Download Serial MR Images and MRS Following Treatment in a Newborn with

J Radiol Sci 2012; 37: 133-138
Serial MR Images and MRS Following Treatment in a
Newborn with Maple Syrup Urine Disease
Yen-Fu Lin1 Meng -Yi Liu1 Twei-Shiun Jaw1,2 Mei-Chyn Chao3,4 Yen-Yu Chou1 Chun-Wei Li5
Chih-Ching Chang1 Wei-Chen Lin1 Yu-Ting Kuo1,2
Department of Medical Imaging1, Department of Pediatrics3, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan
Department of Radiology2, Department of Medical Genetics4, School of Medicine, Collage of Medicine, Department of Medical Imaging and
Radiological Sciences5, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
ABSTRACT
Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder affecting branched-chain
amino acids. We report a newborn with MSUD established by neonatal metabolic screening at 2 days old which
showed elevation of plasma level of leucine/isoleucine and valine. The magnetic resonance (MR) imaging at 16 days
old revealed typical finding of high signal intensity lesions within the myelinated white matter areas on T2-weighted
and diffusion-weighted images(DWI). Proton MR Spectroscopy (MRS) showed elevation of lactate (1.3 ppm) and
BCAA/BCKA (0.9 ppm) peaks. The MRS findings in our case were well-corresponded to the change of serum levels
of leucine, isoleucine, and valine by serial MR images and laboratory data following treatment. MR images and
MRS provided specific diagnosis of MSUD and effective monitoring of the response following treatment and dietary
restriction.
Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder due to decreased decarboxylation
of branched-chain amino acids (BCAA), which include
leucine, isoleucine and valine, leading to the accumulation
of toxic levels of BCAA and branched-chain alpha-keto
acid (BCKA) in the body resulting in severe metabolic
acidosis and neurological deficits. The diagnosis of MUSD
is made clinically based on the peculiar maple syrup or
burnt sugar odor of the urine, encephalopathy, increased
levels of branched-chain amino acids in the plasma and
urine, and the presence of α-hydroxyacid and BCKA in
urine. The presence of plasma L-alloisoleucine and urinary
α-hydroxy isovalerate are pathognomonic for MSUD [1].
Although several previous reports had presented diffusion
MRI and Proton MR Spectroscopy finding in maple syrup
urine disease, correlation between MRI finding and serum
level of BCAA was not mentioned. We report the initial
and post-treatment findings of serial MR images and MR
spectroscopy in a newborn with MSUD.
Case report
A full-term female infant was born by normal spontaneous delivery after an uneventful pregnancy. Her birth
weight was 3,800 g and Apgar scores of 9/10 at 1 and 5 min
respectively. Her mother did not receive any prenatal examination. The activity and respiratory condition was fair after
birth. The plasma BCAA (leucine, isoleucine, and valine)
levels were markedly elevated on chromatogram of neonatal
Correspondence Author to: Twei-Shiun Jaw
Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
No. 100, Tz You 1st Road, Kaohsiung 807, Taiwan
J Radiol Sci September 2012 Vol.37 No.3
133
MRS in maple syrup urine disease
Figure 1
1a
1b
1c
1d
1e
1f
Figure 1. MR images and MRS at 16 days old. a.-d. T2WI(TR=4000ms, TE=103ms), e.-h. DWI(TR=8600ms, TE=75.6ms,
b=1000), i. T2 FLAIR(TR=8627ms, TE=152ms, TI=2100ms) and j. EADC images showed high signal intensity lesions at
the posterior periventricular white-matter, posterior limbs of internal capsules, globus pallidi, lateral thalami, midbrain,
cerebral vermis, pons and brain stem. k. ADC map showed marked hypointensity. l. T1WI (TR=1800ms, TE=9.8ms)
revealed mildly hypointense in the same regions.
metabolic screening at 2 days old. Leucine level was 696
μmol/L (normal value < 300 μmol/L) and valine level was
471.4 μmol/L (normal value < 250 μmol/L). Classic type
maple syrup urine disease was diagnosed. At 8 days, she
was hospitalized because of poor feeding, irritable crying,
and decreased urine output. Hyperammonemia and metabolic acidosis were disclosed clinically. Her chromatogram
at 8 days showed high levels of leucine (3136.2µmol/L),
isoleucine (578.6 µmol/L), and valine (1226.9 µmol/L).
MR images were performed at 16 days old and revealed
bilateral symmetric high signal intensity lesions at the
posterior periventricular white-matter, posterior limbs of
internal capsules, globus pallidi, lateral thalami, midbrain,
cerebral vermis, pons and brain stem on T2-weighted and
diffusion-weighted images (DWI)(Fig. 1). MRS showed
134
elevation of lactate (1.3 ppm) and BCAA/BCKA (0.9 ppm)
peaks (Fig. 2). She received treatments including peritoneal
dialysis, total parental nutrition, sodium benzoate, and
special diet.
Follow-up MR images were performed at 43 days
and 68 days of age and revealed gradual improvement in
the hyperintense lesions on T2-weighted and diffusionweighted images (Fig. 3). MRS showed significant decrease
in the concentration of lactate and BCAA/BCKA at 43 days
of age; and obvious decrease of these abnormal metabolites
at 68 days of age (Fig. 4). Following treatment, the serum
levels of leucine, isoleucine, and valine returned to normal
at 6 months of age (Table 1). We also observed decreased
corresponding peaks of these metabolits on the MRS.
J Radiol Sci September 2012 Vol.37 No.3
MRS in maple syrup urine disease
Figure 1
1g
1h
1i
1j
1k
1l
Figure 2
2a
2b
Figure 2. Proton MRS(TR＝1600ms TE＝288ms) showed elevation of lactate (1.3 ppm) and BCAA/BCKA ( 0.9 ppm )
peaks with decline of NAA.
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135
MRS in maple syrup urine disease
Figure 3
3a
3b
3c
3d
3e
3f
3d
3e
Figure 3. Follow-up MR images after treatment. a.-d. T2 FLAIR (TR=8627ms, TE=152ms, TI=2100ms). At 43 days old
showed mild improvement of the hyperintense lesions in the involved regions as initial study. e.-h. At 68 days old, FLAIR
T2WI (TR=7302ms, TE=121ms, TI=2000ms) revealed significantly diminished hyperintense lesions.
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J Radiol Sci September 2012 Vol.37 No.3
MRS in maple syrup urine disease
Figure 4
4a
4b
Figure 4. Follow-up proton MRS after treatment. a. At 43 days old MRS (TR=1500ms TE=144ms) demonstrated inverted
peaks of lactate and BCAA/BCKA with decline in height. b. At 68 days old MRS(TR=1600ms TE=288ms) revealed only
slightly detectable lactate and BCAA/BCKA peaks.
Table 1. Serum leucine/isoleucine and valine levels. (* Data from other hospitals, ** ages corresponding to MRI
and MRS studies)
Age in days
2*
8*
14**
44**
49
60
67**
74
188
Normal values
Leucine/Isoleucine (μmol/L)
696
3250
1221
922
651
727
822
429
125
< 305
Valine (μmol/L)
471
825
236
131
103
250
316
126
50
< 368
DISCUSSION
MSUD is a genetically heterogeneous aminoacidopathy, resulting in severe impairment or death if the disease
is not recognized and treated. It is an inherited genetic
disease with an autosomal recessive pattern affecting
approximately 1 out of 120,000-500,000 infants worldwide
[2-4]. It is caused by a deficiency of BCKA dehydrogenase,
an enzyme complex catalyzing the oxidative decarboxylation of BCKA, which is produced after transamination of
essential BCAA (isoleucine, leucine and valine). According
to the literature, three (classic, intermediate, and intermittent) or five (classic, intermediate, intermittent, thiamineresponsive, and dihydrolipoyl dehydrogenase-deficient)
forms have been described; these seem to correlate with the
degree of residual enzyme activity [5]. The classic type is
J Radiol Sci September 2012 Vol.37 No.3
the most common form and has most severe clinical manifestation. Infants with MSUD are usually normal at birth.
In the classic type, onset of clinical signs and symptoms
occurs during first week of life with poor feeding, vomiting,
lethargic sleep, alternating periods of hypertonia and hypotonia, irregular respiration and apnea. In the intermediate
type, patient can usually tolerate a greater amount of leucine.
However, when ill or fasting, the child with intermediate
MSUD reacts just like a child with classic MSUD. The intermittent type is a milder form of the disease because of the
greater enzyme activity present. The thiamine-responsive
child will increase the enzyme activity which breaks down
leucine, isoleucine and valine while giving large doses of
thiamine. The dihydrolipoyl dehydrogenase-deficient type
is similar to those of intermediate MSUD, but there is an
accompanying severe lactic acidosis.
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MRS in maple syrup urine disease
MUSD is diagnosed according to specific clinical
findings and abnormal plasma L-alloisoleucine and urinary
α-hydroxy isovalerate level. Specific MR findings also give
a clue to make a diagnosis if lab data cannot be acquired
initially. MR findings in acute phase are quite characteristic, usually revealing profound localized edema (hyperintense on T2WI) in the deep white matter, dorsal brain
stem, cerebral peduncles, and posterior limb of the internal
capsule, perirolandic white matter, and globi pallidi [5-9].
Our case showed typical hyperintensity lesions in similar
distributions. Jan et al. in the diffusion MR study of patients
demonstrated marked restriction of diffusion (decreased
ADC) compatible with cytotoxic or intramyelinic sheath
edema in the involved [10]. The acute toxic effects of BCAA
and BCKA might induce severe intramyelinic edema,
which is associated with a reversible disturbance of the fluid
retention mechanisms of the myelin sheath [11].
Proton MRS in our case demonstrated abnormal peaks
of BCAA and BCKA at 0.9 ppm and lactate at 1.3 ppm
with relative loss of NAA, which are consistent with the
findings in previous reports [10, 12-14]. Heindel et al found
that the use of a long TE is important to avoid contamination with the signal of lipids and macromolecules [13]. At
TE=136 ms, the signal of BCAA/BCKA is inverted [13].
This also happened in our case when TE=144 ms was
used. Lifelong dietary restriction of the BCAA may allow
survival. MRS can be used to monitor response of treatment and diet restriction. The previous reports mention that
abnormal peaks of BCAA and BCKA at 0.9 ppm disappear
with clinical recovery [13, 14]. NAA is also shown to return
to normal and lactate also disappears [15]. The abnormal
peaks at 0.9ppm were still visible after clinical recovery
in few cases reported [14, 15]. In our patient, decline in
the abnormally elevated lactate and BCAA/BCKA peaks
was noted following treatment. The MRS presentations
in our patient were parallel to the improvement of clinical
symptoms. Furthermore, the MRS findings in our case were
well-corresponded to the change of serum levels of leucine,
isoleucine, and valine.
In conclusion, MR images and MRS provided specific
diagnosis of MSUD and effective monitoring of the
response following treatment and dietary restriction.
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