Kenneth

D. Pearsen,

MD

#{149} Alisa

D. Gean-Marton,

Phenylketonuria: Brain with Clinical Fifteen patients with biochemically documented phenylketonuria (PKU) were studied with use of magnetic resonance (MR) imaging with spinecho T2-weighted pulse sequences. The resulting images demonstrated varying degrees of symmetric high signal intensity of the white matter within the posterior cerebral hemispheres. Involvement of the antenior hemispheres was seen only in cases with severe signal intensity changes. There was no involvement of the cerebral cortex, brain stem, or cerebellum. Moreover, no anatomic structural abnormalities were observed. Mild cortical atrophy was observed in eight of the 15 patients. There was no significant correlation between the patients’ IQ scores and the level of MR signal intensity changes. Although MR imaging routinely shows relatively distinct abnormalities in patients with PKU, the clinical severity of the disease does not parallel its imaging severity.

Index terms: Brain, abnormalities, Brain, MR studies, 13.1214 #{149} Brain, ter, 13.879 #{149} Phenylketonuria Radiology

1990;

13.599. white mat-

177:437-440

MD

#{149} Harvey

L Levy,

MR Imaging Correlation’

P

autosomal

recessive

is an

genetic

dis-

order resulting from a deficiency in phenylalanine hydroxylase, the enzyme that converts phenylalanine to tynosine (i). The gene for phenylalanine hydroxylase has been cloned and mapped on chromosome 12. A number of mutations that cause PKU have been identified (2). The block in phenylalanine

elevated

degradation

levels

its organic

results

of phenylalanine

acid

metabolites

in

and in blood

and

tissue (1). The clinical phenotype of PKU is limited to the brain. Mental retardation is the most common characteristic of PKU in untreated patients, but other neurologic abnormalities such as autism, seizures, lack of coordination, hyperactive behavior, and hyperreflexia are also seen (3). Treatment with a phenylalanine-nestricted diet controls the biochemical abnormalities and will prevent mental retardation

if begun

in early

infancy

(4,5). Consequently, routine newborn screening for PKU is conducted to identify affected infants so that early presymptomatic treatment can be mitiated (6). Treatment begun after the appearance of developmental delay and other signs of neurologic damage may reverse some of the clinical features

but

will

not

restore

normal

intelligence (7). Despite this extensive knowledge about PKU, the pathogenesis of the brain damage is unknown. The most striking From the Division partment of Radiology K.R.D.) and the Joseph

of Neuroradio!ogy, (K.D.P., A.D.G.M.,

I

tories,

Department

P. Kennedy

of Neurology

Jr.

DeLabora-

(H.L.L.),

Mas-

sachusetts General Hospital, Harvard Medical School, Boston; and the Biochemical Genetics Unit of the Genetic Service, Children’s Hospita!, Harvard Medical School, Boston, (H.L.L.). Received April 4, 1990; revision requested May 2; revision

received

Supported

by

grant

K.D.P.,

NS-05096. 65

14534. C RSNA,

July

National

Caversham

1990

Address

ii;

accepted

Institutes

reprint Woods,

July

13.

of Health

requests Rochester,

to NY

and

most

frequent

#{149} Kenneth

R. Davis,

MD

of the

(PKU)

HENYLKETONURIA

MD

neuro-

pathologic finding, however, has been white matter hypomyelination (8). Occasionally the myelmn reduction is so prominent and diffuse as to mimic Schilders disease (9,10), but, as shown in Figures 1 and 2, it more often involves several different areas of the brain and is accompanied by foci of gliosis (1 1-13). The myelin reduction in PKU appears to result from reduced myelin synthesis rather than excessive myelin loss, since myelin

degradation products are not present (13). This has led to the characterization of this finding as dysmyelmnation rather than demyelination (14). Gray matter changes in PKU have been reported to be absent, with the notable exception of a study by Bauman and Kemper (15) in which three patients had a higher density of cells, decreased

dendritic

cortical

neurons,

reduced

Nissl

arborization

and

of

atrophy

granules

with

in Betz

cells.

If myelmn loss is related to the mental retardation in PKU, those with the lowest intelligence who had received little or no dietary treatment would be expected to have the most severe gray and white matter changes, whereas those who were treated early and have normal intelligence would be expected to have little or no change. To examine this relationship, we studied the magnetic resonance

(MR)

images

of the

brain

in 15 patients with PKU. We compared the MR findings with the biochemical severity of PKU, the dietary treatment status, and the IQ level for each patient. MATERIALS Fifteen confirmed Fourteen

AND

patients PKU patients

ma pheny!alanine mg/dL), while underwent use

of

levels greater one had atypical

detailed

including

recent either

METHODS

with biochemically underwent MR imaging. had classic PKU (plas-

the

clinical

intelligence Wechsler

than 20 PKU. All

evaluations,

testing

with

Intelligence

Scale for Children (WISC) or, if over age 16 years, the Wechsler Adult Intelligence Scale (WAIS). Plasma phenylalanine 1evels were measured with use of an amino acid analyzer (16) or a fluorometric assay (17). nine

The most recent levels obtained

plasma phenylalawere used for pa-

tients on a normal diet, and, for patients receiving dietary treatment, the confirmatory level obtained before initiation the diet was used. The patient’s intelli-

Abbreviation:

PKU

=

of

phenylketonuria.

437

A

‘TX

‘4

4 4

-



#{234}1P

.k

‘4

,

4

Figure

1. Silver-stained demonstrates myelin

tion

coronal pallor.

brain

sec-

3.

Figures

3, 4. Patient

severe

increased

periatriai

signal

zone

centrum

8.

(3) T2-weighted intensity of the

(arrows).

(4)

MR

image

4. axial MR periventricular

image

demonstrates

of 35-year-old white matter,

severe

patient demonstrates most evident in the signal intensity of the

increased

semiovaie.

-P.--

:

:

4 L’

(‘.

Figure

2. Magnified demonstrates

matter lin-eosin

specimen spongiosis.

of white (Hematoxy-

stain.)

gence capacity was categorically graded as normal (IQ 90 and above), mildly abnormal (IQ 70-85), moderately retarded (IQ 50-70), or severely retarded (IQ less than

5.

50).

MR imaging tients

was performed

by means

Medical

Milwaukee)

technique

proton

with

density

on 13 pa-

of a 1 .5-T system

Systems,

echo

and

with

spin-

use of Ti-weighted, T2-weighted

field

trix. One (Technicare

of view, patient [GE

and

formed

by

(A.D.G.M, assessed

and

anomalies, control

location

matter

the

and

atrophy. were

immediate

Radiology

#{149}

at 0.6 T Mu-

used. that

images

weighted ventricular

12. T2-weighted

no significant

axial MR image signal intensity

matter

only),

deep bral

white

axial

white

matter

of a 35-year-old posteriorly.

of gray

congenital Age-matched The most

the white

periatrial

signal matter

conintenin-

semild white

moderate

matter

hemispheres),

to involve

the

MR

image

signal

severely

(also

of the or severe

anterior

involving

posterior

cere-

(extending

cerebral

hemi-

spheres).

RESULTS

were

severity

with use of T2-weighted was graded as absent,

(involving

ma-

1 (Fonar, Melwas per-

changes,

sistent MR finding, sity of periventricular

438

and

(5) Patient

boy shows

neuroradiologists

and subjects

creased quences,

X 256

was evaluated Medical Systems,

K.R.D.), for

white

two

5, 6.

of a 13-year-old

abnormalities. retarded

moderately

(6) Patient

man

shows

mild

re-

15. T2increased

pen-

se-

a 256

waukee]) and one at 0.35 ville, NY). The examination

6.

Figures tarded

(GE

quences (repetition time of 300 or 1,500 msec; echo time of 30, 60, or 120 msec), a 23-cm

,

The Table shows the clinical and biochemical characteristics and the level of white matter signal intensity of the patients. All but one of the T2-weighted images intensity

matter

showed

symmetric high in the peniventniculan of the posterior cerebral

signal white hemi-

spheres (Fig 3), with extension into the frontal lobes in advanced cases only (Fig 4). There was also mild contical atrophy in eight patients, but this was statistically unrelated to the severity of the white matter abnormalities. No signal abnormalities

were

noted

in the

brain

stem,

cere-

bellum, or cortex. The basal ganglia were uniformly spared. No congenital anatomic anomalies were present. The coefficient of correlation between the severity of the white matten signal abnormalities and the patients’ IQ levels was .5, indicating no

November

1990

A ‘I.,,

4, ..

7.

8.

Figures tients

7-9. have

T2-weighted normal

Clinical Intensity

axial

images

intelligence

and

of patient

moderate

9.

1 (9 years

to severe

and Biochemical Characteristics in Patients with PKU

old) (7), patient

increased

and Level

6 (8 years

periventnicular

of White

signal

Matter

(y)

1

9

29.8

Early

(on)

119

Moderate

2 3

14 17

33.3 30.0

Early Early

(off) (on)

102 100

Moderate Mild

4 5 6 7 8 9

51.6 4i.0 29.0 88.0 29.5 38.7 26.4 17.1

Early Early Early Early Never Never Late Early

(on) (off) (on) (on)

11

8 24 8 10 35 29 31 21

12

13

26.9

Early

42.8 22.2 25.0

Late Never Never

13 14 15

Level

(mg/dL)

26 35 35

Early

diet

discontinued I Poorly

began

before

age

Diet*

3 weeks;

at age 5 years. Late diet compliant on diet.

began

on

or off

after

age

refers

IQ

occurred

(off)

Mild Severe Severe Mild Severe Moderate Mild Mild

(on)t

67

Normal

67 20 20

Moderate Moderate Mild

diet

thus

MR changes

continued

or was

and

or the

of the

MR

ed varies

images

(Figs

5, 6), and

five

pa-

tients with essentially normal intelligence displayed moderate (patients 1, 2) to severe (patients 5, 6, and 8) white matter abnormalities (Figs 3, 4,

7-9).

The

remaining

seven

patients

demonstrated parallel clinical and MR imaging severity. The white matter abnormalities visualized at MR also did not significantly correlate with the diet history of the patients. The cortical eight patients correlate with

Volume

177

atrophy observed did not significantly either diet history

Number

#{149}

2

in or

age

was

not

signifi-

cantly correlated with either the IQ or the MR findings. Although the age when myelination of the peniatnial zone is complet-

greatly

normal brains, mal myelination

zone

in individuals the

with

presence of nonin the periatnial

in all age-matched

control

sub-

jects compared with the abnormal signals in nearly all our imaged PKU patients suggests that this finding is not merely a result of normally debayed myelination. We are aware,

however,

that

increased

signal

inten-

sity of the periatrial zone on T2weighted images may persist into adulthood in some individuals with normal intelligence. No deaths have

IQ

patients

patient

pop-

no neuropathoavailable.

either

the

of the

patient.

with

dietary

normal

were

treated diet from had moderate

MR changes patient’s

far in our

This MR study of the brain in PKU revealed a symmetric T2 high signal intensity in the peniventnicular white matter of the posterior cerebral hemispheres in all but one patient. When the changes were severe, the high signal intensity extended into the frontal lobes. There was no clear conrelation between the severity of the

gence who phenylalanine born period

IQ. The

pa-

DISCUSSION

1 year.

significant correlation (P > .1). Three patients with mild mental retardation (patients 10, 1 1, and 12) and one with severe mental retardation (patient 15) had normal or near-normal

(9). Al! three

Signal

history has

old)

ulation; consequently, gic correlation is yet

Intensity

95 90 90 90 88 85 73 72

to whether

5 (24 years

of White

Matter

Phenylalanine

Patient

10

4

Blood

patient

intensity.

Signal Level

Age

old) (8), and

(patients

Two

intelliwith the low the newto severe

2, 8), while

one

untreated patient with severe mental retardation (patient 15) and another with mild retardation (patient 12) had little or no change at MR imaging. To our knowledge, MR imaging characteristics of the brain in PKU

have

not

although that there

ties

in four

been Allen were

previously

described,

et al (18) no brain

patients.

reported abnormali-

However,

that

study was performed with a lowstrength (0.35-T) MR unit. In another study, the MR image of the brain obtamed in one patient with maple syrup urine disease, a genetic disorder of branched-chain amino acid metabolism, showed an increased T2 signal intensity pattern (19) similar to that observed in our study of PKU. The

Radiology

439

#{149}

MR

changes

in maple

syrup

disease correlated with hypomyelination noted pathologic examination.

It is likely

that

signal

abnormalities

served

in PKU

hypomyelination. clear whether

the

is consonant

bution

of myelin

ies

represent

with loss

of

matter

have

ob-

areas

However, distribution

the

served white logic edge,

white we

also

urine

the regions at neuro-

of

it is not we ob-

the

within

correlated IQ level

Acknowledgment: bregt for coordinating

We thank Deborah the study of these

tients

for

specifically

mention

1.

the

(12,20),

which

white

was

in

14 of

our 15 patients. Conversely, neuropathologic studies have identified fected areas of the brain that were found such sule, mains

2.

matter

observed

3.

af-

to be normal in our study, as the brain stem, internal capand cerebellum (12-14). It reto be seen whether these dif-

ferences

reflect

ing MR imaging neunopathobogic

the

limitations

of us-

dysmyelination

Radiology

#{149}

degree observed

of white at MR

matter was

arranging

many

other

Lobpa-

13.

Scriver CR, Kaufman 5, Woo SLC. The hyperphenylalaninemias. In: Scniver CR, Beaudet AL, Sly WS, Val!e D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989; 495546. Levy HL. Invited editorial: molecular genetics of phenylketonuria and its implications. Am J Hum Genet 1989; 45:667-670. Scriver CR, C!ow CL. Phenylketonunia: epitome of human biochemical genetics. N Eng! J Med 1980; 303:1336-1342, 1394-

Holtzman

NA,

Termination

6.

7.

8.

9.

Welcher

of restricted

phenylketonuria:

DW,

diet

Mellitis

15.

Bauman

Brain

1954;

1959;

82:1-9.

ML, Kemper

and histoanatomic brain in untreated

nuria.

TL.

Morphologic

observations of the human phenylketo-

Acta Neuropathol

(Base!)

1982;

58:55-63.

Spackman

DH, Stein

Automatic recording the chromatography

Chem 17.

WH, Moore apparatus of amino

MW,

Robins

E.

in the determination in serum. J Lab C!in

anine 59:885-890.

con-

18.

19.

20.

Allen

S.

for use in acids. Anal

1958; 30:1190-1206.

McCaman

method

ED.

trolled study. N Engl J Med 1975; 293:1121-1124. Guthnie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 1963; 32:338-343. Bickel H, Gerrard J, Hickmans EM. The influence of phenylalanine intake on the chemistry and behavior of a phenylketonuric child. Acta Paediatr 1954; 43:64-77. Malamud N. Neuropathology of phenylketonuria. J Neuropathol Exp Neuro! 1966; 25:254-268. Jervis GA. Phenylpyruvic oligophrenia (phenylketonuria). Assoc Res Nerv Ment Dis

Poser CM, Van Bogaert L. Neuropathologic observations in pheny!ketonunia.

in children

a randomized

of

Bechar M, Bornstein B, E!ian M, Sandbank U. Phenylketonuria presenting an intermittent progressive course. J Neurol Neurosurg Psychiatry 1965; 28:165-170. Alford EC Jr. Stevenson LD, Vogel FS, Engle RL Jr. Neuropatho!ogica! findings in phenylpyruvic oligophrenia (phenylketonuria). J Neuropathol Exp Neuro! 1950; 9:298-310.

14.

16.

Dobson JC, Williamson ML, Azen C, Koch R. Intellectual assessment of 1 1 1 fouryear-old children with phenylketonunia. Pediatrics 1977; 60:822-827.

Crome L. The association of pheny!ketonunia with leucodystrophy. J Neurol Neurosurg Psychiatry 1962; 25:149-153. Corsellis JAN. The pathological report a case of phenylpyruvic o!igophrenia. Neurol Neurosurg Psychiatry 1953;

16:139-143. 12.

adminis-

needs.

with

pathologically by white matter dysmyelination that can be visualized as increased white matter signal intensity on T2-weighted MR images.

the

5.

10.

1 1.

1400. 4.

in identifying findings on the

greater severity of brain disease in those patients who have been exammed neuropathologicalby. In summary, PKU, which leads to mental retardation in the absence of dietary treatment, is characterized

However,

with cior dietary

References

distni-

involvement

peniventnicular

and

trative

matter reported in neunopathostudies of PKU. To our knowlonly two neunopathologic stud-

of the

440

not significantly then the patient’s treatment. U

RJ, Gebarski

5, Aisen

Fluorometric

of phenyla!Med

A.

1962;

Magnetic

resonance (MR) brain imaging in genetic metabolic disease: diagnostic and therapeutic implications. Pediatr Res 1985; 19:387A. Uziel G, Salvoiardo M, Nardocci N. CT and MRI in maple syrup urine disease. Neurology 1988; 38:486-488. Crome L, Pare CMB. Phenylketonunia: a review and a report of the pathological findings in four cases. J Ment Sci 1960; 106:862-883.

33:259-282.

November

1990

Phenylketonuria: MR imaging of the brain with clinical correlation.

Fifteen patients with biochemically documented phenylketonuria (PKU) were studied with use of magnetic resonance (MR) imaging with spin-echo T2-weight...
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