Computed tomography studies on patients with mucopolysaccharidoses

Neuroradiology (1981) 21:9-23 Neuroradiologg © Springer-Verlag 1981

Computed Tomography Studies on Patients with Mucopolysaccharidoses

R. W. E. Watts 1, Elizabeth Spellacy 1, B. E. Kendall 2, G. du Boulay 2 and Dorothy A. Gibbs 1

IDivision of Inherited Metabolic Diseases, Medical Research Council, Clinica! Research Centre, Harrow, Middlesex, and 2Lysholm Radiological Department, The National Hospital for Nervous Diseases, Queen Square, London, England

Summary. The appearances on computed tomography (CT) in eight patients with mucopolysaccharidosis Type I [five with classical Type IH (Hurler disease)], two with mucopolysaccharidosis Type II (Hunter disease) and two with mucopolysaccharidosis Type IIIB (Sanfilippo B disease) are presented. Reference is also made to two further cases [mucopolysaccharidosis VI and mucopolysaccharidosis IIIB] in which the CT showed special features. Follow-up scans were obtained to assess the evolution of the changes. The interplay of neuronal damage, cerebral atrophy and obstruction to the cerebrospinal fluid (CSF) circulation in the produc- tion of the cerebral manifestations, and the extent to which non-genetic factors influence the expression of the underlying biochemical lesion, are discussed. This series of patients illustrates the problem of classifying those with a-iduronidase deficiency, who do not have the classical Hurler disease phenotype (mucopolysaccharidosis IS and IH/S; Scheie disease and Hurler/ Scheie disease), on the basis of currently available criteria. The place of CT in the diagnosis of complications due to thecal involvement is examined. The density of grey matter on the CT scans was similar to that of normal brain. Inhaled xenon did not produce any special enhancement which could be helpful in assessing the degree of the mucopolysaccharide deposition within cerebral ceils. Symmetrical low attenuation in the white matter was a very common finding. It was not specifically associated with hydrocephalus and its relationship to some of the known neuropathological aspects of mucopolysaccharidoses is discussed. This work has shown that the stage in the evolution of the mucopolysaccharidoses at which hydrocephalus develops as a complication is highly variable and CSF diversion procedures are sometimes indicated to improve the quality of the patients' lives. These indications are briefly discus-

sed. We consider that CT is essential for the adequate appraisal of these patients and to identify some treatable complications.

Key words: Mucopolysaccharidoses - Computed tomography - Hurler disease - Hunter disease - San- filippo disease - Morquio disease - Scheie disease - Hurler/Scheie disease

Introduction

The mucopolysaccharidoses are inborn errors of metabolism in which deficiency of a specific exogly- cosidase prevents the normal lysosomal degradation of the mucopolysaccharides (glycosaminoglycans). The mucopolysaccharide deposits in the lysosomes interfere with the degradation of other ma- cromolecules and this accounts for the intralysosomal accumulation of glycolipids as well as mucopolysaccharides. Cortical neurones have been described as developing large processes ("meganeurites") i n t e r - posed between the axons and perikarya and contain- ing the loaded lysosomes or storage bodies [1, 2]. Inclusions have also been found in astrocytes and in capillary pericytes. The laminated appearance of those in the neurones and astrocytes suggests that they contain glycolipids as well as mucopolysaccharides, whereas the inclusions in the pericytes resemble those in hepatocytes which contain only, or almost entirely, mucopolysaccharides [3-5].

Table 1 summarises the main biochemical, genetic and clinical aspects of the mucopolysaccharidoses. The clinical manifestations of the individual mucopolysaccharidoses vary. This variation is partly inherited, so that mild and severe genetic variants exist, and partly non-genetic. Mechanical factors

0028-3940/81/0021/0009/$03.00

Tab

el 1

. T

he m

ucop

olys

acch

arid

oses

McK

usic

k's

Epo

nym

ous

or o

ther

E

nzy

me

defi

cien

cy

Exc

rete

d In

heri

tanc

e O

rgan

s m

ainl

y af

fect

ed

Cla

ssif

icat

ion a

na

me

glyc

osam

inog

ogly

cans

I H

b

Hur

ler

a-L

-Idu

roni

dase

D

erm

atan

sul

phat

e A

utos

omal

rec

essi

ve

Cen

tral

ner

vous

sys

tem

. S

kele

ton.

H

epar

an s

ulph

ate

Vis

cera

I S

Sch

eie

a-L

-Idu

roni

dase

D

erm

atan

sul

phat

e A

utos

omal

rec

essi

ve

Ske

leto

n (m

ild

rela

tive

to

Hur

ler)

H

epar

an s

ulph

ate

Vis

cera

(m

ild

rela

tive

to

Hur

ler)

I H

/S

Hur

ler/

Sch

eie

a-L

-Idu

roni

dase

D

erm

atan

sul

phat

e A

utos

omal

rec

essi

ve

Phe

noty

pe i

nter

med

iate

bet

wee

n H

epar

an s

ulph

ate

Hur

ler

and

Sch

eie

dise

ases

IIb

Hu

nte

r Id

uron

ate

sulp

hate

sul

phat

ase

Der

mat

an s

ulph

ate

Sex

lin

ked

rece

ssiv

e C

entr

al n

ervo

us s

yste

m.

Ske

leto

n.

Hep

aran

sul

phat

e V

isce

ra

III

A

San

fili

ppo

A

Hep

aran

N-s

ulph

atas

e H

epar

an s

ulph

ate

Aut

osom

al r

eces

sive

C

entr

al n

ervo

us s

yste

m

III

B

San

fili

ppo

B

N-a

cety

l-a-

o-gl

ucos

amin

idas

e H

epar

an s

ulph

ate

Aut

osom

al r

eces

sive

C

entr

al n

ervo

us s

yste

m

III

C

San

fili

ppo

C

a-gl

ucos

amin

e-N

-ace

tyl

tran

sfer

ase

Hep

aran

sul

phat

e A

utos

omal

rec

essi

ve

Cen

tral

ner

vous

sys

tem

III

D

San

fili

ppo

D

N-a

cety

l-gl

ucos

amin

e-6-

sulp

hate

H

epar

an s

ulph

ate

Not

est

abli

shed

C

entr

al n

ervo

us s

yste

m

sulp

hata

se a

IV A

M

orqu

io A

G

alac

tosa

min

e 6-

sulp

hate

sul

phat

ase

Ker

atan

sul

phat

e A

utos

omal

rec

essi

ve

Ske

leto

n

IV B

M

orqu

io B

fl

-gal

acto

sida

se

Ker

atan

sul

phat

e A

utos

omal

rec

essi

ve

Ske

leto

n (O

'Bri

en-A

rbis

ser)

V

c .

..

..

VI

Mar

otea

ux-L

amy

N-a

cety

lgal

acto

sam

ine

4-su

lpha

tase

D

erm

atan

sul

phat

e A

utos

omal

rec

essi

ve

Ske

leto

n (A

ryl

sulp

hata

se B

)

VII

Sl

y fi

-Glu

curo

nida

se

Der

mat

an s

ulph

ate

Aut

osom

al r

eces

sive

C

entr

al n

ervo

us s

yste

m

Hep

aran

sul

phat

e S

kele

ton

Vis

cera

VII

I D

iFer

rant

e N

-ace

tylg

luco

sam

ine-

6 su

lpha

te

Ker

atan

sul

phat

e A

utos

omal

rec

essi

ve

Ske

leto

n su

lpha

tase

H

epar

an s

ulph

ate

- C

hond

roit

in

Not

ide

ntif

ied e

C

hond

roit

in 4

-sul

phat

e N

ot e

stab

lish

ed

Ske

leto

n 4-

sulp

hatu

ria

- C

hond

roit

in

Not

ide

ntif

ied e

C

hond

roit

in 6

-sul

phat

e N

ot e

stab

lish

ed

Cen

tral

ner

vous

sys

tem

6-

sulp

hatu

ria

Ske

leto

n

a M

cKus

ick,

and

his

col

leag

ues

[38]

ori

gina

lly

prop

osed

a n

umer

ical

cla

ssif

icat

ion

of T

ypes

I-V

and

thi

s w

as s

ubse

quen

tly

exte

nded

[2,

41]

b

Bot

h fo

rmer

ly c

alle

d ga

rgoy

lism

bec

ause

of

the

char

acte

rist

ic a

nd s

imil

ar f

acie

s, w

hich

is

also

see

n in

cho

ndro

itin

6-s

ulph

atur

ia,

the

muc

olip

idos

es (

Typ

es I

, II

and

III)

and

som

e ca

ses

of

a-fu

cosi

dosi

s an

d m

anno

sido

sis

[39]

c

Ori

gina

lly

Sch

eie

dise

ase

whi

ch w

as r

ecla

ssif

ied

as m

ucop

olys

acch

arid

osis

IS

whe

n th

e en

zym

e de

fect

was

sho

wn

to b

e th

e sa

me

as t

hat

in H

urle

r di

seas

e. T

he p

ossi

bili

ty th

at H

urle

r an

d S

chei

e di

seas

es a

re d

ue t

o al

leli

c m

utat

ions

and

tha

t th

e in

term

edia

te H

urle

r/S

chei

e ph

enot

ype

(muc

opol

ysac

char

idos

is I

H/S

) is

due

to

doub

le h

eter

ozyg

osit

y fo

r th

e al

leli

c m

utat

ions

co

ncer

ned

has

been

wid

ely

prop

osed

. T

he H

urle

r/S

chei

e ph

enot

ype

coul

d al

so b

e du

e to

hom

ozyg

osit

y fo

r a

thir

d al

leli

c m

utat

ion

at t

he s

ame

gene

loc

us

d T

his

vari

ant

was

des

crib

ed b

y K

ress

e an

d hi

s co

llea

gues

[42

]. T

heir

enz

yme

appe

ars

to a

ct o

n bo

th h

epar

an a

nd k

erat

an s

ulph

ates

und

er d

iffe

rent

con

diti

ons.

Def

icie

nt a

ctiv

ity

tow

ards

he

para

n su

lpha

te o

nly

caus

es S

anfi

lipp

o D

dis

ease

, im

pair

ed a

bili

ty t

o de

grad

e bo

th s

ubst

rate

s ca

uses

DiF

erra

nte

dise

ase.

e

The

se m

ay b

e he

tere

ogen

eous

gro

ups

and

som

e ha

ve b

een

show

n to

be

asso

ciat

ed w

ith

a-L

-Idu

roni

dase

def

icie

ncy

and

ther

efor

e va

rian

t T

ypes

IH

and

IS

[2]

11

associated with the anatomical location of mucopolysaccharide deposits, and the tissue reactions to them, contribute to the non-genetic component. The mental handicap, which is a prominent feature of mucopolysaccharidoses I, II, III and VII, is primarily due to direct neuronal damage by the intralysosomal mucopolysaccharides, but the secondary anatomical abnormalities contribute to this and are mainly responsible for the other neurological manifestations.

Skeletal involvement dominates the clinical picture in mucopolysaccharidoses IV and VI, and there is associated neurological damage due to vertebral subluxation especially at the atlantoaxial joint. A wider range of neurological complications also occurs in mucopolysaccharidosis VI; these include hydrocephalus, arachnoid cysts, pachymeningitis and nerve entrapment.

Recognition of genetic variation within the mucopolysaccharidoses, with the existence of mild variants, emphasises the importance of measures to ameliorate the effects of the non-genetic contribu- tions to the clinical phenotypes. Until recently, further elucidation of such potentially treatable complications as arachnoid cysts and hydrocephalus required pneumoencephalography, and this was potentially hazardous because of the cardiorespira- tory complications associated with systemic mucopolysaccharide deposition. CT gives similar anatomical information and also allows examination of the cerebral substance.

This paper reports our experience with cranial CT in the assessment of a series of patients with mucopolysaccharidoses who were referred to the Clinical Research Centre for assessment because of the clinical trial of repeated fibroblast transplants as a means of enzyme replacement therapy, which is in progress there [6, 7]. Biochemical observations after single transplantations in mucopolysaccharidosis II were reported by others [8]. The clinical assessment of changes in the neurological manifestations during treatment is rendered more difficuk because of their complex aetiology. Direct examination of the central nervous system by CT is therefore essential in order to appraise the progress of the patient and to explain any changes which occur.

Methods

Twelve patients were examined by CT using the EMI 1010 scanner or a 5005 general purpose scanner. Nine of the patients needed general anaesthesia because of inability to cooperate, and one was man- aged with sedation alone. Plain CT and reexamina- tion after intravenous iodide enhancement was per-

formed on all patients. Seven were also examined with xenon enhancement. There were no adverse effects from any of the scanning procedures. Skull radiographs were available for review.

Biochemical Diagnosis

The diagnoses were established biochemically by the following criteria: (i) demonstration of the specific enzyme deficiency (leukocyte and fibroblast a- iduronidase [9] and iduronate sulphate sulphatase [8] in mucopolysaccharidoses IH, IS and IH/S and in mucopolysaccharidosis II respectively, and serum N- acetyl-a-D-glucosaminidase [10] in mucopolysaccharidosis IIIB); (ii) cross correction studies in which it was shown that the abnormal pattern of 35504 uptake and release which is typical of fibroblasts from patients with mucopolysaccharidoses IH, IS or IH/S was corrected by growing the cells in tissue culture medium in which mucopolysaccharidosis II (iduronate Sulphate sulphatase deficient) cells had been grown and vice versa; (iii) demonstration of an abnormal excretion of heparan and dermatan sulphates in mucopolysaccharidoses IH, IS, IH/S, II and of an abnormal excretion of heparan sulphate only in mucopolysaccharidosis IIIB. The urines were initially examined by precipitation of the total mucopolysaccharides with cetylpyridinium chloride [11]. Heparan and dermatan sulphates were later differentiated by thin layer chromatography [12].

Patients

Patient 1 (mucopolysaccharidosis IH) was referred to the Clinical Research Centre at age 5 years 6 months. Although her comprehension was appropriate to her age, her expressive abilities were several years behind her chronological age and her level of visuo- spatial integration corresponded to that of a 3-year- old. She was 86 cm tall (< 3rd centile), weighed 14.2 kg (< 3rd centile) and had the typical physiognomy of the Hurler phenotype (coarse features, depressed widened nasal bridge, excessive hair growth over forehead). Her head was scaphocephalic and large relative to her height with a skull circumference of 51 cm (50th centile) [13]. The other physical components of the Hurler phenotype (corneal clouding, deafness, dysostosis multiplex, hepatosplenomegaly, thickened skin, hypertrichosis, stiff mitral valve on echocardiography and umbilical her- nia) were all present to a marked degree. She became blind due to a combination of glaucoma and an acute vascular occlusion affecting the retina and/or optic

12

Fig. 1 a-g. Patient 1. Mucopolysaccharidosis I/H. a and b CT sections at age 6 years. There is moderate dilatation of lateral ventricles (Evans' index 0.36) and third ventricle. Interhemispheric fissure is slightly dilated. There is ill-defined low density in deep frontal and minimally in deep parietal white matter, e---e at age 7 years 10 months. The hydrocephalus has increased (Evans' index 0.48). Dilated third ventricle extends into sella turcica; fourth ventricle is dilated. More extensive low density in frontal and parietal white matter, f Lateral skull at same age. There is scaphocephaly associated with early fusion of sagittal suture; lambdoid suture is also fused. Vault is thin due to hydrocephalus and sella is large with wide outlet consistent with pressure from dilated third ventricle. Cervical vertebrae show changes of dysostosis multiplex and atlas is closely applied to foramen magnum, g CT sections at age 8 years, 18 days after ventriculoatrial shunt. Tip of the shunt tube is in right lateral ventricle and hydrocephalus has been relieved. Abnormal low density of frontal and parietal white matter persists. Interhemispheric fissure is wider and there is small low attenuation subdural effusion on left.

nerve when she was 6 years 5 mon ths old [14]. She made a good ad ju s tmen t at a school for b l ind children. Al lowing for her mul t ip le disabilit ies her m e n - tal deve lopmen t has paral le led bu t r ema ined abou t 2 years beh ind her chronological age unt i l she was last tes ted at age 9 years 0 months . She developed bi la tera l carpal t unne l m e d i a n nerve compress ion which was successfully decompressed surgically.

The CT scan t aken when she w a s . 6 years 0 mon ths old was repea ted at age 7 years t 0 mon ths and showed a m a r k e d increase in the degree of hydrocephalus (Fig. 1). She began to compla in of headaches at abou t the t ime of t h e second examina- t ion and the skull X-ray (Fig. 1) indica ted raised in t racrania l pressure, bu t there had b e e n no change in her level of consciousness, vomit ing, fits or focal

13

Fig. 2a-c. Patient 2. Mucopolysaccharidosis, I/H. a and b are CT sections at age 23 months. There is enlargement of lateral ventricles, interhemispheric fissure and cortical sulci, and small areas of abnormal low density in white matter adjacent to lateral margin of occipital horus, more evident on left side. c lateral skull. Vault is large with thin bones and prominent lambdoid suture. Arias is closely applied to skull base. Appearances on CT and skull X-rays suggest communicating hydrocephalus

n e u r o l o g i c a l s igns, w h i c h m i g h t h a v e s u g g e s t e d t h e d e v e l o p m e n t o f h y d r o c e p h a l u s o n p u r e l y c l in ica l

s tudy . A v e n t r i c u l o a t r i a l s h u n t was i n s e r t e d a n d a

t h i rd C T scan 18 days p o s t o p e r a t i v e l y s h o w e d tha t t h e h y d r o c e p h a l u s h a d b e e n r e l i e v e d (Fig. 1). T h i s

a n a t o m i c a l i m p r o v e m e n t was m a i n t a i n e d at t h e t i m e of t h e las t e x a m i n a t i o n 14 m o n t h s l a t e r ( age 9 y e a r s

3 m o n t h s ) .

Fig. 3a--e. Patient 3, sister of Patient 4. Mucopolysaccharidosis I/H. a and b CT sections at 5 years 2 months. There is dilatation of Sylvian and interhemispheric fissures and of cortical sulci, and abnormal low density in deep white matter, most prominent in frontal lobes, c and d Similar sections at 6 years 4 months. Hy- drocephalus is more marked (Evans' index 0.48) and white matter low density has increased in extent, e lateral skull X-ray at 5 years 11 months: sagittal and lambdoid sutures are fused, coronal suture widened and sellar outlet open

14

Patient 2 (mucopolysaccharidosis IH) was referred to the Clinical Research Centre at age 13 months when she was judged to be functioning at a level corre- sponding to not more than 2 months behind her chronological age, but the physical stigmata of Hurler disease were already detectable. At age 23 months she was 75.8 cm long (< 3rd centile) weighed 10.8 kg (10-25th centile) and her skull circumference was 53 cm (> 97th centile). She died from cerebral ve- nous thrombosis complicating an acute dysenteric ill- ness when she was 2 years 8 months old. The postmortem findings confirmed the diagnosis of Hurler disease.

The CT scan and skull X-ray (Fig. 2) were made when she was 2 years 4 months old and functioning at the level of a normal 20-month-old child except that her communication and social interactions were at a more retarded level.

Patient 3 (mucopolysaccharidosis IH, sib of Pa- tient 4) was referred to the Clinical Research Centre when she was 4 years 11 months old. Her lying length was 85.9 cm (< 3rd centile), weight 16.0 kg (10-25th centile) skull circumference 56 cm (> 90th centile) and she showed all the classical stigmata of mucopolysaccharidosis IH.

Her overall functional level was assessed as cor- responding to that of a normal 18-24-month-old child except that her communicative and social interactive skills corresponded to a lower age than this and could not be assessed. She had begun to retrogress before she was referred and this has con- tinued until, by the age of 7 years 2 months, she was mute, apathetic and lacking in all purposive activity.

The two CT scans (Fig. 3) were made when she was 5 years 2 months and 6 years 4 months old. Hydrocephalic changes and white matter low density had increased during the intervening period. A ventriculoatrial shunt was not recommended in this case because of her low level of attainment initially and the severe degree of retrogression that had occurred.

Patient 4 (mucopolysaccharidosis IH, sib of Pa- tient 3) was referred to the Clinical Research Centre when she was 2 years 2 months old. At age 2 years 5 months her lying length was 78.9 cm (3rd centile), her weight was 12.3 kg (25th centile) and her head circumference was 51.5cm (> 97th centile). She showed all of the classical features of mucopolysaccharidosis IH although to a lesser degree than her sister. Her overall level of function was assessed as being at about the 2-year-old level except for communication and social interactions which were assessed at being no more than appropriate to a normal 1- year-old. She made some developmental progress so

that at chronological age 4 years 10 months her overall level of function was at about the 21/2-3 year level with verbal comprehension and expressive language scores at the 2-year level having been static for 6 months. CT and skull X-rays (Fig. 4) were made when she was 2 years 6 months, 3 years 10 months, 4 years 1 month, and 5 years old. The last two of these being after the insertion of a ventriculoatrial shunt because hydrocephalus had developed between the first and second scans.

Patient 5 (mucopolysaccharidosis IH) was referred to the Clinical Research Centre when she was 9 months old and her overall functional level was assessed as 7 months. At that time the degree of apparent retardation could have been contributed to by a somewhat deprived social background. She was 67 cm long (10th centile) and weighed 7.05 kg (<10th centile). Her physiognomy suggested, but was not diagnostic of, Hurler disease and her head circumference was 45 cm (50th centile). She had hepatosplenomegaly (liver edge 3 cm below costal margin, spleen tip just palpable), and skeletal changes of dysostosis multiplex were demonstrable radiologically. CT and skull X-rays (Fig. 5) were made when she was 11, 16 and 25 months old. The circumference of her head had increased to 49 cm (75th centile) by age 28 months. Her clinical condition and developmental level did not change appreciably between ages 9 and 11 months, but by 16 months the clinical manifestations of the Hurler disease phenotype were obvious and she had made little progress developmentally. Her most recent assessments, when she was 2 years old, showed that she was then functioning overall at a 9 month to 1 year level with communication skills at only the 3-4-month level.

Patient 6 (mucopolysaccharidosis II) was first seen for a genetic consultation at age i year 8 months well before the clinical trial was being planned and when the physical findings were compatible with a diagnosis of Hunter disease [height 82.5 cm (10-25th centile); weight 13.9 kg (75-90th centile); head circumference 52.3 cm (> 97th centile)]; but he was' not thought to be grossly retarded. His mother had an affected child by her previous marriage. The patient was seen again at age 4 years 8 months when the clinical and radiological features of Hunter disease were more marked than on the previous occa- sion, growth had slowed [height 102.6 cm (10-25th centile), weight 21.7kg (90-97th centile)] and macrocrania was increasing with a head circumference of 55 cm (> 97th centile). His overall function was assessed at the 2 year level with verbal corn-

15

Fig. 4a--d. Patient 4, sister of Patient 3. Mucopolysaccharidosis I /H. CT scan at 2 years 6 months was normal. a lateral skull X-ray at 3 years 3 months shows vault enlarged and widening of coronal and lambdoid sutures, b CT at 3 years 10 months shows dilatation of lateral ventricles; cerebral substance appears normal. c and d CT sections at age 5 years, 1 year after insertion of ventricnlo- atrial shunt into right lateral ventricle. Hydrocephalus has been relieved. There is slight widening of interhemispheric fissure. The density of parietal white mat ter is prominent and probably abnormal

prehension and expressive language scores at the 2 year 2 month, and 2 year 3 month levels. CT scans (Fig. 6) were made when he was 4 years 10 months and 5 years 11 months old, the overall functional level remaining unchanged at about 2 years. Com- prehension and expressive language were also assessed as being at about the 2-year level when he was 5 years 11 months old.

Patient 7 (mucopolysaccharidosis II) was referred to the Clinical Research Centre when he was 3 years 6 months old. He had the classical physical and radiological features of Hunter disease, was 101.5 cm tall (75th centile), weighed 20.1 kg (75-90th centile) and had a head circumference of 52 cm (97th centile). His mother's brother had died when he was 24 years old after a prolonged period of progressively increasing mental handicap and with physical features compatible with a diagnosis of Hunter disease. CT scans (Fig. 7) were made at ages 3 years

7 months, and 4 years 7 months. At the time of the first scan the patient's overall function was assessed at "only a little below his chronological age but with marked deficiency in the area of communication". Although his mother reported developmental progress one year later when the second scan was made, there was no objective evidence of this, his overall functional level being assessed at the 21/2-3 year old level with expressive speech at the 13-month-old level. The physical findings were essentially unchanged except for some overall growth [height 105.4 cm (50th centile), weight 23.3 kg (> 97th centile)] and an increase in head circumference to 53 cm (> 97th centile).

Patient 8 (mucopolysaccharidosis IH/S). This girl was referred to the Clinical Research Centre at age 5 years 3 months because of stiffness of all the joints of the upper and lower limbs. She was 93.4 cm tall (< 3rd centile), weighed 15.4 kg (10th centile) and

16

Fig. 5a-f. Patient 5. Mucopolysaccharidosis I/H. a and b CT sections at age 16 months show slight widening of left trigone, anterior part of interhemispheric fissure prominent, and cerebral substance normal. Skull X-ray e AP and d lateral projections at 2 years of age show fusion of lambdoid and sagittal sutures and scaphocephaly. The coronal suture is markedly widened and sellar outlet is wide. Appearances indicate raised intracranial pressure and suggest that hydrocephalus has developed, e and f CT sections at levels similar to a and b at age 2 years 1 month. There has been minor increase in size of lateral ventricles and slightly diminished attenuation in deep parietal white matter

he r h e a d c i r cumfe rence was 53 cm ( > 97 th cent i le) . H e r in te l l ec tua l a t t a i nmen t s were a p p r o p r i a t e for he r age, as were he r func t iona l abi l i t ies excep t whe re these were l imi ted by the a r th ropa thy . T h e type of jo in t de fo rmi ty r e s e m b l e d tha t seen in H u r l e r disease. She had a mi ld d e g r e e of m ic rogna th i a and her p h y s i o g n o m y did no t suggest a d iagnos is of H u r l e r d isease , a l though she had o t h e r typica l f ea tu res of the H u r l e r d i sease p h e n o t y p e . This c o m b i n a t i o n of well p r e s e r v e d in te l lec t wi th m a r k e d jo in t and viscera l

i n v o l v e m e n t at an ear ly age is c o m p a t i b l e with a d iag- nosis of H u r l e r / S c h e i e d i sease (mucopo lysac - char idos is I H / S ) . The a p p a r e n t b iochemica l a b n o r - mal i t ies a re the same in all t h r e e of the inhe r i t ed a - i du ron idase def ic iency s y n d r o m e s (Tab le 1) and were p re sen t in this pa t ien t . C T scans (Fig. 8) were m a d e at age 5 yea r s 2 months , 6 years 2 months , and 6 years 6 months . T h e pa t i en t ' s men ta l d e v e l o p m e n t had con t inued n o r m a l l y b e t w e e n the e xa mina t i ons and she had grown [height 102 cm ( < 3rd cent i le ) ,

17

Fig. 6 a and b. Patient 6. Mucopolysaccharidosis II. a CT at age 4 years 10 months. There is dilatation of lateral ventricles (Evans' index 0.33), widening of interhemispheric fissure and, to a minor degree, of cortical sulci, b CT scan at 5 years 11 months. Hy- drocephalus has increased (Evans' index 0.40) and interhemispheric fissure and cortical sulci have widened further

Fig. 8a and b. Patient 8. Mucopolysaccharidosis I H/S. a and b CT at age 6 years 2 months. There is abnormal low density in parietal white matter; ventricular system and intracranial subarachnoid spaces are normal

Fig. 7a and b. Patient 7. Mucopolysaccharidosis II. a Normal CT scan at 3 years 7 months of age. b Similar section at age 4 years 7 months. Density of deep parietal white matter is abnormally low

Fig, 9a and b. Patient 9. Mucopolysaccharidosis I H/S. a and b CT at age 3 years 9 months. There is abnormal low density in parietal and deep frontal white matter; ventricles are normal but Sylvian fissures are slightly prominent

weight 16 kg ( < 3 rd cen t i l e ) ] bu t t he re had been no fu r the r e n l a r g e m e n t of the head . H e r ma in dis- abi l i t ies were still a s soc ia t ed with stiffness of the jo in t s and deafness ; the l a t t e r had i m p r o v e d af te r a m y r i n g o t o m y and inse r t ion of g rommets . She had recen t ly c o m p l a i n e d of pa in r ad ia t ing f rom the cervical sp ine to the shou lde r r eg ion on bo th s ides and a l though t h e r e we re no ob jec t ive a b n o r m a l sensory signs and the t e n d o n ref lexes in the a rms were no t pa tho log i ca l l y br isk , she had d e v e l o p e d a f inger j e r k and the k n e e and ank le j e rks were e x a g g e r a t e d a l though the p l an t a r r e sponses were f lexor . T h e s e changes suggest the beg inn ing of cervical co rd com- p re s s ion assoc ia ted with e x t r a d u r a l and du ra l m u c o p o l y s a c c h a r i d e depos i t s as occu r r ed in Pa- t ien t 10.

P a t i e n t 9 (mucopo lysaccha r idos i s / H / S ) . This b o y was r e f e r r ed at age 3 years 9 months . T h e ma in com- p la in ts were stiffness and de fo rmi ty of his f ingers and d e v e l o p m e n t a l delay. H e had heavy bu t no t typica l ly H u r l e r - l i k e facial fea tures . The o t h e r p h e n o t y p i c man i fe s t a t ions were s imi lar to those e n c o u n t e r e d in H u r l e r d i sease bu t to a r e la t ive ly mi ld degree . His he igh t was 9 2 . 2 c m (3rd cent i le) weight 1 5 . 2 k g ( 2 5 t h - 5 0 t h cent i le) and h e a d c i r cumfe rence 54.5 cm (97th cent i le) . T h e b iochemica l f indings were those which are c o m m o n to all of the a - i d u r o n i d a s e def i - c iency mucopo lysaccha r idose s . CT scan was o b t a i n e d at age 3 years 9 months , when his overa l l func t iona l level was assessed at the 2 yea r 6 m o n t h o ld level , with c o m p r e h e n s i v e and express ive l anguage bo th at the 2 yea r 1 m o n t h o ld level , This pa t i en t had also

18

Fig. 10a and b. Patient 10. Mucopolysaccharidosis IS. a and b CT at age 20 years. There is slight dilatation of lateral ventricles; third and fourth ventricles are normal. There is marked widening of subarachnoid space anterior to left temporal lobe suggesting small arachnoid cyst and less marked widening in similar position on right side. Suprasellar cisterns apparently extend into upper part of sella turcica, which was abnormally deep on plain X-rays

Fig. l l a and b° Patient 10. Myelogram a lateral, b oblique projections. Metal tracheostomy tube obscured contrast medium in AP position. Cervical subarachnoid space is narrowed and there is "increase in distance between it and adjacent bony canal due to thickening of meninges. Mid and upper cervical nerve root sheaths are occluded

had congenital posterior urethral valves which were treated by diathermy when he was 3 years old. Although the obstruction to the outflow of urine had been relieved he was left with bilateral hydro- nephrosis.

Patient 10 (mucopolysaccharidosis Type IS). This man (age 20 years 10 months) was referred as a case of Scheie disease; the diagnosis had been made on clinical and enzymological grounds elsewhere and we confirmed the latter. This patient presented particular problems of clinical classification which are discussed later. H e complained of stiffness in all his joints and gross difficulty in walking. He had also had attacks of severe sleep apnoea necessitating a tracheostomy. The presenting symptoms had been stiffness in the hands and an abnormal gait when he was about 4 years old and his disability had increased so that when he was referred to us he had bilateral claw hands and could walk only about 20 yards. H e was 143 cm tail, weighed 35.5 kg with a skull circumference of 57.5 cm (97th centile) and skeletal abnormalities which were not entirely characteristic of dysostosis multiplex. H e had heavy but not specifically Hurler-l ike features, corneal clouding, micro- gnathia, cardiac systolic and diastolic murmurs (the echoeardiogram suggested mild aortic stenosis) and hepatosplenomegaly. The results of pulmonary func-

tion tests indicated a severe restrictive defect. The physical signs of spinal cord compression at the C5-C 6 level, and of bilateral median nerve compression in the carpal tunnel, were present. His intellect was normal. The CTs and myelograms are shown in Fig- ures 10 and 11. The patient had an older brother with the disease who had died following an aortic and mitral valve replacement operation.

Patient 11 (mucopolysaccharidosis I I IB) was referred at age 10 days. The diagnosis had been made in utero

at the 16th week of pregnancy, and the mother had subsequently changed her mind about having the pregnancy terminated. Clinically the patient was a normal baby, but the absence of N-acetyl -a-D- glucosaminidase confirmed the prenatal diagnosis. He r length, weight and head circumferance were: 51cm, 3 .22kg, and 3 6 c m (all 50-90th centile) respectively. CT scans (Fig. 12) were made at age 6 weeks, and 6 months. She was clinically normal when the second scan was made except for a large head with prominent frontal bossing and open anterior fontanelle (circumference 46.8 cm; > 95th centile) and a palpable liver edge 2 cm below the right costal margin.

Patient 12 (mucopolysaccharidosis I I IB, brother of Patient 11) had been a normal full term baby but developmental delay had been apparent to the

19

Fig. 12a and b. Patient 11. sister of Patient 12. Mucopolysac- charidosis IIIB. a, b CT at 6 months of age, following intravenous contrast medium. All deep hemispheric white matter is prominent but is only below normal range of variation in parietal lobes. Ven- tricular system and intracranial subarachnoid spaces are normal

Fig. 13a and b. Patient 12, brother of Patient 11. Mucopolysac- charidosis IIIB. a and b CT at age 7 years 2 months. Ventricular system and intracranial subarachnoid spaces are enlarged

Fig. 14a and b. Mucopolysaccharidosis VI. a and b CT shows abnormal low density throughout frontal and parietal white matter. Ventricular system is dilated due to communicating hydrocephalus. Right lateral ventricle is larger than left, especially right frontal horn. There is more extensive low density anteriorly in right frontal lobe; right side of frontal bone is expanded. These additional findings are due to surgery performed for a suprasellar arachnoid cyst which has recurred and is enlarging sella

Fig. 15. Mucopolysaccharidosis IIIB. There is well-defined low attenuation in left lentiform nucleus consistent with brain destruction following previous infarct. Left Sylvian fissure is relatively wide due to some adjacent atrophy

parents by age 2 years and retrogression from about 41/2 years. When seen by us at age 7 years 2 months just before the CT scan (Fig. 13), he was a very hyperkinetic, whining child with aggressive tenden- cies and short attention span, who showed virtually no interaction with other children or the staff although he recognised his mother. He was 112 cm tall (3rd-10th centile), weighed 23.4 kg (50th centile), and his skull circumference was 57 cm (> 97th centile). The main physical findings were coarse but not specifically Hurler-l ike facial features, moderate generalised hypertrichosis, restricted abduction at the shoulder joints, limited supination of the fore- arms, hepatomegaly (liver edge palpable 3.5 cm

below the right costal margin), a systolic murmur at the cardiac apex and brisk deep tendon reflexes with flexor plantar responses.

Results

The results of the CT examinations and skull radiographs are summarised in Table 2 and in Fig- ures 1-10, 12 and 13. Figure 11 shows the cervical myelogram of Patient 10.

Figures 14 and 15 are CT scans of two patients who do not belong to the main series. These scans show certain additional features which have also been encountered in the mucopolysaccharidoses.

2O

Table 2. Results of computed tomography and skull X-rays [Zero (0) = negative finding. Dash (-) -- no observation made.]

Case Type Age Computed Tomogram Skull y m Hydrocephalus White matter Raised pressure Other Changes

(Evans' Low density Large Wide Cranio- index a) (40) skull suture b stenosis b Sella

1 IH

2 IH

3 IH

4 IH

5 IH

6 II

7 II

8 IH/S

9 IH/S

10 dis

11 IIIB

12 IIIB

6 0 + +(0.36) + +F&P c + 0 +(S) + 7 10 + + + ( 0 . 4 8 ) + + + + 0 +(S) + + 8 0 0(after shunt) + + . . . .

2 4 +(0.3) +P + + (L/C) 0 0

5 2 + +(0.36) + F&P + 0 +(S/L) + 6 4 + + + (0.48) + + F&P + + (C) + (S/L) +

2 6 0 0 . . . . 3 3 - - + + 0 + 3 10 +(0.33) 0 + + + 0 0 4 1 0(after shunt) 0 . . . . 5 0 0 +P + 0 0 0

0 11 0 0 . . . . 1 4 0 0 . . . . 2 0 - - + + + (C) + (S/L) + 2 1 +(0.30) + P . . . .

4 10 +(0.33) 0 . . . . 5 11 + + + ( 0 . 4 0 ) 0 0 0 +(S/L/C) 0

3 7 0 ? P 0 0 + (S) 0 4 7 0 + P . . . .

5 2 0 + P . . . . 6 2 0 + + P . . . . 6 6 0 + + P 0 0 +(S) +

3 9 0 + P&F 0 0 0 0

20 10 +(0.30) 0 0 0 +(S/L/C) + Empty

0 1'/2 0 + P . . . . 0 6 0 + P 0 0 + (S/L/C) +

7 2 + + (0.37) 0 0 0 0 0

a Maximum width of frontal horns/maximum width between inner tables b C=coronal; L=lambdoid; S=sagittal c F=frontal, P=parietal d See text for further discussion of the classification of this patient as either Type IS or IH/S. The present investigations showed a left temporal arachnoid cyst and an empty sella. Myelography showed thick spinal dura

D i s c u s s i o n

T h e i n t e r p l a y of t h e e f fec t s of n e u r o n a l d a m a g e by

l y s o s o m e s d i s t e n d e d w i t h m u c o p o l y s a c c h a r i d e s a n d

g lyco l ip ids , c e r e b r a l a t r o p h y a n d o b s t r u c t i o n to t h e

C S F c i r c u l a t i o n d e t e r m i n e s t h e c e r e b r a l m a n i f e s t a - t i ons o f t h e m u c o p o l y s a c c h a r i d o s e s .

T h o s e d i seases in wh ich t h e r e is a l ack of a - i d u r o n i d a s e ac t iv i ty ( m u c o p o l y s a c c h a r i d o s e s I H , IS

a n d I H / S ) can p r e s e n t m o r e d i f f icu l t p r o b l e m s in c l in ica l d i agnos i s t h a n t h e u sua l d e s c r i p t i o n s sugges t .

In t he i r fu l ly d e v e l o p e d f o r m s , H u r l e r [15] and

S c h e i e [16] d i seases a r e v e r y d i f f e r e n t f r o m o n e a n o t h e r . T h e y b r e e d t r u e w i th in f ami l i e s a n d a re p r e - s u m a b l y d u e to a l le l ic m u t a t i o n s . T h e s ta tus of

H u r l e r / S c h e i e d i s ea se is less c lear . I t has b e e n w i d e l y

p r o p o s e d as b e i n g d u e to d o u b l e h e t e r o z y g o s i t y fo r t h e m u t a n t g e n e s w h i c h c a u s e H u r l e r a n d S c h e i e dis-

eases , a l t h o u g h it c o u l d r e p r e s e n t h o m o z y g o s i t y fo r a t h i rd a l le l ic m u t a t i o n at t h e a - i d u r o n i d a s e g e n e locus

[17, 18]. T h e r e is, h o w e v e r , c o n s i d e r a b l e c l in ica l

h e t e r o g e n e i t y w i th in t h e c l in ica l spec t r a of all t h r e e

d i seases a n d t h e e x t e n t to w h i c h this is g e n e t i c a n d n o n - g e n e t i c is u n k n o w n .

C e r v i c a l p a c h y m e n i n g i t i s a n d m e d i a n n e r v e c o m -

p r e s s i o n in t h e c a r p a l t u n n e l w e r e m a j o r f ac to r s in

d e t e r m i n i n g t h e p h e n o t y p e in P a t i e n t 10, w h o was

o r ig ina l l y c lass i f ied as h a v i n g S c h e i e d i s ea se o n t h e basis of n o r m a l i n t e l l ec t a n d a b s e n t a - i d u r o n i d a s e ac t iv i ty . H o w e v e r , h e h a d m a j o r s y s t e m i c a n d v is -

21

ceral abnormalities attributable to his metabolic lesion and it could be argued that he would be more accurately classified as having Hurler/Scheie disease. The physical signs suggest that cervical cord compression may also be beginning in Patient 8, who is classified as having Hurler/Scheie disease on the grounds of the severe systemic involvement, although unlike Patient 9, another case of Hurler/Scheie disease, she is not mentally handicapped. Consideration of these three cases and those reported in the litera- ture [19-25] shows that clinically Hurler/Scheie and Scheie diseases should be regarded as forming a con- tinuum, and unless biochemical differences can be found by more refined techniques than have been used heretofore, there seems little justification for separating them completely.

Spinal cord compression in the mucopolysaccharidoses can be due to several mechanisms. It has been caused by atlantoaxial subluxation in Morquio disease [26], and in Maroteaux-Lamy disease [27]. Such subluxation is generally associated with laxity of the transverse odontoid ligament but in four of the cases of Blaw and Langer [26] there was also either hypoplasia or absence of the odontoid process. Gib- bus formation, which is most marked in Morquio disease, may cause thoracic cord compression [26]. Dural thickening by abnormal deposition of collagen, causing changes identical to those in Patient 10, have been described in Maroteaux-Lamy and Hurler/ Scheie diseases [28, 29]. The importance of recognis- ing these surgically correctable causes of cord compression is apparent, but marked constriction of the cervical theca may also influence the development of hydrocephalus in the mucopolysaccharidoses. The thecal changes may be visible on CT, especially using 4th generation scanners, and if such patients are sub- mitted to head scanning, inclusion of a section through the cervical cord is suggested.

Mucopolysaccharides and glycolipids must have been present within the nerve cells of our cases, but on CT the density of grey matter was similar to that of normal brain. Inhaled xenon crosses the normal blood-brain barrier and is lipid soluble; because of the energy of its K-shell electron, it causes consider- able enhancement of the images of the brain substance [30], but there is no detectable difference between the enhancement of normal brain and of the abnormal tissue in the mucopolysaccharidoses; also, the blood-brain barrier behaves normally to intravenous contrast medium.

Symmetrical low attenuation in the white matter was seen in nine of our cases; such low density generally indicates increased water content. Three of these patients, all with mucopolysaccharidoses IH, had marked communicating hydrocephalus and in two of

them the low attenuation, in being more marked around the dilated frontal horns, simulated that due to hydrocephalus [31]. It was, however, unusually extensive for this alone and in one of these cases in which a successful ventricular drainage system was inserted, it resolved only partly (Patient 1), and in another (Patient 4) it first developed in the presence of a functioning shunt (Table 2). It occurred in all types of mucopolysaccharidosis in this series except in Patient 10 and we have seen it in mucopolysaccharidosis VI also (Fig. 14). The low density, though often more pronounced adjacent to the ventricles, extended well laterally. The parietal white matter was involved in all cases, and the frontal region also in two. The latter was affected earlier in one of these. It would correlate well with the pitting and cavitation around blood vessels which is visible at autopsy on the cut surface of the white matter in Hurler disease [32] due to concentrations of foam cells within some of the Virchow-Robin spaces [25]. Dekaban and Constantopoulos [33], who differentiate clearly between the parenchymal and leptomeningeal lesions in Hurler disease, also describe greatly dilated periad- ventitial spaces filled with viscous fluid, "gargoyl cells" and mesenchymal elements. This fluid would explain the similarity between the low attenuation of the white matter seen in some of our cases and cerebral oedema. Patient 10 did not show changes i'n the white matter and this would correspond to the repor- tedly less severe leptomeningeal changes in Scheie disease than in Hurler disease [34]. These workers also report that the neuronal changes seen in Hurler disease are absent in Scheie disease. In Sanfilippo A disease also, the nerve damage by mucopolysaccharide and sphingolipid engorgement is accompanied by dilatation of the perivascular spaces in the white matter by mucopolysaccharides [5, 35, 36].

There are several possible reasons for enlargement of the head in the mucopolysaccharidoses. The bones of the vault may be thickened by mucopolysaccharide deposits. Such thickening is evident on skull radiography and on CT, but it was not a pronounced feature in any of our patients. Thickening of the vault may also occur due to deposition of bone on the inner table following relief of hydrocephalus, and this was seen in two of our cases. Remodelling of bone is abnormal in the skull as well as in other bones and may contribute to the abnormal shape of the head. Accumulation of mucopolysaccharides within the meninges and brain substance increases the volume of the intracranial contents. Thickening of the cerebral meninges sufficient to cause enlargement of the head would be revealed by CT but it was not evident in this series. Leptomeningeal cysts are important determinants of the characteristic abnormalities in

22

the sphenoid, especially in the pituitary fossa region [37].

Distention of brain substance may enlarge the brain sufficiently to expand the skull, but growth of the head from this factor alone is slow and unlikely to separate the sutures. Should atrophy occur in such cases, an enlarged vault could be associated with widened intracranial CSF spaces. There was some widening of the Sylvian, and sometimes of the interhemispheric fissures or cortical sulci in ten of our patients. This was usually accompanied by other evidence of raised intracranial pressure.

The presence of moderately severe communicating hydrocephalus, which was unsuspected before CT in three of the cases, and its marked progression over a period of two years in two of them, emphasises the importance of this investigation in the assessment of such patients. The slightly enlarged ventricles in two other cases with widened sutures on plain skull X- rays also strongly suggest communicating hydrocephalus. In one case (Patient 4) aged 21/: years the scan was normal, but the cranial sutures were splayed on the plain skull films and the head was enlarged suggesting raised intracranial pressure. Her 4-year-old sister had manifest communicating hydrocephalus on CT and the younger child subsequently developed it (Figs. 3 and 4). Any difficulty in distinction between atrophy and communicating hydrocephalus can usually be resolved by subsequent CT as in Patient 6. Examination of CSF dynamics using intrathecal indicators such as RHISA or metrizamide may be helpful if a more immediate decision regarding the shunt procedure is necessary.

Although hydrocephalus is a well known autopsy finding in the mucopolysaccharidoses, there have not been, to our knowledge, any studies which have indicated the stage in the evolution of the disease at which it begins. Our observations show this to be very variable, but it can occur early and therefore materially modify the overall prognosis. Ven- triculoatrial shunting operations are only a palliative in this group of diseases, but they are, in our opinion, justified in order to improve the prospect for the immediate quality of life. This is likely to be the case if the hydrocephalus is known to be of recent onset, if the child's overall level of function is relatively well preserved, and if the development of the hydrocephalus has been associated with sudden deterioration or symptoms, such as severe headaches, specifically related to it.

The value of CT in the elucidation of acute cerebral deterioration in general is well established, and it might have allowed antemortem diagnosis in the patient who died from an incidental sagittal sinus thrombosis though the clinical course would probably not have been modified by this knowledge.

There were no other abnormal findings in our series of patients, but we have seen the value of CT in showing other lesions in patients with mucopolysaccharidoses, not included in this series. Examples include a recurrent suprasellar arachnoid cyst associated with communicating hydrocephalus in a patient with Maroteaux-Lamy disease (Fig. 14), and left hemiatrophy with a cavity low in the left putamen in another patient with Sanfilippo B disease and a pre- viously confusing clinical picture which included wasting of the right leg and grand mal convulsions (Fig. 15).

Acknowledgements. We are pleased to acknowledge the following who kindly referred patients to us: Dr. Barbara Ansell, (North- wick Park Hospital, Harrow) Dr. E. M. Carr-Saunders (Cumber- land Infirmary, Carlisle), Dr. P. F. Deasy (Our Lady's Hospital for Sick Children, Dublin), Dr. D. W. Fielding (Chester City Hospital, Chester), Dr. J. L, Greaves (Royal Hampshire County Hospital, Winchester), Dr. S. H. Green (Lea Castle Hospital, Wolverley), Dr. R. Lindop (Manor Hospital, Walsall), Dr. A.J. O'Donnell (The Health Centre, Steyning), Dr. K. Prowse (City General Hos- pital, Stoke-on-Trent), Dr. D. G. H. Stone (Royal Berkshire Hos- pital, Reading). We are greatly indebted to the sisters and nursing staff of Cavendish and Haldane Wards of Northwick Park Hospi- tal, and to the Occupational Therapists, Physiotherapists and Speech Therapists for their work in the management and assessment of these patients. We are most grateful to many colleagues who have advised us on the management of various complications which have arisen in these children in particular: Dr. B. Ansell, Mr. R. Auerbach, Mr. J. L. Kennerley Bankes, Mr. H. B. Eckstein, Mr. A. Kark, Mr. L. Klenerman, Dr. T.E. Stacey and Dr. H. B. Valman. Dr. P. Rudge generously allowed us to admit patients, who required temporary admission for CT scanning, to his beds at the National Hospital for Nervous Diseases. These investigations were approved by the Ethical Committees of North- wick Park Hospital and Clinical Research Centre and the National Hospital for Nervous Diseases.

References

1. Purpura DP, Suzuki K (1976) Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease. Brain Res 116:1-21

2. McKusick VA, Neufeld EF, Kelly TE (1978) The mucopolysaccharide storage dieseases. In: Stanbury JB, Wyngaarden JB, Fredrickson DS (eds) The metabolic basis of inherited diseases. 4th ed. McGraw-Hill, New York

3. Dorfman A, Matalon R (1972) The mucopolysaccharidoses. In: Stanbury JB, Wyngaarden JB, Fredrickson DS (eds). The metabolic basis of inherited disease. 3rd ed. McGraw-Hill, New York

4. Doshi R, Sandry SA, Churchill AW, Brownell B (1974) The cerebellum in mucopolysaecharidosis. A histological, histochemical and ultra-structural study. J Neurol Neurosurg Psychiatry 37:1133-1138

5. Kriel RL, Hauser WA, Sung JH, Posalaky Z (1978) Neuroanatomical and electroencephalographic correlations in Sanfilippo Syndrome, Type A. Arch Neurol 35:838-843

6. Gibbs DA, Spellacy E, Roberts AE, Watts RWE (1977) Pro- gress report on the treatment of Hurler's disease by enzyme replacement therapy. Glycoconjugate Res 2 :885-888

7. Gibbs DA, Spellacy E, Roberts AE, Watts RWE (1980) The treatment of lysosomal storage diseases by fibroblast transplantation: some preliminary observations. Birth Defects 16: 457-474

8. Dean MF, Stevens RL, Muir H, Benson PF, Button LR, Anderson RL, Boylston A, Mowbray J (1979) Enzyme replacement therapy by fibroblast transplantation. J Clin Invest 63:138-145

9. Hall CW, Neufeld EF (1973) a-L-Iduronidase activity in cul- tured skin fibroblasts and amniotic fluid cells. Arch Biochem Biophys 158:817-821

10. Hall CW, Liebaers I, Di Natale P, Neufeld EF (1978) Enzy- matic diagnosis of the genetic mucopoly saccharide storage disorders. Methods Enzymol 50:439-456

11. Pennock CA (1976) A review and selection of simple labora- tory methods used for the study of glycosaminoglycan excretion and the diagnosis of mucopolysaccharidoses. J Clin Pathol 29:111-123

12. Humel R, Chamoles NA (1972) Sequential thin layer chromatography of urinary acid glycosaminoglycans. Clin Chim Acta 40:290-293

13. Westrupp CK, Barber CR (1956) Growth of skull in young children. I. Standards of head circumference. J Neurol Neurosurg Psychiatry 19:52-56

14. Spellacy E, Kennerley, Bankes JL, Crow J, Dourmashkin R, Shah D, Watts RWE (1980) Glaucoma in a case of Hurler disease. Br J Ophthalmol 64:773-778

15. Hurler G (1919) ~ber einen Typ multipler Abartungen, vor- wiegend am Skelettsystem. Z Kinderheilkd 24:220-234

16. Scheie HG, Hambrick GW Jr, Barness LA (1962) A newly reeognised forme fruste of Hurler's disease (gargoylism). Am J Ophthalmol 53:753-769

17. Fortuin JJH, Kleijer WJ (1980) Hybridization studies of fibroblasts from Hurler, Scheie and Hurler/Scheie compound patients. Support for the hypothesis of allelic mutants. Hum Genet 53:155-159

18. Kaibara N, Eguchi M, Shibata K, Takagishi K (1979) Hurler- Scheie phenotype: a report of two pairs of inbred sibs. Hum Genet 53:37-41

19. Danes BS (1977) Variant of iduronidase deficient mucopolysaccharidoses. Further evidence for genetic heterogeneity. J Med Genet 14:246--351

20. Elliot DE, Dorst JP (1974) Mucopolysaceharidoses: possible Hurler/Scheie genetic coumpound (MPS 1-H/S). Birth Defects 10:453-457

21. Kajii T, Matsuda I, Ohsawa T, Katsunum H, Ichida T, Arashima S (1974) Hurler/Scheie genetic compound (mucopolysaccharidosis IH/S) in Japanese brothers. Clin Genet 6:394-400

22. Leisti J, Rimoin DL, Kaback M, Shapiro LJ, Matalon R (1976) Allelic mutations in the mucopolysaccharidoses. Birth Defects 12:81-91

23. Thompson JN, Finley SC, Lorinez AE, Finley WH (1975) Absence of a-L-iduronidase activity in various tissues from two sibs affected with presumbly the Hurler-Scheie compound syndrome. Birth Defects 11:341-346

24. Tondeur M, Vamos-Hurwitz E, Cantz M, Cremer N, Libert J, Pardou A (1976) Clinical, ultrastructural and tissue culture studies in a possible compound Hurler-Scheie case. Aeta Paediatr Belg 29:109-115

25. Winters PR, Harrod MJ, Molenich-Heetred SA, Kirkpatrick J, Rosenberg RG (1976) a-L-iduronidase deficiency and possible Hurler-Scheie genetic compound. Neurology 26: 1003-1007

23

26. Blaw ME, Langer LO (1969) Spinal cord compression in Mor- quio-Brailsford's disease. J Paediatr 74:592-700

27, McKusick VA (1972) Heritable disorders of connective tissue. 4th ed. Mosby, St. Louis, pp 524-686

28. Sostrin RD, Hasso AN, Peterson DI, Thompson JR (1977) Myelographic features of mucopolysaccharidosis: A new sign. Radiology 125:421-424

29. Kennedy P, Swash M, Dean MF (1972) Cervical cord compression in mucopolysaccharidoses. Dev Med Child Neurol 15:194-199

30. Kendall BE, Radii EW, Zilkha E (1978) Xenon enhancement in computed tomography. Xtraet 4 :7 -12

31. Moseley IF, Radii EW (1979) Factors influencing the development of periventricular lucencies in patients with raised intracranial pressure. Neuroradiology 17:65-70

32. Crome L, Stern J (1972) Pathology of mental retardation. 4thed. Churchill Livingstone, Edinburgh London, pp 320-324

33. Dekaban AS, Constantopoulos G (1977) Mucopolysacchari- doses types I, II, IIIA and IV. Pathological and biochemical abnormalities in the neural and mesenchymal elements of the brain. Acta Neuropathol (Berl) 39 :1-7

34. Dekaban AS, Constantopoulos G, Herman M, Steussing JK (1976) Mucopolysaccharidosis Type V (Scheie syndrome). A postmortem study by multidisciplinary techniques with emphasis on the brain. Arch Pathol Lab Med 100:237-245

35. Witting C, Miiller KM, Kresse H, von Figura K, Marx H (1975) Morphological and biochemical findings in a case of mucopolysaccharidosis type IIIA. (Sanfilippo disease type A). Beitr Pathol 154:324-338

36. Cain H, Egner E, Kresse H (1977) Mucopolysaccharidosis IIIA (Sanfilippo Disease Type A). Histochemical, electron microscopical and biochemical findings. Beitr Pathol 160: 58-72

37. Neuhauser EBD, Griscom NT, Gilles FH, Cricker AC (1967) Arachnoid cysts in the Hurler-Hunter syndrome. Ann Radiol 11:434-469

38. McKusick VA, Kaplan D, Wise D, Hanley WD, Suddarth SD, Sevick ME, Maumenee AW (1965) The genetic mucopolysaccharidoses. Medicine 44:445-483

39. Van Hoof F (1974) Mucopolysaccharidoses and mucolipi- doses. J Clin Pathol [Suppl] 8 :1-11

40. Evans WA (1942) An encephalographic ratio for estimating ventricular enlargement and cerebral atrophy. Arch Neurol Psychiatry 47:931-937

41. McKusick VA (1980) Genetic heterogeneity and allelic variation in the mucopolysaccharidoses. Johns Hopkins Medical Journal 146:71-79

42. Kresse H Paschke G, Figura K, Gilberg W, Fuchs W (1980) Sanfilippo disease type D: Deficiency of N-acetylglucosamine -6-sulphate sulphatase required for heparan sulphate degradation Proc Natl Acad Sci USA 77:6822-6826

Received: 28 October 1980

Dr. R. W. E. Watts Division of Inherited Metabolic Diseases Medical Research Council Clinical Research Centre Watford Road, Harrow Middlesex, HA1 3UJ England

Note Added in Proof

"An indium-DTPA intrathecal scan was performed on Patient 6 at age 6 years 8 months. The isotope had entered the dilated lateral ventricles and basal cisterns half an hour after it had been injected into the lumbar theea, and even after 24 hours there was very little isotope over the vertex although isotope was present in the lateral ventricles. These changes show that communicating hydrocephalus was the major abnormality and presumably reflect involvement of the Pachionian granulations in the abnormal storage process.

Computed tomography studies on patients with mucopolysaccharidoses

Documents

Transcript of Computed tomography studies on patients with mucopolysaccharidoses