AJR 2004; 182:1537-1541
© American Roentgen Ray Society
MRI of Five Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy
William S. Millar1,2,
Angela Lignelli1,2 and
Michio Hirano3
1 Department of Radiology, New York Presbyterian Hospital, Columbia-Presbyterian
Center, 177 Fort Washington Ave., Milstein Hospital Bldg., Rm. 3-105, New
York, NY 10032.
2 Department of Radiology, College of Physicians and Surgeons, Columbia
University in the City of New York, New York, NY 10032.
3 Department of Neurology, College of Physicians and Surgeons, Columbia
University in the City of New York, 630 W 168th St., P&S 4-443, New York,
NY 10032.
Received April 15, 2003;
accepted after revision December 3, 2003.
Presented at the 2002 annual meeting of the American Roentgen Ray Society,
Atlanta, GA.
Address correspondence to W. S. Millar
(wsm8{at}columbia.edu).
Abstract
OBJECTIVE. The purpose of this study was to retrospectively review
MR images of the brain in five patients diagnosed with mitochondrial
neurogastrointestinal encephalomyopathy.
CONCLUSION. Our research supports previously reported findings of
confluent abnormal cerebral white matter in patients with mitochondrial
neurogastrointestinal encephalomyopathy. In contrast to prior studies, our
cohort of five patients showed that involvement of the corpus callosum as well
as the capsular white matter, basal ganglia, thalami, midbrain, pons, and
cerebellar white matter is not rare and does not preclude the diagnosis of
mitochondrial neurogastrointestinal encephalomyopathy.
Introduction
Defects in the mitochondrial respiratory chain produce a diverse group of
disorders referred to as mitochondrial encephalomyopathies. Enzymatic defects
of the respiratory chain may be the product of mutant mitochondrial DNA
(mtDNA), defective nuclear DNA (nDNA), or an abnormality of the
interrelationship between these two different genomes
[1,
2]. Mitochondrial
encephalomyopathy with lactic acidosis and strokelike episodes is a primary
mitochondrial disorder commonly caused by the A3243G mtDNA point mutation.
Conversely, mutations in the nDNA gene can lead to secondary mitochondrial
respiratory chain deficiencies; for example, a mutation of the gene encoding
the flavoprotein subunit of the succinate dehydrogenase gene causes complex II
deficiency manifesting as Leigh disease
[3]. Exemplifying the third
situation, mutations in the nDNA gene encoding the enzyme thymidine
phosphorylase located on chromosome 22q13.32-qter lead to an accumulation of
cytoplasmic thymidine (Fig. 1),
which is salvaged in mitochondria
[2,
4]. The abnormal metabolism of
thymidine and deoxyuridine [5]
is thought to produce mtDNA abnormalities, which lead to mitochondrial
neurogastrointestinal encephalomyopathy.
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Fig. 1. —Schematic drawing of mitochondrial thymidine metabolism. Loss
of thymidine phosphorylase (TP) leads to increased levels of plasma thymidine
and deoxyuridine, which is hypothesized to alter mitochondrial deoxynucleotide
pools leading to mitochondrial DNA (mtDNA) abnormalities. TK2 = thymidine
kinase, dNT2 = deoxynucleotidase, TMP = thymidine monophosphate, TTP =
thymidine triphosphate.
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Mitochondrial neurogastrointestinal encephalomyopathy is a rare autosomal
recessive disease associated with multiple deletions and partial depletion of
mtDNA in skeletal muscle [1].
Muscle biopsy usually reveals ragged-red and cytochrome c oxidase
fibers, which are typical histologic findings seen in mitochondrial disorders
[4]. In one study of 35 cases
[1], the average patient became
symptomatic in the second decade of life (average age, 18.5 years) and the
average age of death was 35 years. Gastrointestinal manifestations are
debilitating and include dysmotility, diarrhea, borborygmi, abdominal cramps,
early satiety, nausea, vomiting, intestinal pseudoobstruction, and
gastroparesis. The neurologic manifestations are usually less debilitating and
include peripheral neuropathy, ptosis, ophthalmoparesis, and hearing loss
[1]. Diffuse
leukoencephalopathy is reported in all patients. Despite this
leukoencephalopathy, dementia is not detected clinically and mental
retardation is rare.
In our study, we investigated the incidence and severity of involvement of
brain anatomic structures using MR images in five patients with mitochondrial
neurogastrointestinal encephalomyopathy.
Materials and Methods
We reviewed the clinical records and brain MR images of five patients with
mitochondrial neurogastrointestinal encephalomyopathy who were referred to our
institution for genetic evaluation. All clinical data were collected,
evaluated, and summarized by a board-certified neurologist. The diagnosis of
mitochondrial neurogastrointestinal encephalomyopathy was confirmed in all
five patients by the identification of thymidine phosphorylase mutations, very
low or absent thymidine phosphorylase enzyme activity in buffy coat, and, in
four patients tested, elevated plasma thymidine levels.
All MRI was performed on 1.5-T units (Signa, General Electric Medical
Systems [in the first four patients]; Magnetom Vision, Siemens [in the fifth
patient]). MRI was performed between 1995 and 2002: Three examinations were at
our institution; two were elsewhere. The sequences included four axial FLAIR
images (TR range/TE range, 10,002–9,000/161–110; inversion time,
2,500–2,200 msec; excitations, 2–0.5) and one axial spin-echo
T2-weighted image (TR/TE, 2,200/90; excitation, 1). FLAIR images were not
available for the first patient. Section thickness was uniformly 5 mm;
intersection gap varied (1–2.5 mm) across institutions. Intersection gap
was 1 mm for the three patients at our institution; for the two patients from
outside institutions, the intersection gap was 2.0 mm for one and 2.5 mm for
the other.
Two board-certified radiologists who were unaware of the clinical records
retrospectively reviewed the MR images. We scored the incidence and the
severity of involvement of the cerebral and cerebellar white matter, corpus
callosum, basal ganglia (caudate head, putamen, and globus pallidus), thalami,
white matter capsules, midbrain, and pons. An incidence score (1, present; 0,
absent) and a severity score (4, severe; 3, moderate; 2, mild; 1, minimal; 0,
no involvement) were used. Anatomic structures were rated as 4 (severely
involved), when the entire or most (> 90%) of the structure's visualized
surface area was estimated to show abnormally increased signal intensity; 3
(moderately involved), when structures showed 50–90% involvement; 2
(mildly involved), when abnormally increased signal intensity affected
10–49 % of the structure; 1 (minimally involved), when abnormal signal
intensity affected less than 10% of the structure; and 0 (no involvement).
Each anatomic structure was rated using its most dominant slice; adjoining
slices were used as tiebreakers. Involvement of the rated anatomic structures
was bilaterally symmetric; therefore, a single incidence and severity score
was used for each bihemispheric structure. When rating separate bilaterally
symmetric structures, we used the more extensively involved side. The
subcortical U-fibers were considered to be involved when increased signal
intensity directly reached the inner cortex. Images were independently
reviewed and scored by each radiologist. Scoring differences were resolved by
subsequent interrater consensus. A total lesion incidence score and a total
lesion severity score were calculated as the sum of the scores for each
patient. This retrospective review was performed under a protocol approved by
the university's institutional review board.
Results
Our cohort of five patients with mitochondrial neurogastrointestinal
encephalopathy included four men and one woman who were 34–46 years old
(mean age, 38.6 years) at the time of MRI. The woman was 39 years old. All
five patients had ptosis, ophthalmoparesis, and peripheral neuropathy. Four of
the five patients had severe gastrointestinal dysmotility with recurrent
diarrhea; the remaining patient had intermittent abdominal pain. Thymidine
phosphorylase mutations were present in all five patients: two had a
homozygous G1419A transition, two had a homozygous T2294A mutation, and one
had compound heterozygous mutations (A3371C and G3867C). Thymidine
phosphorylase activity was abnormally low in all five patients and ranged from
0 to 43 nmol/hr per milligram of protein. Normal buffy coat thymidine
phosphorylase activity is (mean ± standard deviation) 667 ± 212
nmol/hr per milligram of protein (n = 19). Plasma thymidine levels
varied from a maximum of 10.4–13.1 to 5.5 µ mol in the four
patients tested. Normal plasma thymidine is undetectable (< 0.05
µ mol). No plasma was available from the 34-year-old man who had a
homozygous G1419A transition.
The incidence and severity of involvement for the evaluated anatomic
structures were recorded and calculated after scoring each patient's MR
images. All patients (5/5) showed severe involvement (mean severity score,
4.0) of the centrum semiovale white matter, as revealed on the FLAIR images
from the 35-year-old and 39-year-old men (Figs.
2A,
2B,
2C and
3A,
3B). Although all five patients
also showed some minimal occasional subcortical U-fiber involvement, usually
at the convexities, the subcortical U-fibers were generally spared. The
caudate heads and the thalami were involved in most patients (3/5), with mean
severity scores of 1.6 and 1.2, respectively, as shown in the 39-year-old man
and the 39-year-old woman (Figs.
3A,
3B and
4A,
4B). The putamina were less
often involved (2/5) with mean severity scores of 1.2 and 1.0. Involvement of
the splenium (mean severity score, 1.8) of the corpus callosum was noted in
almost all patients (4/5), as seen in the 35-year-old and 46-year-old men
(Figs. 2A,
2B,
2C and
5A,
5B,
5C), but the intensity and
extent of involvement were not as severe as those of the centrum semiovale.
The genu of the corpus callosum was less often involved (3/5) with a slightly
lower mean severity score (1.0). The white matter tracts of the internal
capsule were always involved (5/5), with mean severity scores of 2.2 for these
structures. The external capsules were severely involved in the 39-year-old
woman and the 46-year-old man but were otherwise uninvolved in the other three
patients.
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Fig. 2A. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 35-year-old man. Axial FLAIR image (TR/TE, 9,002/157;
inversion time, 2,200 msec) shows confluent abnormally increased signal
intensity in centrum semiovale (severity score, 4). Note sparing of
subcortical U-fibers.
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Fig. 2B. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 35-year-old man. Axial FLAIR image (9,002/157; inversion
time, 2,200 msec) shows abnormally increased signal intensity in midline
corpus callosum (splenium) and internal capsules near thalami bilaterally with
severity scores of 3 and 2, respectively.
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Fig. 2C. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 35-year-old man. Axial FLAIR image (9,002/157; inversion
time, 2,200 msec) shows abnormally increased signal intensity in cerebellar
white matter bilaterally (severity score, 2).
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Fig. 3A. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 39-year-old man. Axial FLAIR image (TR/TE, 10,002/161;
inversion time, 2,220 msec) shows confluent abnormally increased signal
intensity in centrum semiovale (severity score, 4). Note again sparing of
subcortical U-fibers.
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Fig. 3B. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 39-year-old man. Axial FLAIR image (10,002/161; inversion
time, 2,220 msec) shows minimal abnormally increased signal intensity in
caudate heads (severity score, 1). Putamina, globi pallidi, and thalami show
no abnormal signal on inferior slices (severity scores, 0, 0, and 0,
respectively). Slightly increased signal intensity over both thalami is
probably internal capsular white matter fanning into white matter of both
corona radiata.
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Fig. 4A. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 39-year-old woman. Axial FLAIR image (TR/TE, 9,000/110;
inversion time, 2,500 msec) shows abnormally increased signal intensity
bilaterally in caudate heads, putamina, globi pallidi, and thalami (severity
scores: 4, 3, 2, and 3, respectively). Also note abnormally increased signal
intensity bilaterally in internal, external, and extreme capsules (severity
scores: 3, 4, and 4, respectively). Gray matter of claustrum is suggested
between external and extreme capsules.
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Fig. 4B. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 39-year-old woman. Axial FLAIR image (9,000/110;
inversion time, 2,500 msec) shows abnormally increased signal intensity in
pons (severity score, 2).
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Fig. 5A. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 46-year-old man. Axial FLAIR image (TR/TE, 10,002/147;
inversion time, 2,200 msec) shows extensive abnormally increased signal
intensity in corpus callosum (splenium), caudate heads, putamina, globi
pallidi, and thalami (severity scores: 2, 3, 3, 3, and 3, respectively). Also
note abnormally increased signal intensity bilaterally in internal, external,
and extreme capsules (severity scores: 3, 4, and 3, respectively).
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Fig. 5B. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 46-year-old man. Axial FLAIR image (10,002/147; inversion
time, 2,200 msec) shows abnormally increased signal intensity in midbrain
(severity score, 4).
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Fig. 5C. —MR images of mitochondrial neurogastrointestinal
encephalomyopathy in 46-year-old man. Axial FLAIR image (10,002/147; inversion
time, 2,200 msec) shows abnormally increased signal intensity in cerebellar
white matter and pons (severity scores: 3 and 3, respectively).
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The midbrain was involved in only two patients and showed one of the lowest
mean severity scores (1.0). In the posterior fossa, involvement of the
cerebellar white matter was common (4/5) and was associated with a mean
severity score of 2.0. The pons was affected in only two patients and received
a very low mean severity score (1.2).
Discussion
Patients with mitochondrial neurogastrointestinal encephalomyopathy have
been reported to have diffuse confluent cerebral and cerebellar white matter
on T2-weighted images [6].
Abnormal signal intensity in the cerebral white matter is due to an
abnormality of myelin rather than of the axons
[6]. Despite the extensive
central nervous system involvement, patients are generally unaffected
cognitively. In one series of 35 patients with mitochondrial
neurogastrointestinal encephalomyopathy, none had dementia
[1].
In our series, all five patients with mitochondrial neurogastrointestinal
encephalomyopathy had confluent abnormal centrum semiovale white matter, and
most (4/5) had abnormal cerebellar white matter. Our study indicates that
involvement of the corpus callosum (splenium [4/5], genu [3/5]) may be more
common than previously thought
[1,
6]. Although some patients had
moderate-to-severe involvement (Figs.
2B and
5A), others had mild or no
involvement (Fig. 3B).
Abnormally increased signal intensity was clearly shown in the white matter
capsules in most patients (Figs.
4A and
5A). The basal ganglia and
thalami (Figs. 4A and
5A) can also show abnormally
increased signal intensity. Involvement of these structures has not been
previously reported in patients with mitochondrial neurogastrointestinal
encephalomyopathy. We also report variable involvement (Figs.
4B,
5B, and
5C) of the midbrain and pons
[1,
6].
The 46-year-old man and the 39-year-old woman had the highest total lesion
incidence scores (14 and 12, respectively; mean, 9.2) and the highest total
lesion severity scores (40 and 34, respectively; mean, 22.8). These two
patients had no detectable thymidine phosphorylase activity, along with the
35-year-old man, whose lesion scores were intermediate. The 46-year-old man
with the highest scores was the only patient with a compound heterozygous
mutation (A3371C and G3867C). Two of the three remaining patients (the
34-year-old man and the 39-year-old man) with the lowest total lesion
incidence and total lesion severity scores had detectable thymidine
phosphorylase activity and the identical homozygous mutation (G1419A). These
results suggest that brain MRI findings might vary with thymidine
phosphorylase mutations and residual thymidine phosphorylase activity;
however, our sample size is too small to reach any firm conclusions.
Diffusely symmetric abnormally increased MRI signal intensity in the
centrum semiovale white matter on FLAIR or spin-echo T2-weighted images is not
specific for mitochondrial neurogastrointestinal encephalomyopathy. For
example, a diffuse symmetric cerebral white matter abnormality can be the
delayed result of radiation therapy
[7]. Severe cases of radiation
injury generally show sparing of the cortex and the subcortical white matter
and present more commonly as patient age increases. Relative sparing of the
basal ganglia, internal capsule, and posterior fossa have been reported. Most
patients have significant intellectual or neurologic deficits; some patients
may have normal cognitive function.
Toxic encephalopathies may present as diffuse symmetric white matter
abnormalities. Toxic encephalopathies that result from the interaction of
exogenous toxic chemical compounds and the brain parenchyma can occur in any
age group from exposure to any of a large number of exogenous chemical agents
such as organic solvents, mercury, hexachlorophene, and heroin vapor
[8,
9].
Inborn errors of metabolism may produce endogenous toxins such as those
seen in lysosomal storage disorders
[8]. In Krabbe disease,
elevated levels of psychosine and cerebroside both lead to myelin breakdown;
in metachromatic leukodystrophy, elevated levels of sulfatide produce diffuse
myelin damage. MRI findings reported in both Krabbe disease and metachromatic
leukodystrophy include abnormally increased T2-weighted signal intensity in
the periventricular white matter, the corpus callosum, the posterior limbs of
the internal capsules, the cerebellar white matter, and the brainstem.
Canavan's disease is a primary white matter disorder of infancy and early
childhood that has diffuse symmetric abnormal cerebral white matter signal
intensity [10]. The peripheral
subcortical white matter, a region that is spared in Krabbe disease and
metachromatic leukodystrophy, is affected early in the disease. The globi
pallidi can be involved with relative sparing of the putamina
[10]. Kearns-Sayre syndrome, a
mitochondrial disorder characterized by ophthalmoplegia and pigmentary
retinopathy, can also affect peripheral white matter early and preferentially
involve the globi pallidi and thalami. Patients must display neurologic
symptoms before 20 years old
[10].
Congenital muscular dystrophies have diffuse symmetric cerebral white
matter hypomyelination, as noted in a series of 12 patients whose ages ranged
from 8 months to 10 years
[11]. With the exception of
the pure congenital muscular dystrophy classification, all other
classifications of congenital muscular dystrophy (Fukuyama's syndrome,
Walker-Warburg syndrome, and Santavuori-Haltia-Santavuori muscle-eye-brain
disease) are associated with cerebral and cerebellar cortical
abnormalities.
Both cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy and sporadic subcortical arteriosclerotic encephalopathy
have been reported to show diffuse symmetric leukoencephalopathy
[12]. An inherited
microangiopathy with Notch3 mutations in chromosome 19, cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy, has greater abnormal T2-weighted signal intensity in the
anterior temporal lobe and external capsular white matter compared with
sporadic subcortical arteriosclerotic encephalopathy. In one study
[12], patients with cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy were younger (mean age, 49.9 years) than patients with
sporadic subcortical arteriosclerotic encephalopathy (mean age, 65 years).
Patients with pseudomitochondrial neurogastrointestinal encephalomyopathy
have gastrointestinal dysmotility, cachexia, and peripheral neuropathy but
lack evidence of leukoencephalopathy or thymidine phosphorylase dysfunction
[4]. These pseudocases
highlight the importance of MRI in the clinical workup of these symptoms.
Limitations to our study include the small sample size (n = 5),
probable statistical variations in our assessment methods, and institutional
case-selection bias. Gender bias is acknowledged; only one of our five
patients was female. Most of the reported patients have been women
[4]. Some of our patients (mean
age, 38.6 years) were evaluated almost two decades after the mean age of
presentation (18.5 years) in a larger series
[4]. FLAIR sagittal and coronal
planes were not available in this retrospective study, planes that potentially
could have improved our assessment of the corpus callosum and other
structures. Future prospective studies should consider using these additional
planes. Similarly, variation in intersection gap (1–2.5 mm) could not be
controlled retrospectively and does admittedly add some uncertainty to the
rating scheme. Most patients (3/5) were imaged with 1-mm intersection gaps;
the use of intersection gaps of 2.0 and 2.5 mm in two patients might lead to
an underestimation of the incidence and severity scores in some structures
such as the corpus callosum. However, one of the primary purposes in
evaluating this small series of patients was to acknowledge that lesions are
indeed present in many anatomic structures of the brain not previously
reported in the literature. Future clinical, MRI, and autopsy examinations of
patients with mitochondrial neurogastrointestinal encephalomyopathy should be
tailored accordingly. Finally, it is not known whether the brain MRI findings
progress with patient age or clinical disease and at what rate they progress,
if they do. Serial MRI would address these issues.
We chose not to score the T1-weighted images in these five patients for two
reasons. The subtle decreased T1-weighted signal, although noticeable in many
of the severely affected structures, was not always distinguishable, in our
opinion, from the adjoining normal tissues. The anatomic extent of decreased
T1-weighted signal, when detected, also appeared less when compared with the
corresponding FLAIR images. Enhanced T1-weighted images were also available in
three patients; although not formally reviewed, the contrast-enhanced images
did not show abnormal enhancement. Diffusion-weighted images were not
available or obtained during the retrospective time frame (1995–2002)
when the MR images were obtained.
In summary, mitochondrial neurogastrointestinal encephalomyopathy is a rare
autosomal recessive mitochondrial disorder that has been reported to have
diffuse confluent abnormal white matter on MRI. Our MRI evaluation of a small
series of patients with this uncommon disorder of thymidine metabolism
supports these reports. In addition, we show that involvement of the corpus
callosum, the white matter capsules, the basal ganglia, the thalami, the
midbrain, the pons, and the cerebellar white matter may be more common than
previously recognized. These observations may help broaden the radiologic and
pathologic understanding of patients with mitochondrial neurogastrointestinal
encephalomyopathy and assist in the differential diagnosis of
leukoencephalopathy.
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Abstract
Introduction
