D. Nelson, N. Donnell,
Marvin
George
Jr, MD
MD
#{149} John #{149} Francine
Galactosemia:
are
reported.
#{149} Cecelia MD
A. Cross,
Evaluation
The cerebral findings at magnetic resonance imaging in 67 transferasedeficient galactosemic patients (36 female, 31 male; median age, 10 years)
A. Wolff, MD R. Kaufman,
Twenty-two
pa-
G
MS
with
MR Imaging’
an inherited disease of carbohydrate metabolism, results from the deficiency of the enzyme galactose-1-phosphate (Gal-iP)-uridyl transferase (1). The accepted ALACTOSEMIA,
tients had mild cerebral atrophy, eight had cerebellar atrophy, and 11 had multiple small hyperintense lesions in the cerebral white matter on T2-weighted images. The classic galactosemic patients (those without measurable transferase activity) older than 1 year of age did not show the
treatment restriction
normal matter
patients with dietary restrictions 5). The purpose of this study is to port the magnetic resonance (MR) imaging appearance of the brain transferase-deficient galactosernic
dropoff signal
in peripheral
white
intensity on intermediate- and T2-weighted images. The authors postulate that this abnormal signal
intensity
is due
elm formation secondary ability to make sufficient mal galactocerebroside.
to altered
my-
to the inand/or nor-
Index terms:
of galactosemia
of galactose, but neuropsychologic,
neurologic, speech
and
testing out
is dietary
language
patients
erythrocyte
withabnorof (2re-
in 67
AND
Sixty-seven
METHODS
patients
(36
female,
31 male;
age range, 1 month to 42 years; median age, 10 years) (Table 1) underwent MR imaging of the brain. Ti-weighted 500/ 30-50
(repetition
Radiology
msec)
sagittat
184:255-261
mediate40-96)
time and
msec/echo
axial
images
and T2-weighted axial
images
were
and
time inter-
(2,000-3,000/ acquired.
Forty-
patients underwent MR imaging with a 0.5-T system (Technicare, GE Medicat Systems, Milwaukee), and 18 patients were funded by the study to undergo imaging at other MR imaging centers. The other magnets varied in strength from 0.5 to 1.5 T. Imaging parameters were the same as at our institution. Twenty-four patients underwent follow-up MR imaging examinations i-4 years after the initial nine
1 From the Department of Radiology (M.D.N.) and Division of Endocrinology, Department of Pediatrics (G.N.D., F.R.K.), Children’s Hospital Los Angeles, 4650 Sunset Blvd. Los Angeles, CA 90027; Department of Radiology (M.D.N.) and Division of Endocrinology, Department of Pediattics (G.N.D., F.R.K.), University of Southern California School of Medicine, Los Angeles; and Departments of Pediatrics (JAW.) and Medical Genetics (C.A.C.), Waisman Center, University ofWisconsin, Madison. From the 1990 RSNA scientific assembly. Received August 15, 1991; revision requested September 30; final revision received December 19; accepted December 30. Supported by grant no. R01HO26401-01 from the National Institute of Child Development and by a grant from the National Organization of Rare Disorders. Address reprint requests to M.D.N. 0 RSNA, 1992
brain bra!
stem, cerebellum, basal nuclei. The
sity
was
examination. Sixty-three tosemia (no
patients measurable
had
“classic” erythrocyte
galacGal-
i-P-uridyt transferase activity), and four had “variant” gatactosemia. We define “variant” as measurable but low erythrocyte transferase activity confirmed with a sensitive radioactive muttipoint assay (6). AU four patients with the variant variety
had less than 1 % of normal transferase activity. The cerebral MR images were specifically evaluated for the degree of myelination, myelin signal intensity with all sequences, congenital malformation,
cortex, myelin
assessed
in two
bundles
such
stile
corpus
and
with
(7-9)
whom
cereinten-
locations:
cap-
in periph-
studies
were
normal
cerebral
and in the
com-
standards
MR images
obtained
in
group of 500 patients (age range, to 65 years; median age, 9 years) in
MR imaging
yielded
no
on our 0.5-T system
abnormal
findings.
examples
from
resentative groups
general and
published
and
a control 1 week
and signal
as the secondary of corona radiata
tertiary branching cerebrum. pared
focal in the
as the internal
callosum
such
sulcat
enlargement, and lesions
in major
listed
in Table
comparison
Brain, atrophy, 10.83, 10.87 Brain, MR. 10.1214 #{149} Brain, white matter, 10.87 #{149} Enzymes S Galactosemia, 10.879 Metabolism #{149} Myelin 1992;
pa-
tients.
PATIENTS
cerebral
fissure lesions,
The MR imaging
trans-
ferase activity frequently yield mal results, despite compliance
enlargement,
and cerebellar white matter
erat bundles
development
in galactosemic
measurable
detailed and
ventricular
Three
each
1 were
rep-
of the age
used
for
with
the galactosemic patients. No differences in degree of myelination or white matter signal intensity were found when our controls were cornpared with published standards (7-9). RESULTS Patient
age
at initial
diagnosis
ranged from birth to 33 years. age at diagnosis was 8 months. patients had affected siblings had lactose newborns,
nations
Median Nine and had
restriction enforced as until enzymatic determi-
confirmed
the
fect. These nine patients the usual initial metabolic brought on by elevated
transferase did not
dehave
crisis levels of ga-
tactitol and Gal-i-P. The severity of the initial illness in the 63 patients with classic galactosemia varied; 13 had no symptoms, and
symptoms
were
mild
severe in 22. Of the four the low-activity variant, symptoms,
one
had
mild
in 28 and
patients two had
with no
symptoms,
and
one had severe symptoms. Cataracts were present at diagnosis in 12 of 63 with classic galactosemia
Abbreviations: E.C. = Enzyme Gal-i-P = galactose-1-phosphate, uridine diphosphogalactose.
Commission, UDP = Gal-
255
and
in one
ity
of four
variant.
with
Sepsis
the
was
low-activ-
present
diag-
at
nosis in seven of 63 with classic gatactosemia. No variant patients were septic. Hepatic involvement at diagnosis was present in 50 of 63 classic cases and one of four variant cases.
Renal
involvement
was
present
at
diagnosis in five of 13 classic cases but was not present in any patients with the variant disease. No congenital malformations were observed. One patient had a 3-cm retrocerebellar cyst displacing the vermis but not obstructing the outlets of the fourth ventricle.
On
Ti-weighted
images,
had
appropriate for their age. White tensity in all eight tients
at! 67 pa-
myelination matter signal inclassic gatactosemic
patients 1 year old or less was normal for patient age with all sequences (Figs 1, 2). In 52 of 55 classic patients
older
than
riphera! matter
1 year,
however,
cerebral and signal did not
pointense weighted
the
cerebellar become
pe-
white as hy-
on intermediate and T2images as in normal con3-6). The internal capsule
trots
(Figs
and
corpus
ma!
tow
callosum remained of norsignal intensity on T2weighted images (Figs 3-6). This peculiar white matter pattern was seen on images obtained with 0.5- and 1.5-T systems. Variation of the window settings did not change the abnormal white matter appearance relative to the gray matter. Pa-
without
tients
derwent not show
gatactosemia the abnormal
imaging
the
tern. Minor and intensity
variations of the
matter
signal
when
images
3-6). Nine
in the abnormal
intensity
were
extent white apparent
(Figs than
ci.
2 years
follow-up imaging 1-2 years after the initial examination. On the follow-up images, it was evident that the abnormal peripheral myelin pattern had developed in at! nine patients. Fifteen patients from 2 to 25 years of age underwent fotlow-up MR imaging 1-4 years after the
underwent
initial
examination.
The
Three
of four
MR imaging tient
gatactosemic
showed
no
the
variant
normal
peripheral
intensity,
but otherwise
The
256
thatami,
#{149} Radiology
variety
white
results
pa-
had
ab-
matter
of MR
signal
imaging
normal.
caudate
nucleii,
pu-
t.
tamina, g!obi pallidi, and amygda!ae were of norma! volume and signat intensity with alt imaging sequences
in all patients.
were
Brain
not
stem
observed
patients. Twenty-two of 63 classic tosemic patients had mild tricular enlargement. Four
in
any
underwent
at
(Fig 7). A 24-year-old
with
were
variant
abnormalities
e.
Figure 1. Axial (a, d) Ti-weighted (500/30), (b, e) intermediate (2,500/48), and (c, f) T2weighted (2,500/96) MR images obtained at the level of (a-c) the basal ganglia and thalamus and (d-f) the centrum semiovale in a i-month-old boy with unmeasurable transferase activity (classic galactosemia). These MR images are normal for patient age.
abnormalities
abnormal
peripheral white matter pattern had been evident at the initial MR examination, and was unchanged on the follow-up images. patients
C.
un-
were
less
U.
did pat-
compared
of 12 patients
of age
who
same day myetin
d.
follow-up
galaclateral of the
yen22
examinations
performed
were
tion, yet cerebeltar imaging
cerebellar
betlar
sive
changes
showed
at follow-up
progresimaging
later.
None
atactic at neurologic only the two with
1-2 years later, and ventricular size had not changed. None of the other 20 patients with follow-up examinations developed enlarged lateral yentrictes. A 9-year-old patient with mild
atrophy
2 years
of the
other 23 patients who underwent fotlow-up MR imaging developed cerebetlar atrophy. Eight of 63 had enlargement of the fourth ventricle and cerebellar sulci, suggesting cerebeltar atrophy; six had enlargement to a mild degree, and two to a moderate degree (Fig 8a). Ten of 63 patients
tients
had
examinamoderate
atrophic changes at MR were atactic. The four pawith the low-activity variant normal-sized cerebral sutci, cerefissures, and ventricular sys-
tems.
July
1992
i4
Figure 2. 7-month-old
Axial MR images boy with classic
obtained in a galactosemia.
Images
are normal for patient i legend for imaging parameters tomic levels depicted.
age.
See Figure and ana-
Eleven of 63 classic galactosemic patients had two or more 2-15-mmdiameter lesions scattered through the cerebral white matter. The lesions tended
the b.
C.
to cluster
lateral
sions
about
ventricles
were
the
(Fig
either
hypo-
corners
of
8b). The
le-
or isointense
on Ti-weighted images and were hyperintense on intermediateand T2weighted images. No focal white matter lesions were identified in the four patients with the variant disease. One patient who was 1 month old at the initial MR examination and another who was 9 months old at that time developed focal white matter lesions that were evident at follow-up MR imaging 12 months later. Seven patients
(ages:
months; years;
e.
f.
14 months;
2 years 9 years;
2 years
and
and
6 months;
5
9 years;
and
years)
ii
3
had focal white matter lesions at mihal MR imaging that were unchanged in size and number at follow-up imaging 1-3 years later. The distribution of abnormal MR imaging findings by age group is listed in Table 2. DISCUSSION Normal
Galactose
Metabolism
Normal galactose sists of three steps is phosphorytated
metabolism con(1). First, galactose by the enzyme ga-
lactokinase (kinase) (Enzyme Cornmission [E.C.] number 2.7.1.6) to produce Gal-i-P (step 1 in Fig 9). Next, b.
C.
Gal-i-P
reacts
with
undine
triphos-
phate to produce uridine diphosphogalactose (UDP-Gal), by using enzyme Gat-i-P-uridyl transferase (transferase)
(E.C.
2.7.7.12)
(step
the 2 in
Fig 9). Complex molecules galactose are synthesized Gal and include cerebral
that utilize from UDPgangliosides
and
are
cerebrosides,
which
compo-
nents of neuronal cell membranes and myelin. Finally, UDP-Gat is converted into uridine diphosphog!ucose by the enzyme uridine diphosphate galactose-4-epimerase (epimerase) (E.C. 5.1.3.2) and is diverted into the d.
e.
Figure
3. Axial MR images obtained e, and f (intermediateand T2-weighted signal intensity dropoff in the white sum (2 in c) and the lack of the same matter (3 in c). Follow-up imaging 2 matter signal intensity pattern as in and anatomic levels depicted.
Volume
184
#{149} Number
1
f. in a i5-month-old girl with classic galactosemia. In b, c, images), notice the normal signal intensity and T2 matter of the internal capsule (1 in c) and corpus callosignal intensity dropoff in the peripheral cerebral white years later showed the same abnormal peripheral white Figures 4-6. See Figure 1 legend for imaging parameters
glucose
pathways
to meet
energy
de-
mands (step 3 in Fig 9). Uridine diphosphoglucose necessary for steps 2 and 3 can be synthesized from glucose-1-phosphate and uridine triphosphate, from the enzyme uridine diphosphoglucose pyrophosRadiology
#{149} 257
phorylase
(E.C. 2.7.7.9). Alt of the enfor these reactions are present liver, brain, and erythrocytes
zymes
in the (1). Abnormal
Galactose
Patients one
with
of three
Metabolism
galactosemia
disorders
have
of galactose
metabolism: kinase deficiency (McKusick no. 23020), transferase deficiency (McKusick deficiency Clinical with kinase
formation
or epirnerase no. 23035) associated are cataract
(1).
and cerebral edema (1). The aldose reductase (E.C. reduces galactose to galacti-
enzyme
1.1.1.21) tot,
no. 23040), (McKusick abnormalities deficiency
which
accumulates
in the
a.
b.
C.
lens,
causing cataract. As the concentration of galactitol increases, cerebral edema
occurs,
presumably
(1). Both
the
cataracts
may
by osmotic
cerebral
effect
edema
and
be prevented
the
if a tac-
tose-restricted diet is given to the infant (1). To our knowledge, no results of cerebral MR imaging of kinase-deficient patients have been reported. Since UDP-Gat metabolism is not attered in kinase-deficient patients, we postulate that myelin signal intensity
d. Figure
should imaging
mal peripheral See Figure i
be normal sequences.
for age
Two types of epimerase have been identified (1).
common
epimerase
with
all MR
4.
Axial
MR images
cerebral legend
white
for
imaging
e. obtained
matter
f. classic
in a 4-year-old
girl with
signal intensity
is the same as that depicted
parameters
and
anatomic
levels
galactosemia.
The abnorin Figure 3.
depicted.
deficiency The more
deficiency
is con-
fined to erythrocytes and may cause minor elevations of erythrocyte gatactose and Gal-i-P, yet the patient is asymptomatic and has normal growth and development (1). The second type, thought to be due to a widespread unstable variant epimerase, produces the same clinical picture as
the
transferase
edge,
no
defect.
cerebral
MR
of epimerase-deficient
To our
knowl-
imaging
studies
patients
have
been reported. In theory, patients with the common epimerase deficiency limited to erythrocytes should have no abnormalities at cerebral MR imaging. Patients with the wide-
spread
epimerase
deficiency,
a.
b.
C.
how-
ever, should have cerebral MR imaging findings similar to those in transferase-deficient patients, because the epirnerase block causes UDP-Gal levels to build up, which in turn in-
hibits the transferase reaction. Transferase deficiency is the
most
common gatactosemia,
causing in
enzyme
abnormality occurring in one
62,000
live births (1). When the newingests lactose, the sugar in breast milk, abnormally high levels of
d.
galactose and Gal-i-P build body. As in kinase deficiency,
Fire white
born
galactose 258
is reduced
#{149} Radiology
up
to galactitol,
in the excess
i legend
e. 5. Axial MR images matter signal intensity for imaging
parameters
f.
obtained in a 10-year-old that is more extensive and
anatomic
levels
boy
than
reveal abnormal peripheral cerebral that depicted in Figure 6. See Figure
depicted.
July 1992
I
Figure 6. Axial MR images obtained in a 29-year-old woman with classic galactosemia show same lack of signal intensity and T2 signal intensity dropoff in the peripheral ce-
rebral matter Figure anatomic
causing Excess
in Figures
for imaging depicted.
cataract Gal-i-P
liver and degeneration,
b.
as depicted
1 legend levels
and cerebral accumulates
causes
3-5. See
parameters
rapid cirrhosis,
and
edema. in the
onset of fatty hyperbitiru-
binemia, an acute
and jaundice. In the kidneys, tubular degeneration occurs, resulting in galactosuria, glycosuria, aminoaciduria, and atbuminuria. Vomiting, lethargy, and susceptibility to gram-negative organisms are usually also present (1). The mortality rate is high unless the disease is
C-
treated. With tion of lactose,
prompt dietary restricthe renal failure, hepa-
tosplenomegaty,
cerebral
edema,
and
other presenting symptoms resolve. That the cerebral edema is reversible has been documented with cranial
e.
computed tomography (10,11). Most gatactosemic patients survive with normal physical development. With sophisticated neuropsychotogic and speech and language development evaluation, however, galactosemic patients frequently are abnormal, despite adherence to dietary restriction (2-5). Perhaps these clinical problems
f.
are
related
to the
white matter of galactosemic sity
altered
or deficient
noted in our patients.
It is possible changes
that result
population
the signal intenfrom a toxic metab-
olite such as Gal-i-P or gatactitol. This seems unlikely, however, because the abnormal peripheral white matter signal intensity developed in nine patients ostensibly never exposed to lactose. b.
It is tempting white matter
C-
to label this signal intensity
abnormal as
layed myelmnation,” particularly when it is seen in the i-S-year-old age group. Yet, in our population of gatactosemic patients, the pattern was present in patients from age 2 years to our oldest patient, a 42-year-old man. Follow-up
MR
1-3 years showed
no
myelin
signal
ficient
e.
d.
Volume
184
#{149} Number
1
the
change
in 24 patients
initial
study
in the
intensity.
myetmnation”
abnormal
Perhaps would
“de-
be a more
appropriate term. The most reasonable explanation for the abnormal myelin signal inten-
f.
sity
Figure
7. Axial MR images obtained in a 27-year-old asymptomatic woman with the lowactivity variant of transferase galactosemia. No abnormalities are evident. Notice the normal (compare with Figures 3-6) myelination in Ti-weighted images a and d and the normal T2 signal intensity dropoff in the peripheral cerebral white matter (arrows in c, f) in b, c, e, and See Figure 1 legend for imaging parameters and anatomic levels depicted.
imaging
after
f.
is a primary
abnormality
in the
biochemical structure of myetin. Forty percent of the outer myetmn sheath is composed of gatactocerebrosides (12). Low levels of UDP-Gal have been reRadiology
#{149} 259
Figure 8. MR images obtained old atactic woman with classic (a, b) Ti-weighted (500/30) axial the level of the cerebellum. The cerebellar fissures (arrows in a) phy. ages and
in a 23-yeargalactosemia. images at prominent suggest atro-
(c, d) 12-weighted (2,500/96) axial imat the level of the (c) lateral ventricle (d) centrum semiovale. Notice the multi-
ple focal hyperintense lesions tered throughout the cerebral
ported tosemic lactose
(arrows) scatwhite matter.
in transferase-deficient patients (13). Because in galactocerebrosides
donated
by
UDP-Gal,
gatacthe gais
it seems
reason-
able to assume a decrease in galactose, or possibly a substitution for galactose, in the formation of myelin in these patients. In support of this idea, a biochemical assay of brain parenchyma
from
tosemic broside the
an
untreated
patient levels,
adult
a.
galac-
b.
had low galactocerewith an inversion in
glucocerebroside:gatactocerebro-
side
ratio
(14,15).
In any
event,
the
resulting
abnor-
mal myelin signal intensity on MR images is probably due to an increase in the amount of water in the cerebral white matter. The net effect is that the peripheral
cerebral
myelin
appears
of
slightly higher signal intensity on intermediateand T2-weighted images. The signal from the internal capsule and corpus cattosum is not affected, because
the
axon
bundles
are
coher-
ent and tightly packed together. The myetin signal intensity in the infants less than 1 year old appears normal because
and
there
less
more
difficult
normality. less
is relatively
myelmn
1 year
seven
causes
of the
of seven
of age
water
which
appreciation
Yet,
than
more
present,
went
ab-
infants on
d.
C.
to de-
velop the abnormal peripheral white matter signal intensity, evident at follow-up imaging, despite strict dietary compliance. In the patients older than 2 years,
no
change
in the
abnormal
myelin signal intensity was revealed at follow-up examination, suggesting a permanent abnormality of the amount or structure of myelin. The 22 classic with mild lateral
galactosemic ventricular
patients enlarge-
ment have hypoplasia
either mild white matter or mild cerebral atrophy.
No
ventricular
further
enlargement
noted at follow-up examination in four patients. Both cerebral and cerebeltar atrophy have been rewas
ported
in galactosemic
(14,16,17). cerebetlar imaging The
focal 260
patients
Eight of our 67 patients had atrophic changes at MR (Fig 8a). multiple
2-15-mm-diameter
hyperintense
lesions
#{149} Radiology
in the
cere-
brat white matter on T2-weighted images obtained in seven patients represent areas of damaged white matter. No changes in either number were noted
1-3 years
after
the
lesion in these
follow-up
size or patients
exami-
nation. Pathologically, focal areas of damaged rnyelin have been described, as has widespread white-matter gliosis (i4,i6,i7). The cause of
these
focal
white
matter
lesions
is un-
known.
July 1992
performed.
Galactose
Twelve
MR imaging Galacrokinase
SteP l
tients
i-3,
old) Galactose.1.Phosphste
(Gal.1.P)
Synthesis
_________________
I
I-#{248}.for
UDP.Galactose
of
myelin
cell
Step 3
Galactocerebrosides and
neuronal
membranes
Figure
Energy
‘
9.
Diagram galactose metabolism. diphosphoglucose.
UDP
=
we
of normal uridine
no reason
pendently
evaluated
the
normal
versus
tensity.
One
for
galactosemic
patients,
sic gatactosemia
those
and
than 1 year did not dropoff in peripheral
who
a mani-
were
clas-
older
show the normal white matter
signal intensity on intermediateand T2-weighted images. These signal intensity changes we postulate to represent abnormal myelin formation secondary to insufficient and/or altered gatactocerebroside. Associated MR imaging findings include mild cerebrat and cerebellar atrophy and multiple small areas of white matter damage. U
gatactosemic
Volume
184
#{149} Number
1
in-
reviewers series the
7.
indeof cases
for
signal
in-
same
8.
cases
the
age of the patients
in the blinded of abnormal
in this
age
pawere
9.
study,
because
myelination
was
group.
The blinded study showed that both reviewers, on both occasions, correctly identified the abnormal myelin signal intensity i2)
in every more
views, found
than
galactosemic 3 years
abnormal)
of three
controls and
listed
patient
(12
In both
re-
of opinion age group
was for
of age.
a slight difference in the 1-3-year-old
the normal
(one of three
galactosemic
listed
patients
10.
of 11.
as
12.
(two
as abnormal). of the imaging neurotogic
13.
and neuropsycho!ogic tests is not yet completed and will be the subject of a future report.
14.
References 1.
2.
3.
5.
Donnell GN, Bergen WR. The galactosemias. In: Raine DN, ed. The treatment of inherited metabolic disease. Lancaster, England: Medical and Technical, 1975; 91114. Bohles H, Wenzel D, Shin YS. Progressive cerebellar and extrapyramidal motor disturbances in galactosemic twins. Eur J Pediatr 1986; 145:413-417. Lo W, Packman 5, Nash 5, et al. Curious neurologic sequelae in galactosemia. Pediattics 1984; 73:309-312. Packman 5, Koch TK, Schmidt K, Wagstaff J, Ng WG. Galactosemia: new frontiers in research. Bethesda, Md: National Institute of Child Health and Human Development; in press. Manis FR, McBride C, Kaufman FR, Nelson MDJr, Donnell GN. Cognitive functioning in children with classical galactosemia (abstr). Pediatr Res 1990; 27:784.
Ng WG, Kline F, Lin J, Koch R, Donnell GN. Biochemical studies of a human low activity galactose-1-phosphate uridyl transferase variant. J Inherited Metab Dis 1978; 1:145-151. Barkovich AJ, Truwit CL. Normal brain myelination. In: Practical MRI atlas of neonatal brain development. New York: Raven, 1990; 1-52. Barkovich AJ, Kjos BO,Jackson DE, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5 1. Radiology 1988; 166:173-180. Bird CR, Hedberg M, Drayer BP, Keller PJ, Flom RA, Hodak JA. MR assessment of myelination in infants and children: usefulness of marker sites. AJNR 1989; 10:731740. Ng WG, Xu YK, Kaufman FR, Donnell GN. Uridine nucleotide sugar levels in patients with galactosekinase deficiency. J Inherited Metab Dis 1989; 12:445-450. Belman AL, Moshe SL, Zimmerman RL. Computed tomographic demonstration of cerebral edema in a child with galactosemia. Pediatrics 1986; 78:606-609. Marano GD, Sheils WS Jr. Gabriele OF, Klingberg WG. Cranial CT in galactosemia (letter). AJNR 1987; 8:1150-1151. Alberts B, Bray D, LewisJ, Raff M, Roberts
K, Watson
exami-
nation
4.
the reliability of the white intensity abnormality in the patients, a blinded study was
age-
studies
in random order and were The only information given
evidence
ADDENDUM To confirm matter signal
i2
myelin
later,
Statistical correlation findings with detailed with
years
with
abnormal week
in pa-
20-30
MR imaging Two
not included
galactosemic patients to undergo MR imaging. If a transferase-deficient patient is imaged, however, the abnormal peripheral white matter signal intensity should be recognized as a
baseline abnormality and not festation of an acute process. Of these 67 transferase-deficient
and
as normal.
no
found
cerebral
6.
cerebral
each
mixed
terpreted
found
Clinically,
iO-20,
to the reviewers was tient. The 0-12-month-old
Pathways
of pathways
(three
randomly
were placed reevaluated.
UDPGa1acwse-4-Epimerase UDP.Glucose
3-iO,
were
matched
Gal-I-P UridylTransferase
Step2
galactosemic
studies
15.
16.
17.
JD.
In: Molecular
biology
of
the cell. 2nd ed. New York: Garland, 1989; 283. Ng WG, Xu YK, Kaufman FR, Donnell GN. Deficit of uridine diphosphate galactose in galactosemia. J Inherited Metab Dis 1989; 12:257-266. Haberland C, Perou M, Brunngraber EG, HofJ. The neuropathology of galactosemia. J Neuropathol Exp Neurol 1971; 30:431-447. Palmieri MJ, Berry GT, Player DA, Rodgers 5, Segal S. The concentration of red blood cell UDP glucose and UDP galactose determined by high-performance liquid chromatography. Anal Biochem 1991; 194:388393. Crome L. A case of galactosemia with the pathological and neuropathological findings. Arch Dis Child 1962; 37:415-421.
Radiology
#{149} 261
Marvin
George
Jr, MD
MD
#{149} John #{149} Francine
Galactosemia:
are
reported.
#{149} Cecelia MD
A. Cross,
Evaluation
The cerebral findings at magnetic resonance imaging in 67 transferasedeficient galactosemic patients (36 female, 31 male; median age, 10 years)
A. Wolff, MD R. Kaufman,
Twenty-two
pa-
G
MS
with
MR Imaging’
an inherited disease of carbohydrate metabolism, results from the deficiency of the enzyme galactose-1-phosphate (Gal-iP)-uridyl transferase (1). The accepted ALACTOSEMIA,
tients had mild cerebral atrophy, eight had cerebellar atrophy, and 11 had multiple small hyperintense lesions in the cerebral white matter on T2-weighted images. The classic galactosemic patients (those without measurable transferase activity) older than 1 year of age did not show the
treatment restriction
normal matter
patients with dietary restrictions 5). The purpose of this study is to port the magnetic resonance (MR) imaging appearance of the brain transferase-deficient galactosernic
dropoff signal
in peripheral
white
intensity on intermediate- and T2-weighted images. The authors postulate that this abnormal signal
intensity
is due
elm formation secondary ability to make sufficient mal galactocerebroside.
to altered
my-
to the inand/or nor-
Index terms:
of galactosemia
of galactose, but neuropsychologic,
neurologic, speech
and
testing out
is dietary
language
patients
erythrocyte
withabnorof (2re-
in 67
AND
Sixty-seven
METHODS
patients
(36
female,
31 male;
age range, 1 month to 42 years; median age, 10 years) (Table 1) underwent MR imaging of the brain. Ti-weighted 500/ 30-50
(repetition
Radiology
msec)
sagittat
184:255-261
mediate40-96)
time and
msec/echo
axial
images
and T2-weighted axial
images
were
and
time inter-
(2,000-3,000/ acquired.
Forty-
patients underwent MR imaging with a 0.5-T system (Technicare, GE Medicat Systems, Milwaukee), and 18 patients were funded by the study to undergo imaging at other MR imaging centers. The other magnets varied in strength from 0.5 to 1.5 T. Imaging parameters were the same as at our institution. Twenty-four patients underwent follow-up MR imaging examinations i-4 years after the initial nine
1 From the Department of Radiology (M.D.N.) and Division of Endocrinology, Department of Pediatrics (G.N.D., F.R.K.), Children’s Hospital Los Angeles, 4650 Sunset Blvd. Los Angeles, CA 90027; Department of Radiology (M.D.N.) and Division of Endocrinology, Department of Pediattics (G.N.D., F.R.K.), University of Southern California School of Medicine, Los Angeles; and Departments of Pediatrics (JAW.) and Medical Genetics (C.A.C.), Waisman Center, University ofWisconsin, Madison. From the 1990 RSNA scientific assembly. Received August 15, 1991; revision requested September 30; final revision received December 19; accepted December 30. Supported by grant no. R01HO26401-01 from the National Institute of Child Development and by a grant from the National Organization of Rare Disorders. Address reprint requests to M.D.N. 0 RSNA, 1992
brain bra!
stem, cerebellum, basal nuclei. The
sity
was
examination. Sixty-three tosemia (no
patients measurable
had
“classic” erythrocyte
galacGal-
i-P-uridyt transferase activity), and four had “variant” gatactosemia. We define “variant” as measurable but low erythrocyte transferase activity confirmed with a sensitive radioactive muttipoint assay (6). AU four patients with the variant variety
had less than 1 % of normal transferase activity. The cerebral MR images were specifically evaluated for the degree of myelination, myelin signal intensity with all sequences, congenital malformation,
cortex, myelin
assessed
in two
bundles
such
stile
corpus
and
with
(7-9)
whom
cereinten-
locations:
cap-
in periph-
studies
were
normal
cerebral
and in the
com-
standards
MR images
obtained
in
group of 500 patients (age range, to 65 years; median age, 9 years) in
MR imaging
yielded
no
on our 0.5-T system
abnormal
findings.
examples
from
resentative groups
general and
published
and
a control 1 week
and signal
as the secondary of corona radiata
tertiary branching cerebrum. pared
focal in the
as the internal
callosum
such
sulcat
enlargement, and lesions
in major
listed
in Table
comparison
Brain, atrophy, 10.83, 10.87 Brain, MR. 10.1214 #{149} Brain, white matter, 10.87 #{149} Enzymes S Galactosemia, 10.879 Metabolism #{149} Myelin 1992;
pa-
tients.
PATIENTS
cerebral
fissure lesions,
The MR imaging
trans-
ferase activity frequently yield mal results, despite compliance
enlargement,
and cerebellar white matter
erat bundles
development
in galactosemic
measurable
detailed and
ventricular
Three
each
1 were
rep-
of the age
used
for
with
the galactosemic patients. No differences in degree of myelination or white matter signal intensity were found when our controls were cornpared with published standards (7-9). RESULTS Patient
age
at initial
diagnosis
ranged from birth to 33 years. age at diagnosis was 8 months. patients had affected siblings had lactose newborns,
nations
Median Nine and had
restriction enforced as until enzymatic determi-
confirmed
the
fect. These nine patients the usual initial metabolic brought on by elevated
transferase did not
dehave
crisis levels of ga-
tactitol and Gal-i-P. The severity of the initial illness in the 63 patients with classic galactosemia varied; 13 had no symptoms, and
symptoms
were
mild
severe in 22. Of the four the low-activity variant, symptoms,
one
had
mild
in 28 and
patients two had
with no
symptoms,
and
one had severe symptoms. Cataracts were present at diagnosis in 12 of 63 with classic galactosemia
Abbreviations: E.C. = Enzyme Gal-i-P = galactose-1-phosphate, uridine diphosphogalactose.
Commission, UDP = Gal-
255
and
in one
ity
of four
variant.
with
Sepsis
the
was
low-activ-
present
diag-
at
nosis in seven of 63 with classic gatactosemia. No variant patients were septic. Hepatic involvement at diagnosis was present in 50 of 63 classic cases and one of four variant cases.
Renal
involvement
was
present
at
diagnosis in five of 13 classic cases but was not present in any patients with the variant disease. No congenital malformations were observed. One patient had a 3-cm retrocerebellar cyst displacing the vermis but not obstructing the outlets of the fourth ventricle.
On
Ti-weighted
images,
had
appropriate for their age. White tensity in all eight tients
at! 67 pa-
myelination matter signal inclassic gatactosemic
patients 1 year old or less was normal for patient age with all sequences (Figs 1, 2). In 52 of 55 classic patients
older
than
riphera! matter
1 year,
however,
cerebral and signal did not
pointense weighted
the
cerebellar become
pe-
white as hy-
on intermediate and T2images as in normal con3-6). The internal capsule
trots
(Figs
and
corpus
ma!
tow
callosum remained of norsignal intensity on T2weighted images (Figs 3-6). This peculiar white matter pattern was seen on images obtained with 0.5- and 1.5-T systems. Variation of the window settings did not change the abnormal white matter appearance relative to the gray matter. Pa-
without
tients
derwent not show
gatactosemia the abnormal
imaging
the
tern. Minor and intensity
variations of the
matter
signal
when
images
3-6). Nine
in the abnormal
intensity
were
extent white apparent
(Figs than
ci.
2 years
follow-up imaging 1-2 years after the initial examination. On the follow-up images, it was evident that the abnormal peripheral myelin pattern had developed in at! nine patients. Fifteen patients from 2 to 25 years of age underwent fotlow-up MR imaging 1-4 years after the
underwent
initial
examination.
The
Three
of four
MR imaging tient
gatactosemic
showed
no
the
variant
normal
peripheral
intensity,
but otherwise
The
256
thatami,
#{149} Radiology
variety
white
results
pa-
had
ab-
matter
of MR
signal
imaging
normal.
caudate
nucleii,
pu-
t.
tamina, g!obi pallidi, and amygda!ae were of norma! volume and signat intensity with alt imaging sequences
in all patients.
were
Brain
not
stem
observed
patients. Twenty-two of 63 classic tosemic patients had mild tricular enlargement. Four
in
any
underwent
at
(Fig 7). A 24-year-old
with
were
variant
abnormalities
e.
Figure 1. Axial (a, d) Ti-weighted (500/30), (b, e) intermediate (2,500/48), and (c, f) T2weighted (2,500/96) MR images obtained at the level of (a-c) the basal ganglia and thalamus and (d-f) the centrum semiovale in a i-month-old boy with unmeasurable transferase activity (classic galactosemia). These MR images are normal for patient age.
abnormalities
abnormal
peripheral white matter pattern had been evident at the initial MR examination, and was unchanged on the follow-up images. patients
C.
un-
were
less
U.
did pat-
compared
of 12 patients
of age
who
same day myetin
d.
follow-up
galaclateral of the
yen22
examinations
performed
were
tion, yet cerebeltar imaging
cerebellar
betlar
sive
changes
showed
at follow-up
progresimaging
later.
None
atactic at neurologic only the two with
1-2 years later, and ventricular size had not changed. None of the other 20 patients with follow-up examinations developed enlarged lateral yentrictes. A 9-year-old patient with mild
atrophy
2 years
of the
other 23 patients who underwent fotlow-up MR imaging developed cerebetlar atrophy. Eight of 63 had enlargement of the fourth ventricle and cerebellar sulci, suggesting cerebeltar atrophy; six had enlargement to a mild degree, and two to a moderate degree (Fig 8a). Ten of 63 patients
tients
had
examinamoderate
atrophic changes at MR were atactic. The four pawith the low-activity variant normal-sized cerebral sutci, cerefissures, and ventricular sys-
tems.
July
1992
i4
Figure 2. 7-month-old
Axial MR images boy with classic
obtained in a galactosemia.
Images
are normal for patient i legend for imaging parameters tomic levels depicted.
age.
See Figure and ana-
Eleven of 63 classic galactosemic patients had two or more 2-15-mmdiameter lesions scattered through the cerebral white matter. The lesions tended
the b.
C.
to cluster
lateral
sions
about
ventricles
were
the
(Fig
either
hypo-
corners
of
8b). The
le-
or isointense
on Ti-weighted images and were hyperintense on intermediateand T2weighted images. No focal white matter lesions were identified in the four patients with the variant disease. One patient who was 1 month old at the initial MR examination and another who was 9 months old at that time developed focal white matter lesions that were evident at follow-up MR imaging 12 months later. Seven patients
(ages:
months; years;
e.
f.
14 months;
2 years 9 years;
2 years
and
and
6 months;
5
9 years;
and
years)
ii
3
had focal white matter lesions at mihal MR imaging that were unchanged in size and number at follow-up imaging 1-3 years later. The distribution of abnormal MR imaging findings by age group is listed in Table 2. DISCUSSION Normal
Galactose
Metabolism
Normal galactose sists of three steps is phosphorytated
metabolism con(1). First, galactose by the enzyme ga-
lactokinase (kinase) (Enzyme Cornmission [E.C.] number 2.7.1.6) to produce Gal-i-P (step 1 in Fig 9). Next, b.
C.
Gal-i-P
reacts
with
undine
triphos-
phate to produce uridine diphosphogalactose (UDP-Gal), by using enzyme Gat-i-P-uridyl transferase (transferase)
(E.C.
2.7.7.12)
(step
the 2 in
Fig 9). Complex molecules galactose are synthesized Gal and include cerebral
that utilize from UDPgangliosides
and
are
cerebrosides,
which
compo-
nents of neuronal cell membranes and myelin. Finally, UDP-Gat is converted into uridine diphosphog!ucose by the enzyme uridine diphosphate galactose-4-epimerase (epimerase) (E.C. 5.1.3.2) and is diverted into the d.
e.
Figure
3. Axial MR images obtained e, and f (intermediateand T2-weighted signal intensity dropoff in the white sum (2 in c) and the lack of the same matter (3 in c). Follow-up imaging 2 matter signal intensity pattern as in and anatomic levels depicted.
Volume
184
#{149} Number
1
f. in a i5-month-old girl with classic galactosemia. In b, c, images), notice the normal signal intensity and T2 matter of the internal capsule (1 in c) and corpus callosignal intensity dropoff in the peripheral cerebral white years later showed the same abnormal peripheral white Figures 4-6. See Figure 1 legend for imaging parameters
glucose
pathways
to meet
energy
de-
mands (step 3 in Fig 9). Uridine diphosphoglucose necessary for steps 2 and 3 can be synthesized from glucose-1-phosphate and uridine triphosphate, from the enzyme uridine diphosphoglucose pyrophosRadiology
#{149} 257
phorylase
(E.C. 2.7.7.9). Alt of the enfor these reactions are present liver, brain, and erythrocytes
zymes
in the (1). Abnormal
Galactose
Patients one
with
of three
Metabolism
galactosemia
disorders
have
of galactose
metabolism: kinase deficiency (McKusick no. 23020), transferase deficiency (McKusick deficiency Clinical with kinase
formation
or epirnerase no. 23035) associated are cataract
(1).
and cerebral edema (1). The aldose reductase (E.C. reduces galactose to galacti-
enzyme
1.1.1.21) tot,
no. 23040), (McKusick abnormalities deficiency
which
accumulates
in the
a.
b.
C.
lens,
causing cataract. As the concentration of galactitol increases, cerebral edema
occurs,
presumably
(1). Both
the
cataracts
may
by osmotic
cerebral
effect
edema
and
be prevented
the
if a tac-
tose-restricted diet is given to the infant (1). To our knowledge, no results of cerebral MR imaging of kinase-deficient patients have been reported. Since UDP-Gat metabolism is not attered in kinase-deficient patients, we postulate that myelin signal intensity
d. Figure
should imaging
mal peripheral See Figure i
be normal sequences.
for age
Two types of epimerase have been identified (1).
common
epimerase
with
all MR
4.
Axial
MR images
cerebral legend
white
for
imaging
e. obtained
matter
f. classic
in a 4-year-old
girl with
signal intensity
is the same as that depicted
parameters
and
anatomic
levels
galactosemia.
The abnorin Figure 3.
depicted.
deficiency The more
deficiency
is con-
fined to erythrocytes and may cause minor elevations of erythrocyte gatactose and Gal-i-P, yet the patient is asymptomatic and has normal growth and development (1). The second type, thought to be due to a widespread unstable variant epimerase, produces the same clinical picture as
the
transferase
edge,
no
defect.
cerebral
MR
of epimerase-deficient
To our
knowl-
imaging
studies
patients
have
been reported. In theory, patients with the common epimerase deficiency limited to erythrocytes should have no abnormalities at cerebral MR imaging. Patients with the wide-
spread
epimerase
deficiency,
a.
b.
C.
how-
ever, should have cerebral MR imaging findings similar to those in transferase-deficient patients, because the epirnerase block causes UDP-Gal levels to build up, which in turn in-
hibits the transferase reaction. Transferase deficiency is the
most
common gatactosemia,
causing in
enzyme
abnormality occurring in one
62,000
live births (1). When the newingests lactose, the sugar in breast milk, abnormally high levels of
d.
galactose and Gal-i-P build body. As in kinase deficiency,
Fire white
born
galactose 258
is reduced
#{149} Radiology
up
to galactitol,
in the excess
i legend
e. 5. Axial MR images matter signal intensity for imaging
parameters
f.
obtained in a 10-year-old that is more extensive and
anatomic
levels
boy
than
reveal abnormal peripheral cerebral that depicted in Figure 6. See Figure
depicted.
July 1992
I
Figure 6. Axial MR images obtained in a 29-year-old woman with classic galactosemia show same lack of signal intensity and T2 signal intensity dropoff in the peripheral ce-
rebral matter Figure anatomic
causing Excess
in Figures
for imaging depicted.
cataract Gal-i-P
liver and degeneration,
b.
as depicted
1 legend levels
and cerebral accumulates
causes
3-5. See
parameters
rapid cirrhosis,
and
edema. in the
onset of fatty hyperbitiru-
binemia, an acute
and jaundice. In the kidneys, tubular degeneration occurs, resulting in galactosuria, glycosuria, aminoaciduria, and atbuminuria. Vomiting, lethargy, and susceptibility to gram-negative organisms are usually also present (1). The mortality rate is high unless the disease is
C-
treated. With tion of lactose,
prompt dietary restricthe renal failure, hepa-
tosplenomegaty,
cerebral
edema,
and
other presenting symptoms resolve. That the cerebral edema is reversible has been documented with cranial
e.
computed tomography (10,11). Most gatactosemic patients survive with normal physical development. With sophisticated neuropsychotogic and speech and language development evaluation, however, galactosemic patients frequently are abnormal, despite adherence to dietary restriction (2-5). Perhaps these clinical problems
f.
are
related
to the
white matter of galactosemic sity
altered
or deficient
noted in our patients.
It is possible changes
that result
population
the signal intenfrom a toxic metab-
olite such as Gal-i-P or gatactitol. This seems unlikely, however, because the abnormal peripheral white matter signal intensity developed in nine patients ostensibly never exposed to lactose. b.
It is tempting white matter
C-
to label this signal intensity
abnormal as
layed myelmnation,” particularly when it is seen in the i-S-year-old age group. Yet, in our population of gatactosemic patients, the pattern was present in patients from age 2 years to our oldest patient, a 42-year-old man. Follow-up
MR
1-3 years showed
no
myelin
signal
ficient
e.
d.
Volume
184
#{149} Number
1
the
change
in 24 patients
initial
study
in the
intensity.
myetmnation”
abnormal
Perhaps would
“de-
be a more
appropriate term. The most reasonable explanation for the abnormal myelin signal inten-
f.
sity
Figure
7. Axial MR images obtained in a 27-year-old asymptomatic woman with the lowactivity variant of transferase galactosemia. No abnormalities are evident. Notice the normal (compare with Figures 3-6) myelination in Ti-weighted images a and d and the normal T2 signal intensity dropoff in the peripheral cerebral white matter (arrows in c, f) in b, c, e, and See Figure 1 legend for imaging parameters and anatomic levels depicted.
imaging
after
f.
is a primary
abnormality
in the
biochemical structure of myetin. Forty percent of the outer myetmn sheath is composed of gatactocerebrosides (12). Low levels of UDP-Gal have been reRadiology
#{149} 259
Figure 8. MR images obtained old atactic woman with classic (a, b) Ti-weighted (500/30) axial the level of the cerebellum. The cerebellar fissures (arrows in a) phy. ages and
in a 23-yeargalactosemia. images at prominent suggest atro-
(c, d) 12-weighted (2,500/96) axial imat the level of the (c) lateral ventricle (d) centrum semiovale. Notice the multi-
ple focal hyperintense lesions tered throughout the cerebral
ported tosemic lactose
(arrows) scatwhite matter.
in transferase-deficient patients (13). Because in galactocerebrosides
donated
by
UDP-Gal,
gatacthe gais
it seems
reason-
able to assume a decrease in galactose, or possibly a substitution for galactose, in the formation of myelin in these patients. In support of this idea, a biochemical assay of brain parenchyma
from
tosemic broside the
an
untreated
patient levels,
adult
a.
galac-
b.
had low galactocerewith an inversion in
glucocerebroside:gatactocerebro-
side
ratio
(14,15).
In any
event,
the
resulting
abnor-
mal myelin signal intensity on MR images is probably due to an increase in the amount of water in the cerebral white matter. The net effect is that the peripheral
cerebral
myelin
appears
of
slightly higher signal intensity on intermediateand T2-weighted images. The signal from the internal capsule and corpus cattosum is not affected, because
the
axon
bundles
are
coher-
ent and tightly packed together. The myetin signal intensity in the infants less than 1 year old appears normal because
and
there
less
more
difficult
normality. less
is relatively
myelmn
1 year
seven
causes
of the
of seven
of age
water
which
appreciation
Yet,
than
more
present,
went
ab-
infants on
d.
C.
to de-
velop the abnormal peripheral white matter signal intensity, evident at follow-up imaging, despite strict dietary compliance. In the patients older than 2 years,
no
change
in the
abnormal
myelin signal intensity was revealed at follow-up examination, suggesting a permanent abnormality of the amount or structure of myelin. The 22 classic with mild lateral
galactosemic ventricular
patients enlarge-
ment have hypoplasia
either mild white matter or mild cerebral atrophy.
No
ventricular
further
enlargement
noted at follow-up examination in four patients. Both cerebral and cerebeltar atrophy have been rewas
ported
in galactosemic
(14,16,17). cerebetlar imaging The
focal 260
patients
Eight of our 67 patients had atrophic changes at MR (Fig 8a). multiple
2-15-mm-diameter
hyperintense
lesions
#{149} Radiology
in the
cere-
brat white matter on T2-weighted images obtained in seven patients represent areas of damaged white matter. No changes in either number were noted
1-3 years
after
the
lesion in these
follow-up
size or patients
exami-
nation. Pathologically, focal areas of damaged rnyelin have been described, as has widespread white-matter gliosis (i4,i6,i7). The cause of
these
focal
white
matter
lesions
is un-
known.
July 1992
performed.
Galactose
Twelve
MR imaging Galacrokinase
SteP l
tients
i-3,
old) Galactose.1.Phosphste
(Gal.1.P)
Synthesis
_________________
I
I-#{248}.for
UDP.Galactose
of
myelin
cell
Step 3
Galactocerebrosides and
neuronal
membranes
Figure
Energy
‘
9.
Diagram galactose metabolism. diphosphoglucose.
UDP
=
we
of normal uridine
no reason
pendently
evaluated
the
normal
versus
tensity.
One
for
galactosemic
patients,
sic gatactosemia
those
and
than 1 year did not dropoff in peripheral
who
a mani-
were
clas-
older
show the normal white matter
signal intensity on intermediateand T2-weighted images. These signal intensity changes we postulate to represent abnormal myelin formation secondary to insufficient and/or altered gatactocerebroside. Associated MR imaging findings include mild cerebrat and cerebellar atrophy and multiple small areas of white matter damage. U
gatactosemic
Volume
184
#{149} Number
1
in-
reviewers series the
7.
indeof cases
for
signal
in-
same
8.
cases
the
age of the patients
in the blinded of abnormal
in this
age
pawere
9.
study,
because
myelination
was
group.
The blinded study showed that both reviewers, on both occasions, correctly identified the abnormal myelin signal intensity i2)
in every more
views, found
than
galactosemic 3 years
abnormal)
of three
controls and
listed
patient
(12
In both
re-
of opinion age group
was for
of age.
a slight difference in the 1-3-year-old
the normal
(one of three
galactosemic
listed
patients
10.
of 11.
as
12.
(two
as abnormal). of the imaging neurotogic
13.
and neuropsycho!ogic tests is not yet completed and will be the subject of a future report.
14.
References 1.
2.
3.
5.
Donnell GN, Bergen WR. The galactosemias. In: Raine DN, ed. The treatment of inherited metabolic disease. Lancaster, England: Medical and Technical, 1975; 91114. Bohles H, Wenzel D, Shin YS. Progressive cerebellar and extrapyramidal motor disturbances in galactosemic twins. Eur J Pediatr 1986; 145:413-417. Lo W, Packman 5, Nash 5, et al. Curious neurologic sequelae in galactosemia. Pediattics 1984; 73:309-312. Packman 5, Koch TK, Schmidt K, Wagstaff J, Ng WG. Galactosemia: new frontiers in research. Bethesda, Md: National Institute of Child Health and Human Development; in press. Manis FR, McBride C, Kaufman FR, Nelson MDJr, Donnell GN. Cognitive functioning in children with classical galactosemia (abstr). Pediatr Res 1990; 27:784.
Ng WG, Kline F, Lin J, Koch R, Donnell GN. Biochemical studies of a human low activity galactose-1-phosphate uridyl transferase variant. J Inherited Metab Dis 1978; 1:145-151. Barkovich AJ, Truwit CL. Normal brain myelination. In: Practical MRI atlas of neonatal brain development. New York: Raven, 1990; 1-52. Barkovich AJ, Kjos BO,Jackson DE, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5 1. Radiology 1988; 166:173-180. Bird CR, Hedberg M, Drayer BP, Keller PJ, Flom RA, Hodak JA. MR assessment of myelination in infants and children: usefulness of marker sites. AJNR 1989; 10:731740. Ng WG, Xu YK, Kaufman FR, Donnell GN. Uridine nucleotide sugar levels in patients with galactosekinase deficiency. J Inherited Metab Dis 1989; 12:445-450. Belman AL, Moshe SL, Zimmerman RL. Computed tomographic demonstration of cerebral edema in a child with galactosemia. Pediatrics 1986; 78:606-609. Marano GD, Sheils WS Jr. Gabriele OF, Klingberg WG. Cranial CT in galactosemia (letter). AJNR 1987; 8:1150-1151. Alberts B, Bray D, LewisJ, Raff M, Roberts
K, Watson
exami-
nation
4.
the reliability of the white intensity abnormality in the patients, a blinded study was
age-
studies
in random order and were The only information given
evidence
ADDENDUM To confirm matter signal
i2
myelin
later,
Statistical correlation findings with detailed with
years
with
abnormal week
in pa-
20-30
MR imaging Two
not included
galactosemic patients to undergo MR imaging. If a transferase-deficient patient is imaged, however, the abnormal peripheral white matter signal intensity should be recognized as a
baseline abnormality and not festation of an acute process. Of these 67 transferase-deficient
and
as normal.
no
found
cerebral
6.
cerebral
each
mixed
terpreted
found
Clinically,
iO-20,
to the reviewers was tient. The 0-12-month-old
Pathways
of pathways
(three
randomly
were placed reevaluated.
UDPGa1acwse-4-Epimerase UDP.Glucose
3-iO,
were
matched
Gal-I-P UridylTransferase
Step2
galactosemic
studies
15.
16.
17.
JD.
In: Molecular
biology
of
the cell. 2nd ed. New York: Garland, 1989; 283. Ng WG, Xu YK, Kaufman FR, Donnell GN. Deficit of uridine diphosphate galactose in galactosemia. J Inherited Metab Dis 1989; 12:257-266. Haberland C, Perou M, Brunngraber EG, HofJ. The neuropathology of galactosemia. J Neuropathol Exp Neurol 1971; 30:431-447. Palmieri MJ, Berry GT, Player DA, Rodgers 5, Segal S. The concentration of red blood cell UDP glucose and UDP galactose determined by high-performance liquid chromatography. Anal Biochem 1991; 194:388393. Crome L. A case of galactosemia with the pathological and neuropathological findings. Arch Dis Child 1962; 37:415-421.
Radiology
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