□ CASE REPORT □

Familial Pernicious Chronic Intestinal Pseudo-obstruction
with a Mitochondrial DNA A3243G Mutation
Junichiro Suzuki, Mai Iwata, Hideyuki Moriyoshi, Suguru Nishida,
Takeshi Yasuda and Yasuhiro Ito

Abstract
We report the case of a mother and two children who shared a mitochondrial DNA A3243G mutation. The
mother had diabetes mellitus, neurogenic bladder, bradykinesia, dystonia, and slowly progressive cerebellar
ataxia. Her two daughters were diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes at adolescence. They all presented with gastrointestinal symptoms at an advanced clinical
stage. They were diagnosed with chronic intestinal pseudo-obstruction, and they were resistant to therapy. The
mother and her youngest daughter died from aspiration pneumonia because of vomiting. The determination of
chronic intestinal pseudo-obstruction is an important prognostic factor in patients with the mitochondrial
DNA A3243G variant.
Key words: chronic intestinal pseudo-obstruction, mitochondrial DNA A3243G mutation, MELAS, familial
occurrence

(Intern Med 56: 1089-1093, 2017)
(DOI: 10.2169/internalmedicine.56.7753)

presented with chronic intestinal pseudo-obstruction at an
advanced clinical stage.

Introduction
Mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes (MELAS) is a devastating multisystem syndrome that is characterized by progressive encephalopathy and stroke-like episodes leading to disability and
early death. MELAS is most commonly associated with the
mitochondrial DNA A3243G mutation. In addition to neurological symptoms, carriers of the mitochondrial DNA
A3243G mutation experience a wide spectrum of symptoms
involving multiple organs (1). This mutation can give rise to
gastrointestinal symptoms, including bloating, dysphagia, recurrent vomiting and anorexia, chronic diarrhea, and gastrointestinal pseudo-obstruction. Gastrointestinal symptoms are
reported in 15% of patients with mitochondriopathy (2).
Chronic intestinal pseudo-obstruction (CIPO), which is one
of the more severe gastrointestinal disorders, is characterized
by signs of intestinal obstruction and radiographic evidence
of a dilated bowel in the absence of any mechanical obstruction (3). We herein present the case of a mother and her two
children with a mitochondrial DNA A3243G mutation who

Case Report
Patient 1 was a woman who was born at full term with
normal early development. She presented with her first
stroke-like episode, including headache, vomiting, and
blurred vision, at 10 years of age. A genetic analysis of the
mitochondrial DNA from a blood sample demonstrated the
presence of the A3243G mutation, which confirmed the diagnosis of MELAS. Although she was treated with Lcarnitine, coenzyme Q10, and arginine, she was repeatedly
admitted to hospital because of stroke-like episodes such as
headache, vomiting, and convulsions. At 23 years of age,
she was admitted due to abdominal pains and vomiting. On
a physical examination at admission, short stature (140 cm)
and low body weight (25.1 kg) were noted. Her abdomen
was distended, and decreased bowel sounds were observed.
During a neurological examination, she could not speak or
decipher our instructions. A cranial nerve examination was
unremarkable with the exception of hearing impairment. She

Department of Neurology, TOYOTA Memorial Hospital, Japan
Received for publication May 24, 2016; Accepted for publication September 4, 2016
Correspondence to Dr. Junichiro Suzuki, junichiro_suzuki@mail.toyota.co.jp

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B

C

R
Figure 1. Brain T2-weighted magnetic resonance imaging of Patients 1 (A) and 2 (B) showing multiple infarcts and diffuse brain atrophy. Brain T2-weighted magnetic resonance imaging of Patient 3
(C) showing the hot cross bun sign at the pons and brain stem and cerebellum atrophy.

had muscle weakness and atrophy in her body trunk and
four limbs. Her deep tendon reflexes were generally increased and the patient was bilaterally positive for Babinski’s sign. A laboratory analysis revealed the following findings: white blood cell count, 16,100/μL; C-reactive protein,
2.0 mg/dL; creatine kinase (CK), 105 U/L; lactate, 14.7 mg/
dL (normal range: 3.3-14.9 mg/dL); and pyruvate, 0.6 mg/
dL (normal range: 0.3-0.9 mg/dL). Brain T2-weighted magnetic resonance imaging (MRI) showed multiple infarcts and
diffuse brain atrophy (Fig. 1A). A simple abdominal radiograph showed remarkably dilated intestinal loops (Fig. 2A).
Abdominal computed tomography showed no signs of either
a definite obstructive level or bowel wall thickening
(Fig. 2B). After admission, she abstained from eating, and
lactate-free fluid and antibiotics were administered intravenously. Her abdominal distention gradually recovered over
the next several days. However, she was subsequently unable to take in any food or liquid by mouth, and she was
therefore tube-fed. She then began vomiting again, and several methods of therapy, including mosapride citrate, erythromycin, bifidobacterium, and distigmine bromide had no
effect. Pressure was decreased with the use of a nasogastric
tube, and total parenteral nutrition was administered through
a central venous line. At six months after admission, she
died from aspiration pneumonia due to vomiting; she was
23 years of age.

Patient 2 was the older sister of Patient 1. She was born
at full term and her early development was normal. She presented with her first stroke-like episode, including headache
and vomiting, at 12 years of age. Brain T2-weighted MRI
showed multiple infarcts and diffuse brain atrophy (Fig. 1B).
A genetic analysis of mitochondrial DNA of a blood sample
demonstrated the presence of the A3243G mutation, which
confirmed the diagnosis of MELAS. Like her sister, she was
also repeatedly admitted to hospital for stroke-like episodes
such as headache, vomiting, and convulsions. At 22 years of
age, she was admitted to our hospital because of vomiting.
A simple abdominal radiograph showed remarkably dilated
intestinal loops (Fig. 2C). A small bowel series did not show
a definite obstructive level. Total parenteral nutrition was administered through a central venous catheter because of recurrent vomiting, and she ultimately died due to renal failure because of focal sclerosing glomerulonephritis at 22
years of age.
Patient 3 was the mother of Patients 1 and 2. She was diagnosed with diabetes mellitus at 39 years of age and with
urinary retention at 46 years of age. She developed a staggering gait and presented bradykinesia at 47 years of age.
She had rigidity of the upper limbs and dystonia of the
lower limbs at 49 years of age, and showed forced crying
and forced laughing at 50 years of age. At 51 years of age,
she was admitted to our hospital because of fever, abdomi-

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C

D

B

E

Figure 2. Simple abdominal radiographs of Patients 1 (A), 2 (C), and 3 (D) and abdominal computed tomographic scans of Patients 1 (B) and 3 (E) showing remarkably dilated intestinal loops.

nal pains, and vomiting. The physical examination at admission revealed that she was 147.5 cm tall and weighed 47.8
kg. Her abdomen was distended, and her bowel sounds were
decreased. A neurological examination revealed clear sensorium and a euphoric mood. A cranial nerve examination
was unremarkable except for a slow singsong voice. Muscle
weakness (grade 4-5 on a manual muscle test) was observed
in her body trunk and four limbs. Her vibratory sensation
was slightly decreased on the bilateral medial malleolus,
while her pain and touch sensations were intact. She did not
have orthostatic hypotension. There was severe gait and limb
ataxia in the finger-nose-finger test and heel-knee test. Her
deep tendon reflexes were generally increased and she was
bilaterally positive for Babinski’s sign. She used a wheelchair due to difficulty in walking because of ataxia. A laboratory analysis revealed the following: white blood cell
count, 16,000/μL; C-reactive protein, 35.4 mg/dL; CK, 16
U/L; hemoglobin A1c, 7.1%; lactate, 19.4 mg/dL (normal
range: 3.3-14.9 mg/dL); and pyruvate, 1.38 mg/dL (normal
range: 0.3-0.9 mg/dL). Simple abdominal radiography revealed remarkably dilated intestinal loops (Fig. 2D). Abdominal computed tomography did not demonstrate signs indicating either a definite obstructive level or bowel wall
thickening (Fig. 2E). Although her abdominal distension initially recovered following the administration of erythromycin and bifidobacterium, she subsequently had multiple relapses. An ileus tube was inserted, but was ineffective. Total

parenteral nutrition was administered through a central venous line. Brain T2-weighted MRI showed atrophy of the
brain stem and cerebellum, and a hot cross bun sign at the
pons (Fig. 1C). A genetic analysis of mitochondrial DNA
from a blood sample demonstrated the presence of the
A3243G mutation. She died from aspiration pneumonia due
to vomiting at 54 years of age. Autopsy was not permitted
in these three cases. A summary of the cases is presented in
Table.

Discussion
A genetic analysis of the mitochondrial DNA from blood
samples demonstrated the presence of the A3243G mutation
in a mother and her two children. The most important finding was that despite the differences in the patients’ neurological symptoms, they all presented with CIPO at an advanced clinical stage, which was diagnosed according to the
consensus criteria (3). The mitochondrial DNA A3243G mutation is the most frequent heteroplasmic mitochondrial
DNA mutation. Individuals with the mitochondrial DNA
A3243G mutation may manifest either syndromic or nonsyndromic mitochondrial disorders such as kidney disease,
MELAS, inherited progressive external opthalmoplegia, isolated myopathy, cardiomyopathy, and maternally inherited
diabetes and deafness syndrome. In this familial case, the
two daughters (Patients 1 and 2) manifested the classical

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Table. Characteristics of Chronic Intestinal Pseudo-obstruction in Patients with the Mitochondrial DNA A3243G
Mutation.
Patient 1 (youngest daughter)

Patient 2 (oldest daughter)

Patient 3 (mother)

Age at the onset of mitochondrial
disease (years)
Sex
Clinical manifestation

10

12

39

Female
Headache, episodic vomiting,
stroke-like episodes, seizure,
blurred vision

Female
Headache, episodic vomiting,
stroke-like episodes, seizure,
blurred vision

Brain MRI

Multiple infarcts,
brain atrophy

Multiple infarcts,
brain atrophy

Age at the onset of CIPO (years)
Age of death (years)
Cause of death

23
23
Aspiration pneumonia

22
22
Chronic renal failure

Female
Diabetes mellitus, dystonia,
ataxia, urinary retention,
forced laughing,
forced crying
A hot-cross-bun sign of the
pons; brain stem and cerebellum atrophy
51
54
Aspiration pneumonia

CIPO: chronic intestinal pseudo-obstruction, MRI: magnetic resonance image

signs of MELAS, including headache, vomiting, and convulsive seizures. However, their mother (Patient 3) manifested
different clinical signs, which included diabetes, urinary retention, dystonia, cerebellar ataxia, forced crying, and forced
laughing. Her brain T2-weighted MRI showed characteristic
changes with brain stem and cerebellum atrophy and a hot
cross bun sign at the pons; these findings are commonly observed in patients with the cerebellar variant of multiple system atrophy. However, the hot cross bun sign has also been
observed in patients with spinocerebellar ataxia type 2 and
spinocerebellar ataxia type 3 (4). The mitochondrial DNA
A3243G mutation is associated with various central nervous
system manifestations, such as dystonia (5), parkinsonism (6), and ataxia (7-9). Pathologically, patients with the
mitochondrial DNA A3243G mutation show diffuse atrophy
of the cerebellar cortex, gliosis of the cerebellar white matter, and cactus formation in Purkinje cells with the accumulation of mitochondria (10-12). Although we cannot exclude
the possibility that the mother had both mitochondrial disease and spinocerebellar degeneration, we attributed the atrophy of the brain stem and cerebellum and the hot cross
bun sign at the pons to mitochondrial disease. The precise
mechanism that results in different clinical manifestations,
even within a single family, from the mitochondrial DNA
A3243G mutation remains unknown.
Despite these differences, all three of our patients presented with CIPO at an advanced clinical stage. CIPO syndrome is a clinical entity that is characterized by repeated
episodes of intestinal obstruction without evidence of a mechanical obstructive lesion (13). CIPO develops in either idiopathic or secondary form; the latter can be categorized as
disease-induced (such as connective tissue disorders, muscular dystrophies, infiltrative diseases, generalized nerve disease, endocrine disease, metabolic disease, and others) or
drug-induced (antidepressants and anti-anxiety drugs, phenothiazines, and others) (13). CIPO has been reported in
several patients with the mitochondrial DNA A3243G mutation (14-21). In a previous study, CIPO was found to develop in 40% of MELAS patients and the frequency was

higher when the onset of mitochondrial disease occurred in
young age (14). Among patients with mitochondrial disease,
mutated mitochondrial DNA and normal mitochondrial DNA
exist in various ratios at each level of organization, and the
ratio of mutated mitochondrial DNA differs among individuals as well as at different levels of organization and among
individual cells (17). The rate of heteroplasmy of the mitochondrial A3243G mutation also varies considerably among
individuals, even within a single family (17). The percentage
of mutated mitochondrial DNA molecules in the blood is
strongly correlated with the age of onset in patients with
MELAS (1). Unfortunately, the percentages of mutant mitochondrial DNA in the blood were not estimated in our
cases. To our knowledge, there have only been three previous reports of familial cases of CIPO associated with the
mitochondrial A3243G mutation (17-19). However, in these
previous reports, CIPO was not related to the direct cause of
death, unlike our cases. The most frequent causes of death
in patients with mitochondrial disease are cardiopulmonary
failure, status epilepticus, and pulmonary embolism (22).
Given that there are few reports of CIPO as the direct cause
of death in mitochondrial disease (23), this case report highlights the importance of careful clinical observation, including gastrointestinal symptoms, in the management of patients with mitochondrial disease.
Surgical treatment for CIPO is not considered to be an
option, as this intervention can increase lactic acidosis. The
use of mosapride citrate, erythromycin, bifidobacterium, distigmine bromide, octreotide, neostigmine, coenzyme Q10,
and a cofactor of the respiratory chain of the mitochondria
has been proposed. However, as in our patients, the effect of
these treatments is generally transient or limited, and the
prognosis is often poor, with many cases ending in
death (22). Thus, CIPO may reflect a severe end-stage
symptom of mitochondrial cytopathy associated with the
A3243G mutation.
The pathophysiology of CIPO due to the mitochondrial
DNA A3243G mutation remains uncertain; however, several
hypotheses have been put forward. First, the accumulation

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of numerous enlarged, abnormal mitochondria was observed
in the intestinal smooth muscle cells and mucosal layer (20),
and cytochrome c oxidase deficiency was specifically confined to the smooth muscle cells of the muscularis mucosa,
the outer muscularis externa, the inner muscularis externa,
and the smooth muscle lining of large arterioles. In addition,
the mitochondrial DNA A3243G mutation was nearly homoplastic at these sites (24). These findings suggest that the
pathogenesis of CIPO is related to myogenicity. Alternatively, in one reported case of CIPO, no mutated mitochondrial DNA was found in any digestive tract samples, suggesting that dysmotility is related to the autonomic nervous
system (21). In addition, MELAS patients have been reported to show endothelial dysfunction, which results in a
decreased vasodilatory capacity in the small arteries (25),
and to have ischemic colitis associated with the A3243G
mutation (26), which suggests vascular involvement in the
pathogenesis of CIPO.
In conclusion, we herein reported a familial case of CIPO
associated with the mitochondrial DNA A3243G mutation.
This case highlights that CIPO is an important prognostic
factor in patients with the mitochondrial DNA A3243G variant. Thus, careful clinical observation, including the observation of gastrointestinal symptoms, is required in the management of patients with the mitochondrial DNA A3243G
mutation.
The authors state that they have no Conflict of Interest (COI).

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