This document summarizes the clinical presentation and genetics of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. MELAS is caused by mutations in mitochondrial DNA and presents with a variety of neurological and systemic symptoms. The most common symptoms include stroke-like episodes, seizures, short stature, myopathy and lactic acidosis. Diagnosis is supported by finding ragged red fibers on muscle biopsy. Genetically, 80% of cases are caused by the m.3243A>G point mutation in the mitochondrial tRNALeu(UUR) gene. MELAS has highly variable clinical expression even within families and affected individuals may exhibit different combinations of symptoms.

1. Introduction 336
Clinical abnormalities 336
Genetics and pathogenesis 340
Treatment 341
52
Mitochondrial encephalomyelopathy, lactic acidosis
and stroke-like episodes (MELAS)
MAJOR PHENOTYPIC EXPRESSION
Mitochondrial myopathy, shortness of stature, stroke-like episodes, seizures, encephalopathy progressive to dementia,
migraine,diabetes mellitus,lactic acidemia,ragged red muscle fibers and mutations in the mitochondrial tRNA leucine gene.
INTRODUCTION
This syndrome was first defined as such by Pavlakis and
colleagues [1] in 1984, although patients have doubtless been
reported earlier. Among the mitochondrial myopathies this is
one of the more common [2].
The typical clinical presentation includes all of the features
that make up the name of the syndrome, but there is enor-
mous variability. Some affected individuals have only diabetes,
or only migraine. Others have only hearing loss, or hearing
loss and diabetes [3]. The disease is inherited in a maternal
pattern, and the gene is on the mitochondrial genome
(Figure 52.1). Most of the patients have had one of two point
mutations in the mitochondrial gene for the leucine (UUR)
tRNA (A3243G and T3271C) [4–7] (Figure 52.2).
CLINICAL ABNORMALITIES
There is a considerable variety of expression consistent with
the varying heteroplasmy of mitochondrial inheritance. The
typical picture is of normal development followed by a severe,
progressive encephalomyopathy. Onset may be myopathic
with exercise intolerance or weakness (Figure 52.3). Many
patients have shortness of stature, and this may be the first
manifestation of disease (Figure 52.4). One of our patients
had been treated unsuccessfully with human growth hor-
mone by a pediatric endocrinologist; this has also been
reported by others. In many patients the onset of symptoms
is with the first stroke-like episode, usually between 4 and
ND5
Q
MELAS 3243G, 3271C
LHON 3460A
LHON 14448C
LHON 14449A
LHON 11778A
NARP 8993G/C
MERRF 8344G
DEAF 1555G
CY
ND6
Cyt bT
F P
E
12s
16s
PH
PL
QL
OH
ND1
W
D K
G
R
ND2
A
N
COI
COII
COIII
ATP8
ATP6
ND3
ND4
L
S
H
ND4L
I
M
LUUR
SUCN
V
Com
m
on
54kbdeletion–KSS
Figure 52.1 The circular DNA of the human mitochondrial genome.
Shown are the sites of the genes for the mitochondrial genes, as well
as the sites for the most common mutations, including the A3243G
and T3271C mutations associated with MELAS syndrome.

2. Clinical abnormalities 337
15 years-of-age [1,4,8–14]. Less commonly, the onset of dis-
ease may be in infancy [8], often with delayed developmental
milestones or learning disability.
The myopathy may be present before the first stroke. At
one extreme is a floppy infant at 4 months-of-age [8]. More
commonly, there is exercise intolerance, easy fatigability or
frank weakness. Patients may have difficulty going up stairs.
Myopathy may be progressive. Proximal muscles tend to be
more involved than the distal [8]. Musculature is generally
thin.The facial appearance may be myopathic [15].The creatine
phosphokinase activity in the blood may be elevated [13,16].
Some patients have been diagnosed as having polymyositis [11].
The electromyogram (EMG) may demonstrate a myopathic
pattern.
The stroke-like episode is the hallmark feature of this syn-
drome. At the same time, these episodes may occur in only a
few members of a pedigree, in which a much larger number
has the same mutation [15,16]. In one series of four families
[16] stroke-like episodes occurred only in the probands. Two
of the affected mothers were clinically entirely normal. In
other pedigrees no member may have had this defining man-
ifestation. The episode may initially be manifest by vomiting
and headache, convulsions or visual abnormalities [8]. Less
commonly, there may be numbness, hemiplegia or aphasia.
There may be recurrent episodes of headache or vomiting
lasting a few hours to several days. The episode may be fol-
lowed by transient hemiplegia or hemianopia lasting a few
hours to several weeks. Computed tomography (CT) or mag-
netic resonance imaging (MRI) scan of the brain following
such an episode reveals lucency consistent with infarction [17]
A
T A
T A
T A
A T
A T
A T
A T
A T
A
A
A
AA
A
A
A A
A
A
A
A A
A
A T
T T
T
T
T
T
T
T
T
T
T
T
G
G
G G
G
G
G
G
G
G
G
G
G
G C
C
C
C
C
C
C
C
CC
C
C C
C
C
C
5Ј-G C
3Ј-OH
MELAS
np3243
Mitochondrial
encephalomyopathy
or MELAS
np3252
MELAS
np3271
Anticodon
Figure 52.2 The tRNA for leucine, the site of the defect in the
MELAS syndrome. In addition to the point mutation at npA3243G,
the common mutation in MELAS, and npT3271C and npA3252G the
other MELAS mutations, there are a number of other known mutations
in the tRNA leucine which cause mitochondrial diseases. These
include: npT3250C, mitochondrial myopathy; npA3751G chronic
progressive external ophthalmoplegia (CPEO) proximal weakness,
sudden death; npA3260G, adult onset hypertrophic cardiomyopathy
and myopathy; npA3302G, mitochondrial myopathy; and npC3303T,
adult onset hypertrophic cardiomyopathy and myopathy.
Figure 52.3 K.S., a boy with MELAS illustrating his lordotic,
myopathic posture. He presented at 4 years-of-age with weakness
and exercise intolerance. He also had insulin-dependent diabetes
mellitus. Blood concentration of CPK was 462IU/L. Plasma
lactate was 93.1mg/dL. (This illustration was kindly provided
by Dr. Richard Haas of UCSD.)
Figure 52.4 N.F., a boy with MELAS who had strokes on three
occasions and had become demented. Stature was very short.
(This illustration was kindly provided by Dr. Richard Haas of UCSD.)

3. (Figures 52.5 and 52.6). This picture may resolve over hours
or days, but later there may be cerebral atrophy and calcifica-
tions, especially in the basal ganglia [17–24] (Figure 52.6).
Infarcts are most common in the posterior temporal, pari-
etal or occipital lobes, but histologic examination may reveal
clear-cut infarcts widely scattered in the cerebrum, cerebel-
lum or basal ganglia [18,20,25,26]. So these episodes are in
fact strokes. The term ‘stroke-like’may be appropriate in that
no vascular changes of inflammation or atherosclerosis are
found in the brain. We have tended to refer to this type of
lesion as metabolic stroke in other diseases, such as propionic
acidemia (Chapter 2) or methylmalonic acidemia (Chapter 3).
In MELAS mitochondrial angiopathy is evident in contrast
enhancement in affected areas [21,27–29], and even in the skin
as purpuric lesions.
The migraine or migraine-like headaches seen in these
patients may reflect the same process. Headache may be hemi-
cranial. In pedigrees of patients with classic MELAS there are
many members whose only manifestation is migraine [8,15]
(Figure 52.7). Developmental delay, or learning disability [8]
or attention deficit disorder [15], is mainly found in patients
prior to the development of the first stroke. This was the his-
tory of the patient illustrated in Figure 52.4 who did not have
his first stroke until the age of 8, but had been in a special
education program for years. On the other hand, some
patients with considerable myopathy and/or other sympto-
matology may be intellectually normal (Figure 52.3). The
encephalopathy when it develops may be progressive to
dementia (Figure 52.4). The patient may be apathetic and
cachectic [18].
Additional neurologic features include ataxia, tremor, dysto-
nia, visual disturbances and cortical blindness. Some have had
myoclonus. Convulsive seizures may be focal or generalized
tonic-clonic, but may also be myoclonic [7]. The electroen-
cephalogram (EEG) is usually abnormal, and there are usu-
ally epileptiform spike discharges.
Some patients have had ophthalmoplegia or ptosis [11].
Others have had pigmentary degeneration of the retina [30]
like those with the neurodegeneration, ataxia and retinitis
pigmentosa (NARP) mutation (Chapter 54). Patients have
been referred to as having the Kearns-Shy syndrome [11].
Others have presented with the picture of Leigh syndrome
(Chapter 47), in which patients have recurrent attacks of
338 MELAS
Figure 52.5 CT of the brain of M.R., a boy with the A3243 G
mutation, illustrating the posterior infarct and the extensive
calcifications in the basal ganglia, including the caudate, putamen
and globus pallidus. (Illustration kindly provided by Dr. Richard Haas
of UCSD.)
A
B
Figure 52.6 MRI of the brain of N.F. illustrating widespread
cortical atrophy, residual at a right parieto-occipital infarct with
ventriculomegaly and increased T2 signal representing preinfarction
state in left temporoparieto-occipital cortex. (This illustration kindly
provided by Dr. Richard Haas of UCSD.)

4. Clinical abnormalities 339
neurologic regression, pyramidal and extrapyramidal signs,
brainstem abnormalities and leukodystrophy [31,32].
An interesting consequence of the MELAS mutation is
the occurrence of diabetes mellitus [30] (Figure 52.7). This
appears to be the most common manifestation of MELAS. It
is usually type II diabetes [33],but the boy shown in Figure 52.3
had insulin-dependent diabetes mellitus.
Sensorineural hearing loss is another common manifesta-
tion, and it may be seen in individuals with or without diabetes
and no other manifestations of disease [3]. It may also be seen
in patients with the classic syndrome. Deafness has been
reported in about 25 percent of patients [8]. The disease is a
major cause of aminoglycoside-induced hearing loss [34]. This
provides an argument for screening for the MELAS mutation
in patients with antibiotic-induced deafness, in order to test
affected relatives and avoid aminoglycosides in them.
Cardiomyopathy is a less common feature, but may be
found in about 10 percent of patients. It is usually hyper-
trophic cardiomyopathy, but it may be dilated [35]. Patients
with the MELAS mutations have been found to have MELAS
and cardiomyopathy, but others have had isolated cardio-
myopathy and no neurologic disease. There may be conduc-
tion abnormalities – for instance, Wolff-Parkinson-White
syndrome [18] – and often an abnormal electrocardiogram
[36]. Huge accumulation of mitochondria has been observed
in myocardial fibers [18].
Renal involvement may take the form of renal tubular aci-
dosis, and there may be a typical renal Fanconi syndrome
[37]. One patient developed a nephrotic syndrome and had
focal glomerulosclerosis [16]. A variety of other organs has
been involved in individual patients. One had pancreatitis
following valproate administration [15]. Others have had
peripheral neuropathy with or without rhabdomyolysis [38,39].
One had ischemic colitis [40]. Pigmentary abnormalities of
the skin have been reported [37].
The histologic signature of the MELAS syndrome is the
appearance of ragged red fibers in the muscle (Figure 52.8)
[1,12,13,36]. These are best seen in the trichrome stain. In
H and E there may be variation in fiber size and increase in con-
nective tissue. Staining with periodic acid Schiff (PAS), NADH
tetrazolium reductase or for succinic dehydrogenase may show
increased subsarcolemmal activity. Electron microscopy reveals
an increase in number and size of mitochondria (Figure 52.9),
some with paracrystalline inclusion bodies [13,36].
The lactic acidosis is an important feature of this disorder. It
does not usually lead to systemic acidosis, and it may even be
absent in patients with impressive involvement of the central
nervous system. The levels may be elevated in cerebrospinal
fluid (CSF) and normal in blood [32].The patient in Figure 52.4
had repeated determinations of lactate in the blood in the
normal 20mg/dL range; his CSF lactate was 56.3mg/dL. The
CSF concentration of protein may be mildly elevated.
75ϩ
68
8
3
33 38 43
14 13
12
41
7 mo
41
47
55
63
7660’s MI
d57
in 1977
80ϩ
I.
II.
III.
IV.
Developmental delayed
seizures
Parkinson’s
Depression
MELAS
Migraine
Diabetes
Figure 52.7 Pedigree of the family of
N.F. illustrating the occurrence of diabetes,
migraine, seizures and other problems.
Analysis of the blood revealed the
npA3243G mutation.
Figure 52.8 Ragged red fibers of the muscle of a patient with
MELAS. (Illustration kindly provided by Dr. Richard Haas of UCSD.)

5. GENETICS AND PATHOGENESIS
The MELAS syndrome is the result of mutation in mitochondr-
ial genes for tRNA [41].The most common is A-to-G transition
at position 3243 of the tRNALeu(UUR) [4,5] (Figure 52.1).
Approximately 80 percent of affected individuals have this
mutation in the dihydrouridine loop of the gene [8,16,42–44].
The other common mutation, occurring in about 8.5 percent
of individuals, is also in the tRNALeu(UUR) at 3271 in the
anticodon,where there is a T-to-C transversion [7].The G-to-A
transversion at 3252 of the same gene has been reported in
mitochondrial encephalopathy [45]. Another mutation in the
dihydrouridine loop at nucleotide 3250 is a T-to-C transition
[42].Another mutation in this gene is an A-to-T change at posi-
tion 3256 [46].A 5814G in the tRNACys gene was reported in a
patient with cardiomyopathy and myopathy [35].
A quite distinct mutation,an A-to-G transition at nucleotide
11084 in the ND4 gene for the subunit of Complex I of the res-
piratory chain, was reported by Letrit et al. [47] in a Caucasian
patient. This same mutation was later reported by Sakuta and
colleagues [48] in 10–14 percent of Japanese studied, both
patients with mitochondrial myopathy and normal controls,
suggesting that it might be a polymorphism. On the other
hand, this mutation was not found in 109 normal or patient
Caucasians nor in American blacks, nor in a considerable
number of patients with other mitochondrial diseases. So the
issue on this transition is unresolved. A large (10.5kg) dele-
tion was reported in a MELAS patient with a renal Fanconi
syndrome [37].
The common mutation creates a new site for Hae III lead-
ing to a 169bp fragment in controls after electrophoresis and
fragments of 97 and 72bp in patients with MELAS [43].
Sequencing (Figure 52.10) reveals the G in MELAS where
there is an A in control.Varying heteroplasmy among affected
individuals appears to reflect variable segregation in the
ovum. On the other hand, study of the proportion of mutant
DNA in various tissues obtained from a woman and her
two daughters revealed similar proportions in tissues derived
from ectodermal, endodermal and mesodermal germ layers,
indicating little mitotic segregation after early embryogenesis
[49]. The issue of heteroplasmy, which can vary from tis-
sue to tissue making detection difficult has been addressed
in MELAS A3243G by the design of peptide nucleic acids
which bond to the wild type mtDNA at 3243 preventing
PCR amplification and making the mutant the dominant
product [50].
Mutations in the tRNA for leucine might be expected to
have an important effect on translation and hence protein
synthesis in mitochondria. This has been demonstrated in
studies of cybrids [25] by fusing human cell lines lacking
mitochondrial DNA with exogenous mitochondria contain-
ing 0 to 100 percent of the common 3243 mutant DNA.
Cybrids containing more than 95 percent mutant DNA had
decreased rates of synthesis and steady state levels of mito-
chondrial proteins leading to respiratory chain deficiency.
Patients with the MELAS syndrome have been found to
have marked deficiency in the activity of complex I of the
respiratory chain [12]. In mitochondria from muscle,
rotenone-sensitive NADH-cytochrome reductase activity was
0–27 percent of control value, and immunochemical study
revealed a general decrease in complex I subunits. In a patient
with the T-to-C 3250 mutation, complex I activity in muscle
was six percent of control and that of complex IV was 47 per-
cent of control [51]. The productions of CO2 from labeled
pyruvate, malate and 2-oxoglutarate were all reduced [36]. In
a study of four patients with the 3243 mutation, the activity
of complexes I and IV were reduced in muscle and other
340 MELAS
Figure 52.9 Electronmicroscopy of the muscle of the mother of
K.S. She had diabetes, but no symptoms of myopathy. Illustrated are
many pleomorphic mitochondria, abnormal concentric lamellar cristae
and electron-dense bodies. There is also glycogen accumulation.
(Illustration kindly provided by Dr. Richard Haas of UCSD.)
Figure 52.10 Sequencing gel of the MELAS region of the leucine
TRNA of muscle. The npA3243G mutation in K.S.; BB was a normal
control. (Illustration kindly provided by Dr. Richard Haas of UCSD.)

6. References 341
tissues, but there was no correlation between the proportion
of mutant DNA in a tissue and the activity of the respiratory
chain complexes [44].
TREATMENT
A variety of supportive measures is helpful in this disorder, as
in other mitochondrial diseases. Riboflavin therapy has been
reported to be of benefit in a patient with complex I defi-
ciency and the T-to-C 3250 mutation [51]. A dose of 20mg
twice a day was employed in a 2-year-old patient with myopa-
thy who could not ascend stairs and was reluctant to walk.
Improvement in muscle strength occurred, and there was no
further deterioration over three years of observation.
Coenzyme Q has been helpful in a number of patients [14].
Some amelioration of muscle weakness has been observed, as
well as some decrease in plasma levels of lactate. CSF lactate
did not improve. Doses of 30–90mg per day were reported
[14]. In MELAS, doses as high as 300mg per day have been
stated to be required for optimal effects [13,14].
Experience with dichloroacetic acid (Chapter 47) is accu-
mulating; it is clear that levels of lactate are lowered in both
plasma and CSF. MELAS may be one of the disorders that
responds favorably to this agent.
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