Rare disease

CASE REPORT

Uncommon mutation in mitochondrial
encephalomyopathy, lactic acidosis and stroke-like
episodes (MELAS)
Jasna David,1 Julie Omolola Okiro,2 Kevin Murphy,1 Marwa Elamin1
1

Department of Neurology,
Sligo University Hospital, Sligo,
Ireland
2
Department of Medicine, Sligo
University Hospital, Sligo,
Ireland
Correspondence to
Dr Julie Omolola Okiro,
Julieokiro@gmail.com
Accepted 10 February 2017

SUMMARY
A 26-year-old man presented to the emergency
department with new-onset generalised tonic–clonic
seizures. His clinical picture suggested either
autoimmune or infectious encephalitis while his brain
imaging raised the possibility of a stroke. A detailed
developmental and childhood medical history added
suspicion of a mitochondrial defect to the differential.
After several molecular genetic analyses, an uncommon
mitochondrial mutation was confirmed, unequivocally
consistent with mitochondrial encephalomyopathy, lactic
acidosis and stroke-like episodes (MELAS) syndrome.

BACKGROUND
It is increasingly recognised that mitochondrial disorders are more common than previously thought.
The advent of improved diagnostic techniques has
led to a global increase in patients diagnosed with
mitochondrial disorders. Gorman et al1 recently
reported that among inherited neurological disorders, adult mitochondrial diseases are among the
most prevalent, with one in 4300 adults being
affected in the UK.
Patients with mitochondrial disorders still suffer
from delays in diagnoses. General physicians are
often not familiar with these disorders. The diagnosis of mitochondrial diseases is challenging
because of wide variations in phenotypic expression and variable penetrance.2
Mitochondrial encephalomyopathy with lactic
acidosis and stroke-like episodes (MELAS) is one of
the more common mitochondrial disorders. Over
30 mitochondrial DNA gene mutations have been
reported to be associated with this syndrome.3

CASE PRESENTATION

To cite: David J, Okiro JO,
Murphy K, et al. BMJ Case
Rep Published online:
[please include Day Month
Year] doi:10.1136/bcr-2016218133

A 26-year-old man presented with two episodes of
generalised tonic–clonic seizures within a 4-hour
period. He had no history of seizures. His presentation was preceded by a 10-day history of slurred
speech followed by ‘inability to read properly’. He
also had headaches, nausea and vomiting of
2 months’ duration.
He had a normal development apart from being
a late walker. However, he was ‘always clumsy’ and
stuttered. At age of 5 years, he was noted to have
reduced social skills. He developed a phobia for
bandages and disabled people and an aversion to
specific smells.
When he was 6 years old, he had an episode of
bilateral ptosis which was diagnosed as myasthaenia

gravis. His acetylcholine receptor antibodies were
negative and a CT thorax was non-contributory.
He was treated with steroids and pyridostigmine.
His symptoms completely resolved in 3 weeks and
never reoccurred. At 18 years of age, he was diagnosed with Asperger’s syndrome.
There was no family history of epilepsy but his
sister was born with a rare form of dwarfism. She
had a ‘big head, swollen tummy, small limbs, and a
congenital heart and lung disease’. She died soon
after birth. He has three other siblings, all alive and
well. He had three maternal cousins with type I
diabetes. The patient was a non-smoker and did
not consume alcohol.
On clinical examination, he was vague and mildly
encephalopathic. He was afebrile, there was no rash
and he had no palpable organomegaly. Pathologic
findings included right–left disorientation and a
right homonymous hemianopia. There was full
albeit, somewhat saccadic eye movements. Strength
in all four limbs was normal and reflexes were brisk
but symmetrical. There were bilateral withdrawal
responses on planter stimulation. On gait assessment
he appeared to veer to the left hand side.

INVESTIGATIONS
Complete blood counts, renal, liver and thyroid profiles were normal. C-reactive protein (CRP) was
raised to 100 mg/L (<5). CT brain showed left
occipital and parieto-occipital hypodensities with
mild oedema and some contrast enhancement.
Cerebellar atrophy was also noted. EEG was normal.
cerebrospinal fluid (CSF) analysis reported no
white cells, protein of 0.36 g/L (2–4) and glucose of
3.4 mmol/L (2–4). Gram stain was negative and no
pathogens were cultured. CSF PCR for viral panel
including herpes simplex virus type 1 and 2 (HSV1/
2), cytomegalovirus (CMV), Epstein-Barr virus
(EBV), human herpesvirus 6 (HHV 6), enteroviruses
and parachovirus were all negative.
MRI brain showed high signal changes in the left
temporal, parieto and occipital lobes predominantly
affecting the cortex and the deep white matter.
Cerebellar atrophy was again noted. No postcontrast
enhancement. (figure 1). Diffusion-weighted images
were not carried out at initial presentation but on
follow-up scan 3 months later minor restriction diffusion was noted. The imaging appearance raised
the possibility of encephalitis. Ischaemia was also
suspected although the abnormalities included anterior cerebral, middle cerebral and posterior cerebral
artery territories.

David J, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218133

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Rare disease

Figure 1 MRI on presentation. T2-fluid attenuation inversion recovery
(FLAIR) sequence.
Normal laboratory investigations included antibodies against
thyroid peroxidase (TPO), N-methyl-D-aspartate receptor
(NMDA-R), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), gamma-Aminobutyric acid (GABA),
glutamic acid decarboxylase (GAD), voltage-gated potassium
channels-complex protein, antineuronal antibodies, serum immunoglobulins, protein electrophoresis, creatine kinase (CK), ACE,
serology for lyme, HIV, and syphilis and vasculitic screen.
In the context of young-onset stroke and the unusual imaging
appearance, a muscle biopsy was undertaken to out rule a mitochondrial disorder. This showed enhanced staining on Gomori trichrome, nicotinamide adenine dinucleotide hydrate (NADH) and
cytochrome c oxidase (COX), suggesting an underlying mitochondrial dysfunction. However, on undertaking genetic analysis of the
tissue, there were no large scale mitochondrial DNA rearrangements and the common mitochondrial DNA mutations were
absent (m.3243A>G, m.8344A>G, m.8993T>G, m.8993T>C,
polymerase gamma (POLG) mutation).

DIFFERENTIAL DIAGNOSIS
At the top of our differential diagnosis list was infectious encephalitis for which he was treated with acyclovir while we awaited
the result of his CSF virology and culture. However, CSF viral
panel was negative and no pathogens were detected. This
excluded an infectious cause for his symptoms. Autoimmune
encephalitis was also excluded with negative blood and CSF
reports for a vast range of antibodies. Imaging suggested the possibility of stroke. However, there were atypical features: the
stroke-like episode did not respect vascular territories, lack of vascular risk factors, the association with encephalopathy. This led
us to consider the possibility of a mitochondrial disorder.

TREATMENT
For seizure control, the patient was started on lamotrigine. He
was also initially treated with acyclovir. This had no effect on
his encephalopathy and was subsequently discontinued following the negative CSF viral studies. As autoimmune aetiology was
also suspected, he also had a trial of IVIG pending antibody
results with no benefit. He maintained on antiepileptics and
coenzyme Q 10 (based on the suspicion of a possible mitochondrial disorder).

OUTCOME AND FOLLOW-UP
Our patient improved and was discharged with minimal deficits.
However, 3 months post discharge he was admitted with severe
hiccups and vomiting refractory to antiemetics. General examination was normal but neurological examination revealed newonset left-sided hemianopia and optic atrophy. No abnormality
2

Figure 2 Repeat MR brain (FLAIR) during one of our patient’s
subsequent hospital admission’s showing new areas of ischaemia not
conforming to vascular territories.
was found on oesophago-gastro-duodenoscopy. Repeat MR
images showed new areas of ischaemia, again not conforming to
vascular territories (figure 2). Multiple subsequent admissions
were characterised by encephalopathic changes and new changes
on MRI. He subsequently presented with psychosis and suicidal
ideations. He was admitted into the psychiatry unit following an
attempted suicide. He was treated with antipsychotics.
Repeat lactate was noted to be raised to 3.60 mmol/L (0.5–
2.2). As there was still a high index of suspicion for MELAS,
further DNA samples were sent for entire mitochondrial
genome sequencing. This revealed MT-ND5 (13513G>A)
mutation at 59% level of heteroplasmy in his muscle.
Unfortunately, we did not perform analysis on other tissues
during initial investigation. Analysis was undertaken on his
mother to determine whether his mutation was maternally
inherited or had occurred de novo. It was discovered that his
mother harbours the same mutation at a heteroplasmy level of
8% in her urine. No mutation was detected in her blood.

DISCUSSION
MELAS is a progressive multisystem disorder with onset of clinical manifestations usually in childhood or early adulthood.
However, late onset is common.4 Children generally develop
normally but may be short for their age.4 5 Early on, patients
may begin to develop seizures, recurrent headaches, anorexia
and recurrent vomiting caused by lactic acidosis.5 It is not
uncommon for patients to have multiple stroke-like episodes
which may be accompanied by signs of encephalopathy such as
seizures.6 These episodes are often preceded by nausea, vomiting and headache. Ischaemic changes are often located in the
parieto-occipital region and do not conform to vascular
territories.7
Other clinical features may include cardiomyopathy, deafness,
developmental delay or cognitive decline, diabetes mellitus,
gastrointestinal disturbance (constipation and/or irritable bowel
syndrome), migraine, progressive external ophthalmoplegia, retinopathy,3 exercise intolerance, muscle weakness5 and psychiatric manifestations.8
By far the most frequent mutation associated with MELAS is
m.3243A>G of the MT-TL1 gene which accounts for about
80% of cases.7 The frequency of this mutation in the general
population is about 1:15 000.9
The diagnostic criteria described by Hirano et al6 in 1992
proposed that the syndrome should be suspected by the ‘three
invariant criteria: (1) stroke-like episode before age 40 year; (2)
David J, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218133

Rare disease
encephalopathy characterised by seizures, dementia or both and
(3) lactic acidosis, ragged-red fibres (RRF) or both.’ Supportive
criteria included normal development, recurrent headache and
vomiting.6
Subsequent identification of the genetic causes of MELAS
revealed striking variability in phenotypic expression.10 A 2013
study, which examined 129 MELAS patients with confirmed
gene mutations suggested that diagnoses could be missed if it is
only suspected in patients with the ‘classic syndrome.’3
Our patient presented with several features suggestive of
MELAS including stroke-like episodes, seizures, encephalopathy,
headaches and vomiting. Although initial lactate levels were
normal, repeat testing demonstrated lactic acidosis.
While the most frequently reported phenotype associated
with the m.13513G>A gene mutation identified in our patient
is Leigh’s syndrome, the mutation is also reported in 10% of
MELAS cases.11 12 According to Shanske et al,11 MELAS
patients carrying the 13513G>A gene mutation (as opposed to
the more common A3243G mutation) tend to present at a relatively later age and frequently have no family history. Long
before central nervous system involvement becomes apparent,
deafness, Wolff–Parkinson–White Syndrome and ophthalmic
manifestations, including optic atrophy, cataracts and ptosis can
often be observed.13 14 The latter observation is interesting in
the context of our patient who presented with bilateral ptosis at
the age of 6 years which was misdiagnosed as myasthaenia
gravis. In fact, the widely varied clinical presentations in patients
with MELAS often lead to initial misdiagnoses as myasthaenia
gravis, epilepsy, cerebral infarction, encephalitis, gastrointestinal
or heart diseases, resulting in inappropriate therapies and
delayed treatment opportunity.2 5 9 10 15
We can only speculate as to the cause of death of our patient’s
sister. It is likely that she inherited the same mutation making
metabolic acidosis or cardiac arrhythmia possible explanations
for her sudden demise at 4 hours old.
Notably, our patient presented early on with multiple behavioural issues, low mood and was also diagnosed with autism at
the age of 18 years. He also had an episode of psychoses. The
literature suggests a strong association between mitochondrial
disease and psychiatric disorders in particular major depression,
psychoses and anxiety.16 17 Fattal et al18 reported that psychiatric symptoms preceded the diagnosis of a mitochondrial disorder by an average of 7.5 years in their cohort of 36 patients.
It has also been postulated that autism spectrum disorders may
be an early clinical presentation of patients with mitochondrial
disease.8 19 However, most studies have not been able to implicate any specific gene variant in association with psychiatric
manifestations.16
Although the pathologic mitochondrial variant is present in
all tissues in mitochondrial diseases, there is heteroplasmy
(mutant load) where by various tissues have different levels of
mutant mtDNA. Our patient had a heteroplasmy of 59% in his
skeletal muscle sample. On literature review of cases of Leigh’s
syndrome (LS), a mitochondrial disease which has also been
associated with the MT-ND5 mutation m.13513G>A, we
found a wide range of heteroplasmy levels reported in muscle
tissues. Shanske et al11 found that in nine patients with LS and
the m.13513G>A mutation the degree of heteroplasmy ranged
between 41% and 89%.20 In a study by Sudo et al21 out of 84
patients with LS, the six who had the m.13513G>A mutation
had their level between 42% and 70%. Chol et al22 found an
average of 90% mutant load in three patients with LS while
Kirby et al23 reported a lower heteroplasmy of <50% in three
patients. Van Karnebeek et al reported varying levels of
David J, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218133

heteroplasmy in a family with the m.13513G>A mutation.
Their index case, a 10-year-old female who was diagnosed with
MELAS had a muscle heteroplasmy of 30%. She had a very
similar clinical presentation to our patient albeit presenting at a
younger age. Her younger sister, a 1-day-old, had 66% heteroplasmy in a postmortem liver tissue. She died of fatal acidosis.
Their asymptomatic mother had 7% in her urine.14 Our
patient’s asymptomatic mother harboured 8% heteroplasmy in
her urine and also he had a sister who passed away hours after
birth but at that time her tissues were not tested for mtDNA
mutations. No correlation has been found between mutant load
and clinical phenotypes in the m.13513G>A mutation.
No disease modifying treatment has been found for mitochondrial disease. However, a trial of coenzyme Q 10 in our
patient was considered as it may be beneficial in individuals
who have defects of coenzyme Q 10 biosynthesis.23 While there
are limited treatment options for patients with MELAS, making
the correct diagnoses enables physicians to avoid unnecessary
investigations, harmful inappropriate therapies, anticipate complications, treat secondary symptoms and most importantly,
refer the patient for genetic counselling.
Our case highlights the fact that the diagnosis of MELAS
(and mitochondrial diseases in general) is often delayed as
patients may initially present with non-specific symptoms and
signs that do not fulfil the ‘classic’ diagnostic constellation. In
clinical practice, most suspected patients are only screened for
common mutations. The diagnosis in our patient was confirmed
only when the whole mitochondrial genome was analysed
in the context of a negative initial screen for mitochondrial
mutations.

Learning points
▸ Even with the major advances in diagnostics and increasing
awareness of mitochondrial diseases, mitochondrial
encephalomyopathy, lactic acidosis and stroke-like episodes
(MELAS) remains a challenge to diagnose and manage.
▸ MELAS, like other mitochondrial disorders, is characterised
by diverse phenotypic expressions, some of which maybe
non-specific. This often leads to misdiagnoses.
▸ A stroke-like episode in a young patient in whom the
changes do not respect vascular territories should raise
suspicion for MELAS particularly in the context of
headaches, vomiting, encephalopathy and/or seizures.
▸ Behavioural and psychiatric disorders including autism
spectrum are common in mitochondrial disorders and can
precede the other manifestations of the disease by several
years.
▸ A negative family history does not exclude the diagnoses of
a mitochondrial disorder. MELAS is caused by multiple
pathogenic gene mutations which might not all be included
in initial screening gene panels. In cases where there is a
high index of suspicion whole mitochondrial genome
sequencing should be considered.

Contributors JD contributed in discussion, learning point, references. JOO
contributed in summary, background, case presentation, investigations, treatment,
outcome and follow up, consent, gathering case data. ME contributed in discussion,
background, learning point, differential diagnosis, overview. KM contributed in case
title, summary, case presentation, investigations, differential diagnosis treatment,
outcome and follow up, overview.
3

Rare disease
Competing interests None declared.

11

Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.

12

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David J, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-218133