AFB, MS 39534. E-mail: matthew.carroll@
keesler.af.mil.
Copyright © 2007 by Lippincott Williams & Wilkins
ISSN: 1076-1608/07/1306-0334
DOI: 10.1097/RHU.0b013e31815c2516

334

sine 5⬘-triphosphate (ATP) production from faulty electrochemical gradients inside mitochondria leads to widespread
cellular dysfunction, especially in tissues heavily dependent
on oxidative metabolism, such as the brain and skeletal
muscle. It is important for a rheumatologist to recognize
MELAS because the protean clinical manifestations of this
disorder can mimic conditions treated by our specialty.

CASE
The Rheumatology Service at our hospital was consulted to evaluate a 26-year-old white man admitted for
profound constipation. At the time of his presentation to the
emergency room in mid-April 2006, the patient reported
having anorexia and diarrhea for about 2 weeks along with
nausea and feculent vomiting for 2 to 3 days. During his
initial evaluation, he was febrile and abdominal X-ray film
revealed a profuse amount of stool. The results of several
serologic tests at the time of presentation are listed in Table
1. The patient’s elevated white blood cell count and C-reactive protein were concerning, and a serum lactate level drawn
to screen for bowel ischemia or infarction was also elevated
(see Table 1). This prompted further evaluation with a CT
abdomen/pelvis, which revealed massive dilation of the sigmoid colon caused by densely packed stool throughout the
large intestine and secondary blockage of the small intestines.
The patient was taken to the operating room and 18 pounds of
feces removed. Biopsies of the stomach, small intestine, and
colon were obtained. Review of the biopsy specimens revealed a patchy but marked neutrophilic infiltrate and scattered eosinophils within the vessel walls of capillaries and
small vessels of the colon only. Larger vasculature throughout the stomach and intestines were spared. Histologically,
the vessel wall inflammation suggested a small vessel vasculitis, and thus rheumatology was consulted.
Just 6 weeks earlier, the patient had been hospitalized at
our facility by the neurology service for evaluation of acute
encephalopathy. He had been in his usual state of health up to
early February 2006 when he experienced new migraine-like
headaches and patchy cortical blindness. His mother reported
that during this time the patient also had a personality change,
noting a new interest in gambling. The patient was hospitalized when he experienced a rapid decline in his mentation,
developed a new left facial numbness and experienced a brief
loss of consciousness associated with bizarre eye movements
and head jerking. A very thorough evaluation was performed;
however, most of his work-up was unremarkable with the
exception of an initially elevated cerebrospinal fluid protein
level and an electroencephalogram testing that demonstrated
periodic lateralized epileptiform discharges and continuous

JCR: Journal of Clinical Rheumatology • Volume 13, Number 6, December 2007

JCR: Journal of Clinical Rheumatology • Volume 13, Number 6, December 2007

TABLE 1. Results of Serologic Tests at the Time of the
Patient’s Presentation to the Emergency Room
Patient’s Value
White blood cell count
Hemoglobin
C-reactive protein
Lactate level
Blood urea nitrogen
Creatinine

9

14.6 (⫻10 /L)
13.9 g/dL
27.5 mg/dL
3.5 mmol/L
7.14 mmol/L
70.7 s␮mol/L

TABLE 2. Results of Key Autoimmune and Infectious
Serologic Tests Performed During Patient’s Hospitalization

Normal Range
9

4.3–10.0 (⫻10 /L)
13.5–17.5 g/dL
0–1.0 mg/dL
0.5–2.2 mmol/L
1.79–7.85 mmol/L
61.9–132.0 ␮mol/L

arrhythmic slow activity in the right hemisphere. Magnetic
resonance imaging (MRI) of his brain confirmed the presence
of a right hemispheric process revealing gyral edema and
regions of laminar cortical necrosis within the right parietal
and occipital lobes (Fig. 1). Magnetic resonance angiography
however showed normal intracranial vasculature without evidence of aneurysm or intracranial stenosis. Brain biopsy was
performed, which revealed marked lymphohistiocytic inflammation of pia-arachnoid and Virchow-Robin space with numerous capillaries and small vessels demonstrating neutrophilic infiltration. Hemosiderin laden macrophages suggested
the extravasation of blood. Associated reactive changes were
noted without dural involvement. Based on these abnormalities, a diagnosis of primary central nervous system vasculitis
was made. No treatment was instituted since the patient had
gradually started to improve, and he was discharged for
further monitoring.

FIGURE 1. Axial T2 weighted FLAIR magnetic resonance image of the brain. Gyral edema and regions of laminar cortical necrosis within the right parietal and occipital lobes are
noted (arrow). At the time of the study, a new area of restricted diffusion was seen within the optic radiations of the
right temporal lobe.
© 2007 Lippincott Williams & Wilkins

MELAS Masquerading as a Systemic Vasculitis

Test
ANA
RPR
PR3-ANCA
MPO-ANCA
Rheumatoid factor
Hepatitis B virus surface antibody
Hepatitis C virus antibody

Patient’s Result
Negative
Nonreactive
Negative
Negative
Negative
Negative
Negative

Although the patient had no chronic medical conditions, he did have a history of 2 previous bouts of intestinal
dysmotility. In March 2001, he was hospitalized for sigmoid
volvulus and underwent laparoscopic surgery. Postoperatively, he remained in the hospital for 2 months because of
difficulty advancing his diet, recurrent vomiting, and ileus. In
January 2002, he was hospitalized for laparoscopic correction
of a superior mesenteric artery syndrome. Again, his postoperative course was complicated by difficulty tolerating advances in his diet, episodic vomiting, but this time by constipation and colonic dysmotility as well. Evaluation failed to
reveal an etiology for his complicated postoperative course.
He had a normal developmental history, meeting age appropriate goals and progressing through school without limitations. He had no difficulty meeting the physical demands of
military basic training or fitness testing. He did not smoke
tobacco routinely but did have an occasional alcoholic drink.
The patient had 2 older siblings who were in a good state of
health, and his mother and father were both alive and well.
Upon our evaluation, the patient was found to have an
unremarkable clinical examination. He had no organomegaly,
no synovitis, no evidence of skin tightening, no digital ulcerations, and no cutaneous findings to support a vasculitic or
autoimmune condition. The results of various serologic tests
are shown in Table 2. Despite having initially elevated
markers of inflammation, he had no proteinuria, hematuria,
renal dysfunction, or evidence of hemolysis. He did have a
persistently mild elevation in his serum lactic acid. Initially,
on the basis of the results of his colon biopsy and previous
diagnosis of primary central nervous system vasculitis, our
service felt that the patient had evolved to an unspecified
systemic vasculitis. In our differential diagnosis, we included
MELAS because his symptoms failed to meet a specific
vasculitic condition and his history of encephalopathy/seizures, elevated lactic acid levels, and stroke-like event
seemed unusual for a previously healthy adult. Although
genetic testing for MELAS was being performed, cytotoxic
therapy was considered but the patient suffered multiple
consecutive infections, persistent encephalopathy, and pulmonary embolism. As a temporizing measure, IVIg 400
mg/kg was given for a total of 5 days. When genetic testing
for MELAS returned with the detectable presence of the
characteristic A3243G point mutation, his diagnosis was
definitively made. L-carnitine therapy was instituted shortly
after his diagnosis but with no obvious immediate clinical
effect.

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JCR: Journal of Clinical Rheumatology • Volume 13, Number 6, December 2007

Carroll

TABLE 3. Common Initial Clinical Manifestations of MELAS
Initial Symptom or Sign

Frequency (%)

Seizures
Recurrent headaches
Gastrointestinal symptoms (recurrent vomiting, anorexia)
Short stature/stopped growth
Stroke
Altered consciousness/impaired mentation
Hearing loss
Exercise intolerance
Visual symptoms
Developmental delay

28
28
25
18
17
12
10
10
8
5

Modified from DiMauro S, Hirano M. MELAS 关Myopathy, Mitochondrial-Encephalopathy-Lactic Acidosis-Stroke; Mitochondrial Encephalomyopathy, Lactic Acidosis,
and Strokelike Episodes兴. October 13, 2005. Available at http://www.geneclinics.org.
Accessed May 15, 2006.

DISCUSSION
MELAS is a disorder of mitochondrial genetics characterized by a point mutation in the gene MT-TL1, which
encodes tRNALeu(UUR).1 This tRNA gene sequence encompasses 78 nucleotides of the 16,569 positions found in normal
mitochondrial DNA. To date, 5 point mutations have been
found to occur in the MT-TL1 gene, but the 2 most common
are the adenine to guanine substitution at nucleotide position
3243 (A3243G) and the thymine to cytosine substitution at
nucleotide position 3271 (T3271C). In combination, both of
these point mutations are found in nearly 90% of patients
diagnosed with MELAS, with the A3243G point mutation
responsible for nearly 80% of cases. With either point mutation, a taurine modification deficiency at the anticodon wobble position occurs leading to a codon specific translational
defect and likely translational depression of ND6, a component of Complex I (NADH-coenzyme Q reductase) of the
respiratory chain.2 Complex I gathers electrons from reduced
cofactors such as NADH and FADH2 formed by the metabolism of carbohydrates, fats, and proteins. These electrons
then flow down an electrochemical gradient, and energy
liberated in the process is used to pump protons out of the
mitochondrial matrix into the intermembrane space. The
proton gradient established is then used by Complex V (ATP
synthase) to synthesize ATP.3
Since all cells rely on mitochondrial synthesis of energy
to perform daily functions, the symptoms and signs of
MELAS are protean and can reflect a multisystem disorder.1
Typically, patients present during childhood but presentation
over the age of 20 can occur as in our patient. It is exceptionally rare to be diagnosed over the age of 40, although
there are patients in the medical literature who have manifested other nonspecific symptoms years before the full syndrome was recognized.4 Early development is typically normal with the exception that some patients have short stature.
Common initial clinical manifestations of MELAS are listed
in Table 3.1 Seizures can be accompanied by stroke-like
episodes of transient paresis, cortical blindness, or altered
mentation. Headaches eventually occur in most affected individuals, have a migranous quality, and can be severe at the

336

beginning of a stroke-like event. Recurrent vomiting and
anorexia are also common symptoms, with pseudo-obstruction of the bowel possible. To our knowledge, our patient’s
acute and profound intestinal blockage was the most severe
documented. Over time patients with MELAS may also
develop sensorineural hearing loss, diabetes mellitus, congestive heart failure from cardiomyopathy, cardiac conduction
blocks, or progressive external ophthalmoplegia. When
symptoms are focal, as they initially were in our patient, an
autoimmune disorder, vasculitic process, or myositis may be
confused with MELAS.
To diagnose a patient with MELAS, criteria established
by Hirano et al in 1992 are used. On the basis of their review
of 69 cases in the literature and the 2 common point mutations associated with the disorder, they stated that a diagnosis
of MELAS should be suspected based on 3 invariant criteria5:
1. stroke-like episode before the age of 40,
2. encephalopathy characterized by seizures, dementia, or
both, and
3. lactic acidosis, ragged red fibers, or both.
Ragged red fibers refer to the appearance of muscle
fibers on light microscopy when stained with succinate dehydrogenase. Sporadic muscle fibers accumulate mutant
mtDNA which leads to massive mitochondrial proliferation
and markedly increased staining.6 The diagnosis could be
considered “secure” if a patient also had at least 2 of the
following:
1. normal early development,
2. recurrent headaches, or
3. recurrent vomiting.
Although some patients with MELAS may have clinical manifestations that overlap with other mitochondrial genetic disorders, Hirano et al maintained that “clinical differences can almost always be discerned.”5 Sporadic cases of
MELAS or relatives of a patient with MELAS who have the
same mtDNA mutation may have an incomplete syndrome or
just one finding (such as diabetes or hearing loss) rather than
the cardinal MELAS features. Acknowledging this limitation
of their clinical definition, Hirano et al recommended analysis
of mtDNA in partial or confusing cases.5 Although our
patient met the established clinical criteria, we pursued serum
genetic testing fearing misdiagnosis. Serum genetic testing
currently available for MELAS can potentially yield falsenegative tests because of the mitochondrial genetic phenomenon called heteroplasmy. Heteroplasmy refers to the mixture
of mutant and wild-type mtDNA that can occur in a cell. The
amount of mutated mtDNA can vary widely from organ to
organ and even between cells. It is possible for leukocytes or
platelets in a serum sample to have too low to detect levels of
mutant mtDNA, thus yielding a negative test result. Submitting
a different specimen, with the most reliable being muscle tissue,
can potentially yield a different though more accurate result.
Although typical pathologic changes in MELAS can be
found on muscle biopsy, in our patient tissue samples were
obtained only from involved organs. Case reports of antemortem brain biopsy specimens have demonstrated changes
© 2007 Lippincott Williams & Wilkins

JCR: Journal of Clinical Rheumatology • Volume 13, Number 6, December 2007

specifically in cerebral small vessels (smaller than 250 ␮m in
diameter) while sparing larger vessels. Arterioles, specifically
pial arterioles, show narrowing of the lumen from metabolic
damage to the endothelial cells. Secondary smooth muscle
hypertrophy may occur. Surrounding cortex and white matter
demonstrate changes such as gliosis, presence of reactive
gemistocytes, spongioform degeneration, and pyknotic appearing neurons suggestive of apoptosis.4 On MRI, signal
changes involving both the gray and white matter with
preferential involvement of the posterior temporal, occipital,
and parietal tissues is noted. Newer MRI techniques, which
use an apparent diffusion coefficient, have shown that this
coefficient is elevated after a clinical event and is consistent
with the presence of extracellular edema.7,8 Such changes
reflect cortical injury and vasogenic edema in the white
matter and suggest the presence of a metabolic disorder.8
Similar vascular and cortical changes were noted on our
patient’s brain biopsy specimen and on his MRI. The marked
lymphohistiocytic inflammation and involvement of only
small vessels on biopsy, and cortical laminar necrosis on
imaging, suggest a nonvasculitic process. Somewhat confounding was the extravasated blood and the hemosiderin
laden macrophages noted on brain biopsy. Although the
specimens were reviewed twice with our Pathology department who felt strongly about the presence of a small vessel
vasculitis, the significance of this remained unclear, especially since similar extravasation was not noted on the bowel
biopsy specimens. It is possible this was artifactual or a local
hemorrhagic complication. In contradistinction, the histopathologic abnormalities seen in focal arterial ischemic
events reflect cellular necrosis, with widespread cell swelling
and an acute inflammatory response. MRI shows perfusion
deficits in established vascular territories and typically involves larger vessels. Additionally, the apparent diffusion
coefficient is depressed, which reflects cellular edema and
impending necrosis.7
The prognosis for patients with MELAS is variable but
in general worse than that seen in other mitochondrial disorders.9 Patients typically die between 10 and 35 years of age,
often from intercurrent infections, intestinal obstruction, recurrent stroke-like events, or status epilepticus. In an 8-patient follow-up series from Taiwan, 50% died within 7 years
of presentation, with 25% having significant mental deterioration and 25% remaining stable. Substantial morbidity occurs from the cumulative effects of the stroke-like episodes
and seizures. Deafness, if it develops, further contributes to
the morbidity of this disorder. Treatments to date have mainly
focused on dietary supplementation of vitamins or cofactors,
specific coenzyme Q10, L-cartinine, and L-arginine. Efficacy
for dietary supplementation is currently limited to case reports, although some observational studies suggest that Larginine, a substrate for the synthesis of nitric oxide and
creatine, may reduce the severity and frequency of acute

© 2007 Lippincott Williams & Wilkins

MELAS Masquerading as a Systemic Vasculitis

stroke-like episodes.10 A randomized, placebo controlled trial
published in 2006 assessing the efficacy of dichloroacetate
was ended early because of peripheral nerve toxicity, which
lead to a high rate of medication discontinuation.11 Our
patient was started on L-carnitine 100 mg twice a day shortly
after diagnosis, but as of the writing of this case report, it was
too early to assess the efficacy of this therapy.
In summary, MELAS is a mitochondrial genetic disorder with multiorgan involvement but which can present with
atypical symptoms. Examination as well as serologic and
radiologic studies may often show nonspecific findings, further confounding the diagnosis. This was the case with our
patient’s elevated white blood cell count and C-reactive
protein. It is possible both were abnormal because of the
stress of his dysmotility or concomitant infection complicating his presentation. Our patient was a diagnostic enigma
during the 3-week period it took his genetic testing results to
return to our facility. Fortunately, his results returned before
the institution of cytotoxic therapy for a presumed unspecified systemic vasculitis. With population-based studies suggesting that mitochondrial disorders may be at least as common (1 case per 8500 people) as other sporadic or inherited
neurologic illnesses, they should be more frequently incorporated in our differential diagnosis as Rheumatologists.8
I am indebted to Dr. F. Silva for his assistance in the
care of this patient and help in establishing the diagnosis.
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www.geneclinics.org. Accessed May 15, 2006.
2. Kirino Y, Yasukawa T, Ohta S, et al. Codon-specific translational defect
caused by a wobble modification deficiency in mutant tRNA from a
human mitochondrial disease. PNAS. 2004;101:15070 –15075.
3. Chinnery PF, Schon EA. Mitochondria. J Neurol Neurosurg Psychiatry.
2003;74:1188 –1199.
4. Gilchrist JM, Sikirica M, Stopa E, Shanske S. Adult-onset MELAS.
Evidence for involvement of neurons as well as cerebral vasculature in
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5. Hirano M, Ricci E, Koenigsberger MR, et al. MELAS: an original case
and clinical criteria for diagnosis. Neuromuscul Disord. 1992;2:125–
135.
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J Med. 2003;348:2656 –2668.
7. Oppenheim C, Galanaud D, Samson Y, et al. Can diffusion weighted
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8. Dickerson BC, Holtzman D, Grant PE, Tian D. Case 36 –2005: a woman
with seizure, disturbed gait, and altered mental status. N Engl J Med.
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10. Geberhiwot T, Chakrapani A, Hendriksz C. Case 36-2005: A woman
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11. Kaufmann P, Englestad K, Wei Y, et al. Dichloroacetate causes toxic
neuropathy in MELAS. Neurology. 2006;66:324 –330.

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