Molecular Genetics and Metabolism 116 (2015) 4–12

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Molecular Genetics and Metabolism

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MELAS syndrome: Clinical manifestations, pathogenesis, and

treatment options
Ayman W. El-Hattab a, Adekunle M. Adesina b, Jeremy Jones c, Fernando Scaglia d,⁎
a
Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates
b
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
c
Singleton Department of Radiology, Texas Children's Hospital, Houston, TX, USA
d
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

a r t i c l e i n f o a b s t r a c t

Article history: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the
Received 13 May 2015 most frequent maternally inherited mitochondrial disorders. MELAS syndrome is a multi-organ disease with
Received in revised form 14 June 2015 broad manifestations including stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent
Accepted 14 June 2015
headaches, hearing impairment, diabetes, and short stature. The most common mutation associated with
Available online 15 June 2015
MELAS syndrome is the m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR).
Keywords:
The m.3243ANG mutation results in impaired mitochondrial translation and protein synthesis including the mi-
Mitochondrial diseases tochondrial electron transport chain complex subunits leading to impaired mitochondrial energy production. The
Encephalomyopathy inability of dysfunctional mitochondria to generate sufficient energy to meet the needs of various organs results
Lactic acidosis in the multi-organ dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial
Nitric oxide deficiency proliferation in the smooth muscle and endothelial cells of small blood vessels leading to angiopathy and
Arginine impaired blood perfusion in the microvasculature of several organs. These events will contribute to the compli-
Citrulline cations observed in MELAS syndrome particularly the stroke-like episodes. In addition, nitric oxide deficiency
Angiopathy
occurs in MELAS syndrome and can contribute to its complications. There is no specific consensus approach for
Endothelial dysfunction
treating MELAS syndrome. Management is largely symptomatic and should involve a multidisciplinary team.
Unblinded studies showed that L-arginine therapy improves stroke-like episode symptoms and decreases the
frequency and severity of these episodes. Additionally, carnitine and coenzyme Q10 are commonly used in
MELAS syndrome without proven efficacy.
© 2015 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2. Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1. Neurological manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2. Muscular manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3. Lactic acidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.4. Cardiac manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.5. Gastrointestinal manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.6. Endocrine manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.7. Renal, pulmonary, dermatological, and hematological manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1. Molecular genetic defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.2. Energy deficiency and angiopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.3. Nitric oxide deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.4. Pathogenesis of various complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.5. Phenotype variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

⁎ Corresponding author at: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX 77030, USA.
E-mail address: fscaglia@bcm.edu (F. Scaglia).

http://dx.doi.org/10.1016/j.ymgme.2015.06.004
1096-7192/© 2015 Elsevier Inc. All rights reserved.
 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 116 (2015) 4–12 5

4.1. Evaluation of multi-organ involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

4.2. Management of complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.3. Medications to avoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1. Introduction myopathy, recurrent headaches, hearing impairment, diabetes, and

Mitochondria are double membrane organelles found in all nucleated
human cells and perform a variety of essential functions, including the
generation of most cellular energy in the form of adenosine triphosphate
(ATP). The inner mitochondrial membrane harbors the electron trans-
port chain (ETC) complexes that transfer electrons, translocate protons,
and produce ATP. Mitochondria contain extra-chromosomal DNA (mito-
chondrial DNA, mtDNA). However, only a very small proportion of mito-
chondrial proteins are encoded by that DNA; whereas the majority of
mitochondrial proteins are encoded by nuclear DNA (nDNA). Mutations
in mtDNA or mitochondria-related nDNA genes can result in mitochon-
drial dysfunction leading to mitochondrial diseases. Dysfunctional mito-
chondria are unable to generate sufficient ATP to meet the energy needs
of various organs, particularly those with high energy demand, including
the nervous system, skeletal and cardiac muscles, kidneys, liver, and
endocrine systems. Some patients with mitochondrial diseases display
a cluster of clinical features that fall into a discrete clinical syndrome.
However, there is often considerable clinical variability, and many af-
fected individuals do not fit into one particular syndrome [1].
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes (MELAS) syndrome is one of the most frequent maternally
inherited mitochondrial disorders which was first delineated in 1984
[2]. The molecular basis of MELAS syndrome was initially discovered
in 1990 when adenine to guanine transition at position 3243 of
mtDNA (m.3243ANG) in the MT-TL1 gene encoding tRNALeu(UUR) was
found to be associated with this syndrome [3,4]. In 1992, clinical diag-
nostic criteria for MELAS syndrome were published indicating that the
clinical diagnosis of this syndrome is based on the following three
invariant criteria: 1) stroke-like episodes before age 40 years, 2) enceph-
alopathy characterized by seizures and/or dementia, and 3) mitochon-
drial myopathy evident by lactic acidosis and/or ragged-red fibers
(RRFs). The diagnosis is considered confirmed if there are also at least
two of the following criteria: 1) normal early psychomotor develop-
ment, 2) recurrent headaches, and 3) recurrent vomiting episodes [5].
More recently, the MELAS study group committee in Japan published
other diagnostic criteria by which the diagnosis is considered definitive
with at least two category A criteria (headaches with vomiting, seizures,
hemiplegia, cortical blindness, and acute focal lesions in neuroimaging)
and two category B criteria (high plasma or cerebrospinal fluid (CSF)
lactate, mitochondrial abnormalities in muscle biopsy, and a MELAS-
related gene mutation) [6]. The prevalence of MELAS syndrome has
been estimated to be 0.2:100,000 in Japan [6]. Other mtDNA mutations
were subsequently found to cause MELAS syndrome; however, the
m.3243ANG remained the commonest universally. The m.3243ANG,
which was subsequently found to be associated with other phenotypes
that collectively constitute a wide spectrum ranging from MELAS
syndrome at the severe end to asymptomatic carrier status, was found
to be relatively common with a prevalence of 16–18:100,000 in
Finland [7,8]. In this review, we summarize the clinical manifestations
of MELAS syndrome along with its pathogenic mechanisms and manage-
ment options.
2. Clinical manifestations
MELAS syndrome is a multi-organ disease with broad manifesta-
tions including stroke-like episodes, dementia, epilepsy, lactic acidemia,
short stature. Childhood is the typical age of onset with 65–76% of
affected individuals presenting at or before the age of 20 years. Only
5–8% of individuals present before the age of 2 years and 1–6% after the
age of 40 years [6,9–11].
Individuals with MELAS syndrome frequently present with more
than one initial clinical manifestation. Table 1 summarizes the initial
manifestations in affected individuals [6,9,10]. Table 2 summarizes the
clinical manifestations of MELAS syndrome organized according to
their prevalence [6,9–11]. Below the manifestations of MELAS syndrome
are presented according to the organ or system involved.
2.1. Neurological manifestations
Stroke-like episodes are one of the cardinal features of MELAS
syndrome that occur in 84–99% of affected individuals [6,9,10]. These
episodes present clinically with partially reversible aphasia, cortical
vision loss, motor weakness, headaches, altered mental status, and
seizures with the eventual progressive accumulation of neurological
deficits. The affected areas in neuroimaging do not correspond to classic
vascular distribution (hence called “stroke-like”), are asymmetric,
involve predominantly the temporal, parietal, and occipital lobes, and
can be restricted to cortical areas or involve subcortical white matter
[5,11] (Fig. 1). Brain magnetic resonance (MR) angiography is usually
normal; whereas MR spectroscopy shows decreased N-acetylaspartate
signals and accumulation of lactate [11]. The high ventricular lactate
measured using MR spectroscopy was found to correlate with the de-
gree of the neurological impairment in individuals with MELAS syn-
drome [12].
Dementia occurs in 40–90% of affected individuals [6,9,10]. Both
the underlying neurological dysfunction and the accumulating cortical
injuries due to stroke-like episodes contribute to the observed dementia
which affects intelligence, language, perception, attention, and memory
function [11]. Additionally, executive function deficits have been ob-
served despite the relative sparing of the frontal lobe in neuroimaging
suggesting an additional diffuse neurodegenerative process besides
the damage caused by the stroke-like episodes [11].
Epilepsy is another common neurological manifestation occurring
in 71–96% of individuals with MELAS syndrome [6,9,10]. Epilepsy in
Table 1
Initial manifestations of MELAS syndrome.
Frequency Manifestations
N25% Seizure
Recurrent headaches
Stroke-like episode
Cortical vision loss
Muscle weakness
Recurrent vomiting
Short stature
10–24% Altered consciousness
Impaired mentation
Hearing impairment
Diabetes
b10% Developmental delay
Fever
6 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 116 (2015) 4–12

Table 2
Overall manifestations of MELAS syndrome.

Frequency Manifestations

≥90% Stroke-like episodes

Dementia
Epilepsy
Lactic acidemia
Ragged red fibers
Exercise intolerance
75–89% Hemiparesis
Cortical vision loss
Recurrent headaches
Hearing impairment
Muscle weakness
50–74% Peripheral neuropathy
Learning disability
Memory impairment
Recurrent vomiting
Short stature
25–49% Basal ganglia calcification
Myoclonus
Ataxia
Episodic altered consciousness
Gait disturbance
Depression
Anxiety
Psychotic disorders
Diabetes
b25% Optic atrophy
Pigmentary retinopathy
Progressive external ophthalmoplegia
Motor developmental delay
Cardiomyopathy
Cardiac conduction abnormalities
Nephropathy
Vitiligo

individuals with MELAS syndrome is heterogeneous. Despite the

frequent focal nature of the brain insult by the stroke-like episodes,
not only focal, but also primary generalized seizures can occur. Primary
generalized seizures in MELAS syndrome can occur with normal neuro-
imaging or abnormalities including stroke-like episodes, white matter
lesions, cortical atrophy, and corpus callosum agenesis or hypogenesis.
Seizures can occur in MELAS syndrome as a manifestation of a stroke-
like episode or independently, and may even induce a stroke-like
episode [13].
Recurrent headaches occur in 54–91% of individuals with MELAS
syndrome [6,9–11]. Migrainous headaches in the form of recurrent
attacks of severe pulsatile headaches with frequent vomiting are typical
in individuals with MELAS syndrome and can precipitate stroke-like
episodes [14]. On the other hand, these headache episodes are often
more severe during the stroke-like episodes [10].
Hearing impairment occurs in 71–77% of individuals with MELAS
syndrome [9–11]. Sensorineural hearing loss in MELAS syndrome is typ-
ically mild, insidiously progressive, and often an early clinical manifes-
tation [11].
Peripheral neuropathy is another common manifestation of MELAS
syndrome occurring in 22–77% of affected individuals. The neuropathy
in MELAS syndrome is usually a chronic and progressive, sensorimotor, Fig. 1. Neuroimaging for a 9 year old girl with MELAS syndrome who presented with headache:
A) axial CT image demonstrates basal ganglia calcification as well as diffuse decreased
and distal polyneuropathy. Nerve conduction studies typically show an attenuation in the right occipital lobe involving both gray and white matter, B) sagittal recon-
axonal or mixed axonal and demyelinating neuropathy [11,15,16]. structed image reveals vermian atrophy, C) axial FLAIR image reveals increased signal in the
Other neurological manifestations in MELAS syndrome include cortex and subcortical white matter of the right occipital lobe as well as a smaller focus in the
learning disability, memory impairment, myoclonus, ataxia, episodes right lateral temporal lobe, D) axial diffusion weighted images demonstrated restriction
in the subcortical white matter of the right occipital lobe, E) axial ADC (apparent diffusion
of altered consciousness, basal ganglia calcifications in neuroimaging,
coefficient) map confirms restricted diffusion, and F) axial post contrast T1-weighted image re-
and elevated protein in CSF analysis [9,10]. Ophthalmological complica- veals increased sulcal enhancement, which may represent hyperemia or luxury perfusion. Six
tions include optic atrophy, pigmentary retinopathy, and ophthal- months later, the same girl presented with left sided weakness: G & H) FLAIR images demon-
moplegia [9,10]. Psychiatric illnesses can occur in MELAS syndrome strate resolution of abnormal signal at the right occipital pole with evolving encephalomalacia
and include depression, bipolar disorder, anxiety, psychosis, and per- in the lateral occipital lobe. New extensive cortical/subcortical signal abnormalities are
appreciated in the right temporal lobe, bilateral frontal lobes, and bilateral parietal lobes.
sonality changes [17].
 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 116 (2015) 4–12 7

2.2. Muscular manifestations

Myopathy is a cardinal manifestation of MELAS syndrome. Exercise

intolerance and muscle weakness occurs in 73–100% and 42–89% of
affected individuals, respectively [6,9–11]. Motor developmental delay
was reported in 23% of affected children [18].
Histologic examination of muscle tissue from individuals with MELAS
syndrome shows scattered vacuolated muscle fibers with clear sur-
rounding rim using hematoxylin and eosin (H&E) staining. Using the
Gomori trichrome stain, the RRFs can be seen which represent mito-
chondrial proliferation below the plasma membrane of the muscular
fibers causing the contour of the muscle fiber to become irregular.
These proliferated mitochondria in RRFs also stain strongly with the suc-
cinate dehydrogenase (SDH) stain giving the appearance of ragged blue
fibers. Although RRFs are present in many other mitochondrial diseases
e.g., MERRF (myoclonic epilepsy with ragged red fibers), most of the
RRFs in MELAS stain positively with the cytochrome c oxidase (COX)
histochemical stain unlike other mitochondrial diseases where RRFs do
not react with COX. In MELAS syndrome, the COX stain of muscle tissue
can be decreased, normal, or increased which may reflect variable
m.3243ANG heteroplasmy in different muscle fibers (Fig. 2). Another
characteristic feature in MELAS syndrome is the excessive mitochondrial
proliferation observed in smooth muscle and endothelial cells in intra-
muscular blood vessels revealed with the SDH stain and called strong
SDH reactive blood vessels (SSVs). Biochemical analysis of respiratory
chain enzymes in muscle extracts usually shows multiple partial defects,
especially involving complex I and complex IV [10,11].

2.3. Lactic acidemia

Lactic acidemia is a cardinal sign that is present in 94% of affected

individuals. CSF lactate is also elevated in the majority of individuals
with MELAS syndrome [9,10]. Lactic acidemia is not specific for MELAS
syndrome as it can occur in other mitochondrial diseases, metabolic
diseases, and systemic illness. On the other hand, lactate level can be
normal in a minority of individuals with MELAS syndrome [9,10].

2.4. Cardiac manifestations

Cardiomyopathy occurs in 18–30% of individuals with MELAS

syndrome [6,9,10]. Both dilated and hypertrophic cardiomyopathies
have been observed in MELAS syndrome, however, the more typical is
a non-obstructive concentric hypertrophy [11]. Cardiac conduction
abnormalities including Wolff–Parkinson–White syndrome has been
reported in 13–27% of individuals with MELAS syndrome [9,10,18,19].

2.5. Gastrointestinal manifestations

Gastrointestinal complications are common in individuals with
MELAS syndrome and occur in 64–77% of affected individuals [9–11].
Recurrent or cyclic vomiting is the commonest observed gastrointesti-
nal complaint in MELAS syndrome. Diarrhea, constipation, gastric
dysmotility, intestinal pseudo-obstruction, and recurrent pancreatitis
have also been reported in MELAS syndrome [20]. Failure to thrive has
been reported in 28% of children with MELAS syndrome [6].
2.6. Endocrine manifestations
Fig. 2. Muscle histopathologic changes in individuals with MELAS syndrome: A–C
show ragged red fiber with modified Gomori trichrome, NADH tetrazolium reductase,
and cytochrome c oxidase histochemistry, respectively. The arrow identifies the ragged
red fiber. The images are at 400× magnification each.
has occasionally been found in individuals with MELAS syndrome [22].
Hypothyroidism, hypogonadotropic hypogonadism, and hypoparathy-
roidism have also been reported in individuals with MELAS syndrome
[23–25].

Diabetes occurs in 21–33% of individuals with MELAS syndrome [6,

11]. Diabetes in MELAS syndrome manifests at the average age of
38 years and can be type 1 or type 2 in nature. Individuals with type 2
diabetes can initially be treated by diet or sulfonylurea. Significant
insulinopenia can develop and affected individuals may require insulin
treatment [21]. Individuals with MELAS syndrome are typically shorter
than their unaffected family members. Short stature has been reported
in 33–82% of affected individuals [6,9–11]. Growth hormone deficiency
2.7. Renal, pulmonary, dermatological, and hematological manifestations
Renal manifestations of MELAS syndrome include Fanconi proximal
tubulopathy, proteinuria, and focal segmental glomerulosclerosis [26].
Pulmonary hypertension has been rarely reported in individuals with
MELAS syndrome [27]. Dermatological complaints, including vitiligo
and diffuse erythema with reticular pigmentation, are infrequent
8 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 116 (2015) 4–12
manifestations in MELAS syndrome [28,29]. Chronic anemia has
been reported in individuals with MELAS syndrome [30].
3. Pathogenesis
The pathogenesis of MELAS syndrome is not fully understood. The
observed phenotype of MELAS syndrome can be explained by several
interacting mechanisms including impaired mitochondrial energy pro-
duction, microvasculature angiopathy, and nitric oxide (NO) deficiency
(Fig. 3).
3.1. Molecular genetic defects
The m.3243ANG mutation in the MT-TL1 gene encoding tRNALeu(UUR)
is found in 80% of individuals with MELAS syndrome. Additional muta-
tions (e.g., m.3271TNC and m.3252ANG) in the MT-TL1 gene can also
cause MELAS syndrome. Rarely, mutations in other mitochondrial
genes have been reported to cause MELAS syndrome including MT-TL2
encoding tRNALeu(CUN), MT-TK encoding tRNALys, MT-TH encoding
tRNAHis, MT-TQ encoding tRNAGln, MT-TF encoding tRNAPhe, MT-TV
encoding tRNAVal, MT-ND1, MT-ND4, MT-ND5, and MT-ND6 encoding
subunits of complex I, MT-CO2 and MT-CO3 encoding subunits of complex
IV, and MT-CYB encoding a subunit of complex III [10,31]. In addition,
mutations in the nuclear gene POLG encoding the mitochondrial DNA
polymerase gamma have been associated with a MELAS-like phenotype
[32].
3.2. Energy deficiency and angiopathy
The m.3243ANG mutation results in impaired mitochondrial transla-
tion that leads to decreased mitochondrial protein synthesis affecting
the ETC complex subunits. Decreased synthesis of ETC complexes
results in impaired mitochondrial energy production [33,34]. The inabil-
ity of dysfunctional mitochondria to generate sufficient ATP to meet the
energy needs of various organs results in the multi-organ dysfunction
observed in MELAS syndrome (Fig. 3).
Energy deficiency can also stimulate mitochondrial proliferation.
Angiopathy due to mitochondrial proliferation in smooth muscle and
endothelial cells of small blood vessels occurs in MELAS syndrome and
leads to impaired blood perfusion in microvasculature contributing
significantly to the complications observed in MELAS syndrome partic-
ularly stroke-like episodes [11,35,36] (Fig. 3).
3.3. Nitric oxide deficiency
In addition to energy depletion there has been growing evidence
that NO deficiency occurs in MELAS syndrome and can contribute signif-
icantly to its complications [37–39]. NO is formed from arginine via the
enzyme nitric oxide synthase (NOS), which catalyzes the conversion of
arginine to citrulline. Citrulline can be converted to arginine via argin-
inosuccinate synthase and argininosuccinate lyase. Therefore, both cit-
rulline and arginine are considered as NO donors. Citrulline is a non-
essential amino acid for which the main source is the de novo synthesis
in small intestine enterocytes through a number of mitochondrial en-
zymes [40].
NO produced by vascular endothelium plays a major role in vascular
smooth muscle relaxation that is needed to maintain the patency of
small blood vessels [41,42]. Therefore, NO deficiency in MELAS syn-
drome can result in impaired blood perfusion in the microvasculature
of different organs that can contribute to the pathogenesis of several
complications [38,39]. NO deficiency in MELAS syndrome is believed
to be multifactorial in origin (Fig. 3). Mitochondrial proliferation in
vascular endothelial cells can result in impaired normal endothelial
function (endothelial dysfunction), and impaired endothelial NO syn-
thesis can reflect one aspect of endothelial dysfunction. Decreased avail-
ability of NO precursors, arginine and citrulline, may have a major
contribution in impaired NO production. Low plasma citrulline may
result from decreased citrulline synthesis in the mitochondria of
enterocytes due to mitochondrial dysfunction [37,43]. Most of the
citrulline flux is directed toward arginine synthesis; therefore, lower
citrulline availability can result in decreased de novo arginine synthesis
and lower intracellular arginine availability [37–39]. Decreased NO
production can also result from impaired NOS activity due to reactive
oxygen species (ROS) overproduction (oxidative stress) resulting from
the ETC impairment [44,45]. Oxidative stress due to mitochondrial
dysfunction may also result in increased asymmetric dimethylarginine
(ADMA), which is an endogenous inhibitor of NOS [37,39,46]. In addi-
tion to impaired NO production, postproduction NO sequestration can
contribute to the NO deficiency in MELAS syndrome. Mitochondrial
proliferation in endothelial cells in MELAS syndrome can be associated
with increased COX activity, which can react with and thus sequester
NO [11,43]. In addition, oxidative stress can result in decreased NO
availability by shunting NO into reactive nitrogen species (RNS) forma-
tion [47].
3.4. Pathogenesis of various complications
During early stages of stroke-like episodes in MELAS syndrome,
SPECT (single photon emission computed tomography) scanning stud-
ies have demonstrated hypoperfusion in the affected regions, indicating
that these episodes are due to ischemic insults [48]. It is believed that
these ischemic insults result from impaired perfusion in cerebral micro-
vasculature due to the angiopathy and NO deficiency that occur in
MELAS syndrome [11,37–39,43,48].
The inability of dysfunctional mitochondria to generate sufficient
ATP to meet the energy needs of muscle tissue can explain the observed
myopathy in MELAS syndrome. NO deficiency may also play a signifi-
cant role in the myopathic manifestations of this syndrome. Normally,
endothelial cells release basal and stimulated NO. During physical activ-
ity increased muscular blood flow stimulates endothelial NO production
that contributes significantly to exercise-induced hyperemia in mus-
cular tissue [40]. Decreased NO availability can potentially lead to
impaired muscle exercise-induced hyperemia and thus contribute to
the exercise intolerance reported in individuals with MELAS syndrome.
In addition, NO deficiency may result in decreased basal muscular
perfusion, leading to limited availability of nutrients such as amino
acids, and thus decreased muscle protein synthesis that may contribute
to the myopathy and muscle wasting observed in MELAS syndrome
[39].
Lactic acidemia in MELAS syndrome results from the inability of
dysfunctional mitochondria to adequately oxidize glucose, leading to
the accumulation of pyruvate and shunting of pyruvate to lactate [11].
Moreover, hypoperfusion may result in lactic acidosis due to decreased
oxygen delivery to peripheral tissues and a shift to anaerobic glycolysis.
NO deficiency in MELAS syndrome can result in decreased blood perfu-
sion and therefore may aggravate lactic acidosis [39].
Diabetes develops in MELAS syndrome due to multiple defects in
insulin and glucose metabolism including insulin deficiency, increased
gluconeogenesis, and insulin resistance [49]. In pancreatic β-cells, an
ATP sensitive potassium channel is required for insulin release. De-
creased ATP synthesis as a result of mitochondrial dysfunction can
result in impaired insulin secretion and insulinopenia [11,21]. Two fac-
tors may contribute to increasing gluconeogenesis in MELAS syndrome:
insulin resistance, which results in reduced insulin inhibition of hepatic
gluconeogenesis, and lactic acidemia, which can fuel gluconeogenesis in
the liver [49]. The etiology of insulin resistance in MELAS syndrome is
likely to be multifactorial. First, decreased glucose oxidative capacity
due to the mitochondrial dysfunction can result in impaired insulin
responsiveness. Second, through enhancing endothelial NOS (eNOS)
activity, insulin can induce vasodilation that results in an adequate
delivery of glucose and insulin to muscle tissue [50]. Therefore, NO
deficiency in MELAS syndrome may lead to impaired insulin-mediated
 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 116 (2015) 4–12
Fig. 3. Pathogenesis of MELAS syndrome (NO: nitric oxide, NOS: nitric oxide synthase, ADMA: asymmetric dimethylarginine, RNS: reactive nitrogen species).
vasodilation, resulting in impaired insulin delivery and contributing to
insulin resistance [49]. Finally, increased ROS production due to mito-
chondrial dysfunction can play a role in impaired insulin responsiveness
and the development of insulin resistance [51].
Renal Fanconi syndrome is believed to result from impaired activity
of ATP-dependent sodium–potassium pumps that are needed in the
tubular reabsorption process. Growth failure may reflect the effects of
a chronic systemic state of energy deficiency [11].
3.5. Phenotype variability
The m.3243ANG mutation is associated with variable phenotypes
that collectively constitute a wide spectrum, ranging from MELAS
syndrome at the severe end in only ~ 10% of individuals with the
m.3243ANG mutation to asymptomatic carrier status in another ~10%
of m.3243ANG mutation carriers. Between these two extremes inter-
mediate phenotypes exist including single organ involvement (e.g.,
cardiomyopathy or DM) and multi-organ involvement with various
combinations of symptoms (e.g., myopathy, diabetes, and deafness)
that occasionally constitute distinctive syndromes including mater-
nally inherited deafness and diabetes (MIDD) and progressive exter-
nal ophthalmoplegia (PEO) [11,52]. Other mitochondrial syndromes
including Leigh syndrome and MERRF have been associated with the
m.3243ANG mutation as well [53,54].
The extreme variability in phenotypes associated with the
m.3243ANG mutation is a common observation in many mtDNA-
related mitochondrial diseases. Similarly to the majority of mtDNA mu-
tations, the m.3243ANG is a heteroplasmic mutation, i.e., present in
some copies of mtDNA, and therefore the cells harbor a mixture of
mutant and normal mtDNA. During cell division, mutant mtDNAs are
distributed randomly among daughter cells. Therefore, the percentage
of mutant mtDNAs differs in different tissues and organs within the
same individual. These tissues and organs have different thresholds in
heteroplasmy percentage before clinical phenotypes manifest thus
9
accounting for the clinical diversity seen in individuals harboring this
mutation [1]. Interestingly, it has been demonstrated that the muscle
m.3243ANG heteroplasmy correlates with maximum oxygen uptake
and workload, resting plasma lactate, and muscle morphology abnor-
malities in individuals with MELAS syndrome indicating that the
threshold of muscle mutation load at which oxidative impairment
occurs is about 50% [55].
4. Management
There is no specific consensus approach for treating individuals with
MELAS syndrome. Management is largely symptomatic and should
involve a multidisciplinary team that may include a neurologist, cardio-
logist, endocrinologist, audiologist, ophthalmologist, physical and occu-
pational therapists, psychologist, and social worker.
4.1. Evaluation of multi-organ involvement
Upon diagnosis, a comprehensive evaluation for the multi-organ
involvement is needed. Affected individuals should also be followed at
regular intervals to monitor progression and screen for potential compli-
cations. Performing the following evaluations has been recommended at
time of diagnosis and as needed during regular follow up visits: compre-
hensive neurological examination with cognitive assessments, brain
MRI, audiologic and ophthalmologic examinations, growth assessment,
echocardiogram and electrocardiogram, screening for hypothyroidism,
and screening for diabetes by fasting blood glucose and glucose tolerance
test [10].
4.2. Management of complications
Sensorineural hearing loss has been successfully treated with
cochlear implants [56]. Seizures respond to traditional anticonvulsant
therapy and standard analgesics can be used for migraine headaches.
10 A.W. El-Hattab et al. / Molecular Genetics and Metabolism 116 (2015) 4–12
Cardiac manifestations can also benefit from standard pharmacologic
therapy. Diabetes can be managed by dietary modifications with or
without oral hypoglycemic agents. However, insulin therapy is often
required [10]. Nutrition support is needed for children failing to thrive
and rehabilitation with physical and occupational therapy is needed
after stroke-like episodes. Psychiatric evaluation and treatment are
needed for individuals with psychiatric manifestations.
Regular exercise can improve exercise capacity in individuals with
MELAS syndrome and other mitochondrial myopathies. Endurance
training can induce mitochondrial biogenesis whereas resistance train-
ing can induce transferring normal mitochondrial templates from satel-
lite cells to mature muscle that may lower the mutation heteroplasmy
[57].
Several supplementations, including antioxidants and cofactors,
are being used in MELAS syndrome based on limited clinical trials
[58]. Unblinded studies have showed that L-arginine therapy can
be beneficial in stroke-like episode treatment and prevention. Intrave-
nous L-arginine infusion during the acute phase has been shown to
improve stroke-like episode symptoms whereas oral L-arginine supple-
mentation during the interictal phase has been shown to decrease the
frequency and severity of stroke-like episodes [48,59]. The suggested
intravenous L-arginine dose is 0.5 g/kg for children or 10 g/m2 body
surface area for adults with a similar daily dose to be given orally in
three divided doses during the interictal phase [58]. The therapeutic
effect of arginine in stroke-like episodes in MELAS syndrome is pro-
posed to be due to increase NO availability leading to improve intrace-
rebral vasodilation and blood flow. This potential mechanism has been
supported by the demonstration that arginine supplementation to sub-
jects with MELAS syndrome results in increased NO production and im-
proved flow-mediated dilation (FMD), which is considered a measure of
NO synthesized by endothelial cells in response to re-perfusion [37,60].
Although the clinical effects of citrulline administration in MELAS syn-
drome have not been studied, a stable isotope study demonstrated
that citrulline supplementation to subjects with MELAS syndrome re-
sulted in increased NO production. Interestingly, citrulline supplemen-
tation was found to induce a greater increase in the NO synthesis rate
than that associated with arginine supplementation, indicating that cit-
rulline is a more effective NO precursor than arginine. Therefore, citrul-
line may have a better therapeutic effect than arginine [37].
Additionally, increasing NO availability with arginine or citrulline sup-
plementation will potentially improve perfusion in all microvasculature
compartments. Therefore, the effect of arginine and citrulline
supplementation may not be limited to improving stroke-like episodes,
but may also lead to improvements in other clinical features of MELAS
syndrome, including muscle weakness, exercise intolerance, and lactic
acidosis. Interestingly, arginine and citrulline supplementation has
been reported to result in a reduction in plasma alanine and lactate
concentrations, suggesting that such supplementation may improve
lactic acidemia in MELAS syndrome by increasing NO production and
improving perfusion and oxygen delivery [37,61]. Additional clinical
studies assessing the clinical effects of citrulline and arginine supple-
mentations on different manifestations of MELAS syndrome are needed
to determine their potential therapeutic utility in this syndrome.
Coenzyme Q10 (CoQ10) facilitates electron transfer from complexes
I and II to complex III of ETC and stabilizes the ETC complexes by provid-
ing protective antioxidant effects. Some studies showed beneficial
effects on muscle weakness, fatigability, and lactate level for CoQ10 in
individuals with MELAS syndrome [62,63]. The recommended doses
are 5–10 mg/kg/day for children and 200–400 mg/day for adults [58].
Creatine, which is mainly stored in muscle, heart, and brain, is
metabolized to phosphocreatine which is an essential phosphate
donor for ATP regeneration in muscle and brain. Creatine monohydrate
supplementation was shown to increase the strength of high-intensity
anaerobic and aerobic activities in individuals with MELAS syndrome
and other mitochondrial cytopathies [64]. The recommended doses
are 100 mg/kg/day for children and 2–5 g/day for adults [58].
Additionally, a randomized, double-blind, placebo-controlled study
showed that a combination therapy including creatine monohydrate,
CoQ10, and lipoic acid resulted in improved muscle strength and lower
plasma lactate in individuals with MELAS syndrome and other mito-
chondrial cytopathies [65].
CoQ10 does not cross the blood–brain barrier; therefore, it may have
limited effect on the central nervous system. Idebenone is a CoQ10
analog that can cross the blood–brain barrier and has been shown to
improve neurological complications in some case reports [66,67].
L-Carnitine is required for long-chain fatty acid transportation to
the mitochondrial matrix where it undergoes β-oxidation. Secondary
carnitine deficiency can be rarely observed in MELAS syndrome [58,
68]. Carnitine supplementation can potentially enhance β-oxidation
and replenish the intracellular pools of coenzyme A [58]. The carnitine
can be given at doses of 3 g daily in three divided doses for adults and
100 mg/kg/day for children in three divided doses [58].
4.3. Medications to avoid
Valproic acid should be avoided in the treatment of seizure because
of its deleterious effects on mitochondrial function. Clinically, valproic
acid may result in worsening or triggering seizures in individuals
with MELAS syndrome [69,70]. Other antiepileptic drugs which may af-
fect the mitochondrial metabolism, include phenobarbital, carbamaze-
pine, phenytoin, oxcarbazepine, ethosuximide, zonisamide, topiramate,
gabapentin and vigabatrin [71]. Metformin should be avoided in individ-
uals with MELAS syndrome because of its propensity to cause lactic
acidosis [11]. Dichloroacetate, which reduces lactate by activating the
pyruvate dehydrogenase enzyme, should be avoided in MELAS syn-
drome. A study evaluating the effect of dichloroacetate in individuals
with MELAS syndrome was terminated because of onset or worsening
of peripheral neuropathy indicating that dichloroacetate can be associ-
ated with peripheral nerve toxicity [72]. Individuals with MELAS syn-
drome should also avoid agents with potential mitochondrial toxicity
including aminoglycosides, linezolid, and alcohol [10]. Cigarette smoke
contains hundreds of compounds many of which can accumulate in mi-
tochondria and disturb the function of the ETC including phenolic com-
pounds, aldehydes, heavy metals, carbon monoxide, nicotine, and aromatic
compounds [73]. Therefore, smoking can aggravate mitochondrial dysfunc-
tion in individuals with mitochondrial diseases.
5. Conclusions
MELAS syndrome, which is a frequent maternally inherited mito-
chondrial disorder, is a multi-organ disease with broad manifestations
including stroke-like episodes, dementia, epilepsy, lactic acidemia, and
myopathy. The m.3243ANG mutation in the MT-TL1 gene occurs in
80% of individuals with MELAS syndrome. Several mechanisms can
interact to result in the multi-organ phenotype of MELAS syndrome
including impaired mitochondrial energy production, microvasculature
angiopathy, and NO deficiency. Management of MELAS syndrome is
largely symptomatic and should involve a multidisciplinary team. Sev-
eral supplementations, including antioxidants and cofactors, are being
used in MELAS syndrome based on limited clinical trials. Valproic acid,
metformin, and dichloroacetate should be avoided in individuals with
MELAS syndrome.
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