Acta Neuropathol (2003) 105 : 69–75
DOI 10.1007/s00401-002-0604-y

C A S E R E P O RT

Kurenai Tanji · Josep Gamez · Carles Cervera ·
Fermin Mearin · Arantxa Ortega · Javier de la Torre ·
Julio Montoya · Antoni L. Andreu · Salvatore DiMauro ·
Eduardo Bonilla

The A8344G mutation in mitochondrial DNA
associated with stroke-like episodes and gastrointestinal dysfunction
Received: 11 April 2002 / Revised: 12 July 2002 / Accepted: 12 July 2002 / Published online: 7 September 2002
© Springer-Verlag 2002

Abstract We report an unusual case of encephalo-entero-myopathy associated with the A8344G mutation in
the tRNALys gene of mitochondrial DNA (mtDNA). This
patient had mitochondrial myopathy, multiple lipomatosis, mild hearing loss, stroke-like episodes, and paralytic
ileus, but she lacked the canonical clinical features of
MERRF, myoclonus, epilepsy, or ataxia. We conducted
genetic, biochemical, histochemical, and immunohistochemical studies in skeletal muscle, brain, intestine, and
lipoma tissue. The mutation was abundant in all tissues,
and cytochrome c oxidase (COX) activity was selectively
decreased in brain and small intestine. COX deficiency
was also documented histochemically and immunohistochemically in the small intestine, suggesting that mitochondrial dysfunction played a role in the pathogenesis of
paralytic ileus. This case illustrates an unusual and dramatic clinical phenotype of the A8344G mutation, characterized by stroke-like episodes and acute ileus.
Keywords MERRF · Intestinal dysfunction · Stroke-like
episodes

S. DiMauro · E. Bonilla (✉)
Department of Neurology of the College of Physicians
and Surgeons of Columbia University,
Room 5–431, 630 West 168th Street, New York, NY 10032, USA
e-mail: eb19@columbia.edu,
Tel.: +1-212-3053836, Fax: +1-212-3053986
K. Tanji · E. Bonilla
Department of Pathology of the College of Physicians
and Surgeons of Columbia University, New York, USA
J. Gamez · C. Cervera · F. Mearin
Department of Neurology, University Hospital Vall D’Hebron,
Barcelona, Spain
A. Ortega · J. de la Torre
Department of Pathology, University Hospital Vall D’Hebron,
Barcelona, Spain
J. Montoya · A.L. Andreu
Centre D’Investioació en Bioquimica i Biologia Molecular
of the University Hospital Vall D’Hebron, Barcelona, Spain

Introduction
Mitochondrial dysfunction has emerged as an important
cause of neurological, endocrine, cardiac, and renal disorders, and point mutations in tRNA genes of mitochondrial
(mt) DNA play a significant role in the pathogenesis of
such disorders [1]. Specific mutations in tRNA genes
have been associated with distinct clinical entities, including myoclonus epilepsy and ragged-red fibers (MERRF)
and mitochondrial encephalopathy, lactic acidosis and
stroke-like episodes (MELAS) [2, 3]. The typical clinical
picture of MERRF includes myoclonus, generalized or
partial seizures, myopathy, ataxia, and, less consistently
dementia, neuropathy, hearing loss, and optic atrophy [4]
However, MERRF is clinically heterogeneous and overlap syndromes between MERRF and MELAS have been
reported [5, 6, 7].
We have studied a patient with the typical MERRF
mutation in the tRNALys(A8344G) gene, whose clinical
presentation was strikingly different from typical MERRF
because it was characterized by lipomatosis, stroke-like
episodes and gastrointestinal dysfunction. We report molecular genetic, biochemical, and morphological findings
in the most affected tissues, including brain, adipose tissue muscle, and small intestine.

Case report
This patient and her family history has been reported previously
[8]. Briefly, this 39-year-old woman had familial lipomatosis and
progressive exercise intolerance since age 20, and was diagnosed
with MERRF-8344 at the age of 36 years. Neurological examination at that time showed only neurosensory hearing loss. During
her stay in the hospital, she had the first stroke-like episode manifested by dysartria and dysphagia, followed by ventilatory insufficiency and lactic acidosis. Magnetic resonance imaging (MRI) of
the brain showed two small bilateral frontal lesions. She survived
the respiratory insufficiency, but had residual difficulties swallowing and speaking. Two years later, she was admitted to the emergency room because of abdominal distention. X-rays of the abdomen indicated paralytic ileus. Eight days later, she had a generalized tonic-clonic seizure followed by right hemiparesis and bilat-

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Fig. 1 a T2-weighted image showing scattered cerebral infarcts,
particularly in the occipital lobes. b H&E stain illustrating an infarct region in the occipital cortex of the patient. c SDH and COX
histochemistry on frozen sections of ileum from a control and from

the patient. Note the reduced stain for COX in all layers of the intestinal wall in the patient’s sample (H&E hematoxylin and eosin,
SDH succinate dehydrogenase, COX cytochrome c oxidase). b ×55,
c ×2.5

71
eral cortical blindness. CT scan and MRI confirmed the presence
of infarcts in the posterior part of the frontal lobes and showed new
lesions in both occipital lobes (Fig. 1a). After 50 days in the intensive care unit, the patient developed aspiration pneumonia and
died. An autopsy was performed 4 h postmortem.

coded iron-sulfur subunit of complex III (FeS) [9]. Additional
4-µm-thick sections were stained with hematoxylin and eosin (H&E)
for routine histological evaluation of the small bowel.

Results
Materials and methods
Pathological examination
The cerebrum was bisected, and the left part was fixed in formaldehyde, while the right part was frozen and kept at –70°C until analyzed. Samples from the small intestine (ileum) were also fixed in
formaldehyde and frozen. Samples from lipoma tissue, non-lipoma
abdominal fat, and skeletal muscle were also frozen for mtDNA
studies. Routine samples from formaldehyde-fixed brain were processed for conventional neuropathological study.

Mutation analysis
Total DNA was extracted from frozen postmortem samples of
brain (frontal, temporal and occipital lobes), muscle, lipomatous
tissue, non-lipoma abdominal fat, and small intestine according to
conventional methods. The previously studied muscle biopsy and
lipoma tissue [8] were also processed simultaneously for DNA extraction to allow comparison with the corresponding postmortem
samples. A PCR-based assay was used to determine the proportion
of mutant and wild-type mtDNA. The primers used were as follows: reverse primer 5’-CTACCCCCTCTAGAGCCCAC-3’, spanning from nucleotides 8278–8257; forward primer 5’-GTAGTATTTAGTTGGGGCATTTCACTGTAAAGCCGTGTTGG-3’,
spanning from nucleotides 8386–8344 of mtDNA, with the “wildtype” AG dinucleotide replaced by a CC dinucleotide (underlined).
The dinucleotide substitution in the forward primer creates a restriction site for the enzyme Bgl1 when the A8344G mutation is
present. PCR amplification was carried out on a Perkin Elmer Cetus thermocycler using the following protocol: 1 min denaturation
at 94°C, 1 min annealing at 60°C, and 1 min extension at 72°C, for
28 cycles. To quantitate the relative proportions of mutant and
wild-type mtDNA, approximately 0.5 µCi [α-32P]dATP was added
immediately before the last cycle. The 108-bp PCR samples were
digested with Bgl1 for at least 6 h and were run on a 12% acrylamide gel. Bgl1 digestion produces two fragments, one of 35 bp
and one of 73 bp, which can easily be differentiated from the uncut wild-type fragment by gel electrophoresis. The gel was dried,
exposed and analyzed on a PhosphorImager.

Histopathology of nervous system
By routine histological analysis, in the frontal, temporal
and occipital lobes, we observed cortical infarcts of various sizes associated with different degrees of astrocytosis
and capillary proliferation. The most severely affected region was the occipital lobe, where foci of infarction were
widespread and had a patchy distribution (Fig. 1b). Spongiform degeneration, the neuropathological “hallmark” of
mitochondrial encephalopathies [10], was remarkable in
the cerebral cortex and in the subcortical white matter of
temporal and occipital lobes. In addition, both cerebral
cortex and white matter showed diffuse and moderate
lymphocytic infiltration with mild cuffing around the
blood vessels, but typical neuronophagia was not observed, and there were no obvious foci of infection. Neuronal loss, which is the most typical neuropathological
feature of MERRF [10], was only very mild in the Purkinje
cell layer of the cerebellar cortex, and absent in the dentate nucleus of the cerebellum, the red nucleus of the midbrain, and the olivary nucleus of the medulla.
Mutation analysis
Table 1 shows that tissues had high proportions of mtDNA
carrying the A8344G mutation. The mutation was rather
homogeneously distributed in the brain, ranging from
82% in the occipital lobe to 87% in the frontal lobe.
Lipoma tissue carried 77% of mutants mtDNA, while
non-lipoma abdominal fat tissue had 69%. In skeletal
muscle and lipoma tissue, we did not observe any significant changes in the percentages of the mutation between
biopsy and autopsy samples obtained 2 years apart (90%
vs 89% in muscle and 81% vs 77% in lipoma). The small

Biochemistry
Biochemical measurements of cytochrome c oxidase (COX; complex IV), NADH dehydrogenase (complex I), rotenone-sensitive
NADH-cytochrome c reductase (complexes I and III), succinatecytochrome c reductase (complexes II and III), and citrate synthase
activities were performed in samples of brain and small intestine as
described [4].
Histochemistry and immunohistochemistry
For histochemical studies, frozen samples of muscle and small intestine were cut into 6-µm-thick sections and stained for succinate
dehydrogenase (SDH) and COX activities [9]. For immunohistochemical studies, paraffin-embedded blocks of small intestine
from the patient and normal controls were cut into 4-µm-thick sections and deparaffinized. Subsequently, the sections were stained
immunohistochemically using the ABC method with monoclonal
antibodies against the mtDNA-encoded subunits I of COX, and
with polyclonal antibodies against the nuclear DNA (nDNA) en-

Table 1 Mutation analyses

Tissue
Biopsy specimens
Skeletal muscle
Lipoma
Autopsy specimens
Skeletal muscle
Brain regions
Frontal
Temporal
Occipital
Adipose tissue
Lipoma
Small intestine

Mutated
mtDNA
90%
81%
89%
87%
84%
82%
69%
77%
84%

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Table 2 Biochemical analyses. Activity is given in µmol/min per
g; normal control values are shown in parentheses [COX cytochrome c oxidase (complex IV), SCCO succinate cytochrome c

Brain
Frontal
Temporal
Occipital
Ileum

oxidase (complex II+III), NADH-CCR NADH-cytochrome c reductase (complex I+III), NADH-D NADH dehydrogenase (complex I), CS citrate synthase, N/D not determined]

COX

SCCO

NADH-CCR

NADH-D

CS

0.16 (0.46)
0.09 (0.46)
0.16 (0.72)
0.10 (0.27)

0.45 (0.32)
0.44 (0.40)
0.36 (0.39)
1.19 (1.18)

0.90 (0.51)
0.91 (0.31)
0.56 (0.36)
0.70 (N/D)

6.92 (7.11)
7.01 (6.54)
6.23 (6.16)
4.09 (N/D)

4.15 (5.94)
5.09 (4.09)
12.8 (7.12)
2.26 (3.40)

Fig. 2a–e Histochemistry on serial sections of the patient’s ileum.
a H&E stain illustrates vacuolation (black arrow) of the arterial
wall of a vessel in the submucosa. b SDH stain illustrates in the
same artery regions of increased oxidative activity. c COX stain

shows reduced activity in the arterial wall. d The SDH stain of the
smooth muscle layers and myenteric plexus, and e reduced COX
stain in the muscle layers (asterisk) as well as in some of the nerve
cells of the plexus (arrow) are shown. a–e ×180

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Fig. 3a–d Immunohistochemistry on serial sections of the patient’s ileum using the nDNA-encoded FeS subunit of complex III
and the mtDNA-encoded subunit I of COX. The FeS immunoreaction is normal in the arterial wall of a submucosal vessel (a), and
in muscle layers and nerve cells of the myenteric plexus (c). The
COX I immunoreaction is reduced in the arterial wall (arrow) (b),
and in the muscle layers (asterisk) and in some nerve cells of the
myenteric plexus (arrows) (d). a, b ×180; c, d ×100

intestine showed an average mutation load of 84%. Samples of small intestine were taken from two different areas
of the ileum, one that showed discoloration of the mucosa
and thinning of the wall, and the other part with normal
appearance. The former harbored 83% mutants mtDNA
and the latter 85%.
Biochemistry
The results of biochemical analyses in postmortem samples from the brain and the intestine small bowel are
shown in Table 2. The samples showed a selective decrease of COX activity, confirming the characteristic vulnerability of this complex to the A8344G mutation [4,
11].

Histochemistry and immunohistochemistry
Histochemical changes in the muscle biopsy have been
previously reported [8]. Postmortem muscle showed scattered ragged-red fibers (RRF), group atrophy, and a few
degenerating fibers with phagocytotic activity. All RRF
were COX negative. Focally, the intramuscular arteries
showed strong reactivity with SDH, while COX histochemistry revealed decreased enzyme activity in the same
vessels (data not shown).
Sections from the ileum stained with H&E showed that
the mucosa was generally thin and intestinal pits were
shallow. In addition, the mucosal epithelial cells had lost
their normal histological appearance, possibly due to
postmortem changes. The lamina propria and the submucosal layers were fibrous. In the submucosa, the smooth
muscle layers of some small arteries showed microvacuolation (Fig. 2a). However, we did not observe hyaline degeneration, necrotic changes, or inflammation in the
blood vessel walls. In the circular and longitudinal muscle
layers of the intestinal wall, there were no obvious degenerative changes, necrosis, or perforation.
Histochemical reactions on frozen sections from small
bowel of the patient and that of a normal showed a general
reduction of COX activity in the patient’s muscle layers
and in the submucosal connective tissue, including the
blood vessels (Figs. 1c, 2c). Focal absence of COX stain
was noted in some nerve cells of Meissner’s and Auer-

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bach’s plexuses of the patient (Fig. 2e). In contrast, SDH
enzymatic activity was homogeneous in all structures of
the intestinal wall in both patient and control samples.
Immunohistochemical studies of the small bowel from
normal controls, using anti-COX I and anti-FeS antibodies, showed that the immunostaining pattern was essentially the same with the two antibodies and consisted of
finely punctuate immunoreactivity in the circular and longitudinal muscle layers. In addition, there was immunoreactive material in Meissner’s and Auerbach ganglion cells
as well as the walls of arterioles (data not shown). In the
patient’s sample, the immunostaining patterns differed
widely with the two antibodies. With anti-FeS antibodies
the pattern was similar to that of normal controls in all regions studied (Fig. 3a, c), whereas with the anti-COX I antibodies, immunoreactivity was markedly decreased. COX I
deficiency involved all muscle layers of the intestinal
wall as well as the walls of arterioles of the submucosa
(Fig. 3b, d). In the enteric plexi, COX I deficiency was
also evident in some ganglion cells (Fig. 3d).

Discussion
In its typical expression, MERRF is characterized by myoclonus, generalized seizures, mitochondrial myopathy,
and cerebellar ataxia. Less common signs include dementia, hearing loss, optic atrophy, peripheral neuropathy, pigmentary retinopathy, ophthalmoparesis, and multiple lipomatosis [4]. Three point mutations in the tRNALys gene,
A8344G, A8356G, and G8363A, and a T7512C mutation
in the tRNASer(UCN) have been found in typical MERRF
patients [12, 13, 14], although most patients harbor the
A8344G mutation [2]. Although she harbored the
A8344G mutation, our patient manifested an unusual clinical phenotype because she lacked the typical clinical features of MERRF. Instead, she presented with stroke-like
episodes and ileus, which are seen more commonly in
MELAS patients. In fact, cases of the MERRF/MELAS
overlap syndrome have been associated with the tRNALys
T8356C and the tRNASer(UCN) T7512C mutations [15, 16].
These patients, however, all had the clinical hallmark of
MERRF, myoclonic epilepsy, variously complicated with
stroke-like episodes or migrainous attacks.
Our patient was different from the previously reported
MELAS/MERRF overlap cases because stroke-like episodes
and ileus were not accompanied by any of the typical features of MERRF. In agreement with these observations,
the neuropathology of our patient also failed to show
the typical MERRF lesions; neuronal loss in dentate and
olivary nuclei, a typical neuropathological feature of
MERRF [10], was absent in our patient. Instead, brain
pathology was characterized by foci of cortical infarctions
and by spongiform degeneration, two features consistently observed in MELAS patients [10].
Gastrointestinal dysfunction is not uncommon in mitochondrial disorders associated with mtDNA mutations, including point mutations in tRNA genes and large-scale rearrangements [17, 18, 19, 20]. Two autopsy studies of

such cases showed microvacuolation, foci of necrosis, and
abnormal mitochondria in the proper muscle of the intestine [21, 22]. In the present case, we observed a generalized reduction of COX histochemical stain in the intestinal wall, without any focal necrosis or degenerative
changes of the muscle proper. We also noted focal COX
deficiency in the smooth muscle cells of blood vessels and
in the ganglion cells of the enteric plexi. These observations prompted us to study the steady-state levels of mitochondrial translation products by visualizing one mtDNAencoded polypeptide (COX I), and one nDNA-encoded
polypeptide (FeS). We found decreased expression of
COX I in all structures of the intestinal wall of our patient,
in contrast with a normal immunoreactivity of FeS. The
relative amount and distribution of wild-type mtDNA and
mutant mtDNA in the different cellular components of the
intestinal wall may account for the different immunoreactivity patterns between COX I and FeS, because the phenotypic expression of an mtDNA mutation is regulated by
the “threshold effect,” that is, the mutant phenotype (in
this case, defective mtDNA translation) is expressed in
heteroplasmic cells only when the relative proportion of
mutant mtDNA reaches a certain minimal value [2, 3].
The enteric nervous system controls motility, exocrine
and endocrine secretions, and microcirculation of the gastrointestinal tract [23]. The myenteric plexus (Auerbach’s)
primarily provides motor innervation to the circular muscle, and the submucosal plexus (Meissner’s) innervates
the muscularis mucosa, intestinal endocrine cells, and
submucosal blood vessels [23]. The presence of focal
COX deficiency in the ganglion cells of the enteric plexi
in our patient strongly suggests that all of functions were
disturbed. Although both mtDNA-encoded and nDNA-encoded subunits of the respiratory chain appear to be
highly sensitive to denervation [24, 25], we assume that
the global reduction of COX activity in the muscle layers
of the intestinal wall and the focal COX deficiency of
blood vessels in the submucosal layer were not due to
denervation of the enteric nervous system. We base this
assumption on immunohistochemical evidence that the
nDNA-encoded FeS was well preserved in those same
layers despite COX deficiency. We propose that COX deficiency in the smooth muscle of the blood vessels as well
as of the enteric neurons results in disturbed regulation of
the local blood circulation and dysmotility of the gut.
Acknowledgements This study was supported by grants from the
National Institutes of Health (NS11778 and PO1HD32062), and
by a grant from el Fondo Español de Investigaciones Sanitarias
(FIS 00/0797). We thank Ms. L. Monzon and Ms. H.B Huang for
skillful technical assistance.

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