HOMOCYSTINURIA: A REPORT IN TWO SIBLINGS Charles Kennedy, Vivian E. Shih and Lewis P.

Rowland Pediatrics 1965;36;736

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/36/5/736

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1965 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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HOMOCYSTINURIA:
Charles
Childrens Medicine, Neurological

A REPORT
Vivian
and

IN TWO
and
of Clinical

SIBLINGS
P. Rowland,
and Neurology, Center York) and of the

Kennedy,
Hospital of University

M.D.,
Philadelphia of Institute,

E. Shih,
the Departments

M.D.,

Lewis
Research (New

M.D.
School the of

Pediatrics Center

Pennsylvania, Columbian-Presbyterian

Neurological Medical

Department

of Neurology,
Carson

Columbia
perspiration. fusely and seizure he

University
The electroencephalogram with considered Although in the history, frequent to visual have anterior paroxysmal a impairment was diencephalic had dislocation not of difbursts,

S
found cases

INCE

THE

original

report

of

et

al.1 to cystine have constellation acterizes error

as

of in

two excrete the been

mentally large urine,

retarded amounts approximately

2, 3, 4

of

siblings homo20 charinborn to the

cases,

abnormal, was state. elicited

been

A consistent now referred to

all

of clinical this newly metabolism,

mentation

findings recognized generally In

found

the lenses discission.

grade led

was noted and subsequently The boys poor performance

to psychometric an I.Q. being Two and of testing, 45-50. the

treated in
results

by first
of

of

which
He
parents,

indicated
was the

third

child

of
Irish symptoms

healthy,
and the were similar

unrelated
father healthy; to and of his of

homocystinuria.

addition
in

the
had is described at term

mother
extraction. seizures were

defective

Irish-French
a third

siblings pregnancy as

fine fair hair, subluxation lenses, and patchy flushing especially

always seen.

of of

the

optical the skin, almost

valgum

and
livery

below.

The

deand

recalled

uneventful, had from age, he the but been gain cows began

in the
Pes

malar
cavus

regions,
and genu

are half is have

there
cance. sistent seemed

were no perinatal circumstances In the first 3 months there

vomiting to subside with with poor a weight change

signffiperwhich to to

are ably

common shortened

and Life

more due

than to a

had for

convulsions.

expectancy

considerof the 10 survived diagnosis other

has Two

tendency

goats milk. At about 1 year of have breath-holding spells, during

become flaccid to and sit at pale alone and at progress 10

which

he would
mother He walked at times.

thrombosis of major vessels. Two patients reported by Gauli et al.5 into the third decade, but the has been
and

provoking respiration months,

to perform had learned

mouth-to-mouth 1 year.

been

made
and

in childhood
death in the

in all the
first decade

without
quent parents

support developmental

Details
were

of
vague

his
to

subseboth

patients

but they
Additionally,
with little

had

recorded with
whose 22,

in

at least this

7 cases.345 now
since

slow.
cried

always considered he was easily upset

Blotchy

him
and
patches

to be
often
of

individuals childhood scribed bolic the basis

disorder,
cotirse

ages
early

15

provocation.

clinical

reddening

of the

skin,

especially
infancy. clinic

over
7 years

the
ago,

cheeks,
he has

has below. derangement of this CASE

been Certain report.

known aspects were

to

us of the

are and

demetaare

had

been
Since last

present
seen

since
in our

studied

attended a special though phenobarbital the parents a few

seizure state had no was subsequent PHYSICAL 5 ft., pressure were normal anxious; 1965.) Health Service 7

school
had

for
been

the

retarded. discontinued

Alby
been 15 lb. he The slight high blond, was

months
been of

after

the
there

diencephalic
had of a with wavy, erythema when elicited.

recognized, attacks.

PRESENTATIONS

recurrence EXAMINATION: in. was large apparent. in distribution. and present tall and 120/80. hands The

At

the
There and

age
123 was feet

Case
J. G.
of attacks current

1
was of during first seen at the pain age of which 6 years had because been rewere abdoniinal

weighed

blood
arches and was April 26, inconstantly

kyphoscoliosis;

almost daily hut at times

stiffening, (Submitted This loss

the previous ear. These in occurrence and were usually they were severe and accompanied
of consciousness, 20; was 18th accepted supported pallor, for and

hair Blotchy

was prominent was

mild, b
profuse

more

he

dermatographism

readily

January

publication in part by

investigation (C.K.)

Public

Research

Grants

B-3359

and

B-3102.
ADDRESS:

and

Bainbridge

Streets,

Philadelphia

46, Pennsylvania.
PEDimIcs,

Vol.

36, No. 5, November

1965

736

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ARTICLES
Highly myopic vision
estimate

737

had
of

been
acuity

partially
could

corrected
be made

but

no

exact

because of his mental state. He was like gutteral and nasal utterances,
while inflected were ment of understandable, in normal. the a bizarre There liver or and was manner. was spleen. no The poorly The evidence gait, in heart

prone and
and of while

to ticspeech,
and lungs enlargehalting

articulated

and
was

manneristic,
awkwardness

was in
or evidence

not the
a

remarkable,
the

but
use of

there
the

hesitation

arms
handling made

and with
was his to

hands
a spoon

simple
glass. of His

skills was
muscle the

of quite

dressing,
while

signature, weakness

hesitant
no mental observations

deliberation,
state of limited

legible.
al-

There
though largely

evaluation activity.

spontaneous

Rapid
but
tendon plantar

alternating
no ataxia
reflexes

movements
or dysmetria
were

were
was

grossly
found.
increased.

impaired,
The deep
The

symmetrically stimulation.

response
on was

could
light

not be assessed
Superficial

because
sensa-

of

withdrawal
tion

vibration On the
Ammons

unaltered, but a satisfactory estimate of and position sense could not be made. basis of a modification of the Ammons and
Picture to be Vocabulary betsveen STUDIES: 6i test, and 7 his mental age was highly there 2,4-dini-

was

judged

years.

LABORATORY

The
gm/100
routine nitroprusside ferric

blood
findings, chloride disclosed

count
was reaction; or

normal: normal
positive

hemoglobin,
with
in the reaction trunk and respect cyanide with

13.4
to

ml. A urinalysis,

was
of the

no

trophenylhydrazine. osteoporosis bral bodies

bones rowed. gram in at contrast of The 14 the

Roentgenograms
extremities

of the

bones

generalized

with (Fig.
hands skull years to the

secondary collapse of the verte1). Joint spaces between the small

and was of are age the feet was results were An tracing. of determinations within markedly electroencephalonormal limits narnormal.

Fic.

1. Roentgenogram of the herniation of the intervertebral

tebral bodies with

spine

(J.G.)

shows

discs

into

the

ver-

osteoporosis.

examination

previous

The

following

teinized presence
performed

of the cerebrospinal fluid ( deprowithin 15 minutes ) failed to reveal the of homocystine, another spinal tap was and the so fluid obtained elsewhere4 was allowed was of and used the the was fluid, Methionine concentration acids were Glutamine increased have amounts by Perry values arisen Several exceeding and for Joness these in in as were amino to for drop analysis. are in also in present all dipicric

of blood contents: 100 ml, cholesterol 0.4 mg/100 ml,

dansky minase tent of electrophoretic units, thymol serum pattern

blood 103 alkaline 12 units.

was

urea nitrogen mg/100 ml, phosphatase

0.9 units,

8 mgm./ bilirubin 5.5 Botransa-

rectly
acid. Criteria peak

into
The for are

a graduated
fluid the given identification

cylinder

containing

turbidity

homocystine results found although

( SCOT)
the

The
7.0

total

gm/100

protein conml and the

elevation

disclosed

a slight

recorded It can
urine, it three is present not in fluids.

in Table
be seen and

I.
that homocystine cerebrospinal present. increased other

of -1-globulin
ulin 0.34 gm/100

(albumin
gm/100 ml,

3.4
a-2

gm/100
globulin

ml,
0.72 and studies

a-i

glob-

plasma, normally markedly

gm/100 y-globulins included

was

ml
1.82

Il-globulin,

0.75
1131).

gm/100
Hematologic and

ml,

Several

prothrombin time and recalcification

Venous coagulation

prothrombin

consumption,

in
good

the

urine
niaxinsum,

in

amounts

slightly
none

exceeding
abnormal and the part the but substances other

the
as glutaspinal from amino mean the

time,
time

all of which
was limits. of plasma, out Stein,7 acid and by 7 minutes,

were
with

normal. time

normal

but
homocystine. distinctly might of

methionine
hue fluid; aci(l the were values normal not known.

and
were latter present

clot
was

retraction.
also within acid

The
normal analysis was picric
ii

partial

thromboplastin
urine, the removal After including Dowex-2.

Amino

and
method

cereof deproof the one

decomposition acids

glutamine. in

brospinal
Spackman, teinization picric acid

fluid
with on

carried and

Moore

normal
actual are

given niaxinium

column

of

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738 Case the 2

HOMOCYSTINURIA

IN
girl

TWO
with an

SIBLINGS
extremely muted similar of feet and She voice. She to the were weighed her of appeared

S. G., now 22 years old, case described above,

in mental 3 years,
lenses

is the

older

sister

of the the of
the

older
responded Malar not size

than
flushing present. and

her
in a The

chronoiogic
manner and hands blotchiness

age,

but

behaved
skin 106

and
brother. were normal Ib,

and

was

seen
of

years of her

previously

the

outpatient state. Poor had led to

in another

department

Childrens
retarded age of
dislocated

Hospital

of Philadelphia
vision, surgical
hospital.

because

noted at treatment
She was

configuration.

of four pregnancies and no remarkable event wa known of the perinatal period. As was true of her brother, feeding difficulties marked the early months, and breath-holding spells were frequent, beginning at 9 months of age and lasting fo about a year. Details of her early development wdre poorly recalled, the fact of her walking alone at 10 months being a single certainty. Retardation was not suspected until the early school years. She suffered no form of seizures. Except for the first three grades, her education had been in a special school for the retarded.
PHYSICAL EXAMINATION:

first

measured 5 ft, 23 in. tall, and the blood pressure was 110/74. Her vision was highly myopic. The teeth were carious and a denture was worn because of multiple extractions. An innocent heart murmur
was liver sexual normal, co-ordination audible nor at the spleen gross motor was apex were was diflicult carry and pulmonic and Muscle was judge because area. Neither secondary tone intact; of was fine her palpable normal. to functioning

development

limited
quicker
tendon sponses judged

ability
and
reflexes were to be at

to
less

out

awkward
were

requests. than her

the 7 years

She seemed brother. The

plantar function by the Test. rewas Am-

hyperactive, Intellectual level of

equivocal. the

This

was

a thin,

timid

mons
I
FLUID

and

Ammons

Picture

Vocabulary

TABLE
ITIuNAnY, PLASMA AND CEREBROSPINAL

AfINo

ACIDS

IN

HOMOCYSTINLRIA

Urine
(ng/R4

Plasma !,r) (mg/100 ml)

Amino Cerebrospinal (mg/100

.4cids ml)

of Fluid

Normal Children
(a)

.lfazimum Adults Sir. G. Mrs. G. S.G.

Normal

Normal Sir. G.

J.G.

Jfazimuni (c)

S.G.

1G.

Mean (d)

S.G.

J.G.

(b)
300
10 61 47

Taurine Aspartic Threonine Serine GIut-N1li-Asp-N11 Proline Gliitnmic Citrufline Glycine Alanine

153 7

58 IS
36

54 S
15

102

0.8 0.7
1.7

0.5 0.03 0.6

0.4
0.05

0.7 0.07 1.5

1.1

.07 .01

1.6
tr

.07 tr .68

tr
9

S
46 64 102 0 10 tr

30
.55 III 0.5

1.2

.57

.60 10.9 0 0

76 141 16
10

15
59 0

43 70
0

51 II tr

1.3
8.3

0.5

I. 1
6.!

.53
3.55

.23
.03 .23 tr .07 .20

3.5
0.9 0.8 0.4
0.7

3.3 0.5
1.7

5.4 1.0 0.2 1.9

40
7 105

4
tr

27
tr

5
0

5.9 2.4 1.7

0.4 I .6 2.2

.11 tr .11

.20
0
.08

500 35

36 IL
tr

155
54 5 8 8 8 8 7
7

100
9
tr

210
34

55
8 Ii

3.7

1.9 0

2.2
0
0.1

.29
0

.14
0 tr

AAA
ABA \nlrne Cystine Cystathionine Methionine Isoleucine Leucine Tyrosine Phenylalanine

14
5 tr

0
.01

0
tr .16 tr 0

S 10 40
11 18 30 7 tr

tr tr tr 4 22 50 40

0.4 3.7 1.3

0.07

0.1
1.6

1.4 0.5

1.3
0.3 0 0.05 3.6 0.4
0.7

.17 0
0

37

tr
7

0.5 0.05 2.4 0.4

17 IS 10

0
0.4 1.3 2.3 0.2 0.4
0.7

tr
.01 .01
. . .

0 1.24 .07
.

4
S

.74
.08

39 8.6 40
18

10 53
15 0 9t1

55
50
30 0 17

3
9
5
. .

11
33 Si 3.6 tr
6

4
13 7 131.9 0 4 19 7
54 64

0.8
0.7 0.5 1.4
0 0

13 IS 15 0

13

.16
.32 .25

1.5 I .0
0

0.6 0.4
0

0.6 0.5

.25 .20 0
0

Ilomocystiiie
BAIB Ornithine Ethanolamine Lysine

3080
0 10

1.4
1.2

.05
0 .16 tr tr

4
4 II 37
135 61

0 0.8
0.5 tr

S
55 58 18.5 137 40
30

10

2.1

.05

.07 tr

57
116

31 58
153 150

30

tr 1.8 tr 0.9 1.7 0

tr
2.1 0
.08

55
74
210

3.0 0.2 1.5

0 .

1.3 tr 0.6

.09 0
.

i:iii
Ilistkline

518
350 69 tr

.23
.50

0
tr

10

3M11
Tryptophztr Arginine

43 tr
0

64 tr
0

50 tr

45

13 0.6

0
0

0 0
.17
.

0
0 .27

tr

0 0.5
1.3

4
bee normal figures values AAA indicate of Perry =cx-amino Asp.N11, high and

10
values. Jones,0 adipic (a) acidS

tr
2-10.
(.

15
(h)
.)

1.9

10

Bold Mean

14

males trace

age

8 normal not acid.

adults5 BA1B.amino

phs

Stein

et al

(e) acid,

Values MI!

of Stein

and

Moore,

(d) Glut.-

(e) Tr. ABA Tr trace.

amounts; a-amino

measured. isohutyric =Methylhistidine,

Abbreviations:

butyric

NI!2

=glutamine.

=asparagine.

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ARTICLES
lABORATORY STUDIES:

739

Blood

count

and

urinalysis was with-

were
ill

normal. norlilal joint the

II1OC

The

electroencephalogram

lilnits.
spaces. slnali bones of
pronounced

Roentgenograisss
with narrowing The bones than appeared urine narrowed of both in (Fig. of

showed
the hands her 2). was
biiirubin

generalintervertespaces and The feet and nitrofollows: 0.2 mg/

ized l)rai

o.tcoporosis

joint brother

involving was

rnaiiv
prusside Analysis

fused test of ml; thvmol

the

was
ml 0.5

strongly
as

positive.

the
110

blood
mg/10() turbidity

contents

cholesterol
100

units;

transaminase

( SCOT)
Bodansky grn/100 follows: 0.26

10
units. ml

units
The and nil; an(l

and
total the 3.57 u-2, y-globulin,

alkaline
protein gm/100 0.70 1.47 electrophoretic

phosphatase
content ml; gni/100 gm/100 u-i ml; was pattern globulin,

1.9 6.7
as

albumin, gm/100

f-0M7 nil.

gm/100

ml;

The
are
given

amino
in to

acid
Table those

analyses
I. The
of her

of blood
results
brother. are

and
similar

urine
in

all

essentials

COMMENT
The generally findings similar in these to those two children described are by It is to their a the

Gatill,2 Vhite et al., and Carson.1 remarkable that both have survived present thrombotic cause
death went

ages of focal in other

several

with episode

no

incident

to suggest is commonly

which

neurologic reported
surgical

cases.

abnormality or Each underthe boy

FIG.

procedures;

was general Tests

admitted for

to the

hospital

five

times

and

rowing but tation

2. Roentgenogram of hand (S.C.) of spaces between carpal bones

langes.
may, OIl

ShOVS

nariia-

and

anesthesia blood 1)latelet this

which

was given each time. coagulation were normal, is stickiness test was the only clotting
been found in

the

other extreme

hand,

be

a manifeslability the childfor

and

but the performed;

normality
cases.#{176}

not abother

of of both

the

emotional

contintiously

has

hood The elevated

nary

seen throtighout children. defect levels

of

Serum

y-globulins

were a finding found a cases.

somewhat not prereduction fatty in in

enzymatic serum
excretion

responsible and increased shown in the and formed

accumtilates by

the tin-

increased viously of changes autopsied

these, The as

in both cases, noted. Carson in two the cases,

otirs,

methionine

homoMtidd

a-globulins in
in

Aithotigh been present ftinction tests

not

cystine and of steine. his

has

recently from
by

been serine readily

oxidation,

liver the
were

have liver
osteoporosis,

associates#{176} to be Homocystine,

formation homocyfrom urine.

synthe-

cystathionine

normal. men-

prominent

homocysteine

tioned

in previous

reports,

may

have

conIt has exyears

the the
Mudd,

serum case
the

and of liver
assay

overflows homocsytinunia
of

into
cystathionine

the

in In by

tribtited to the orthopedic deformities. not otherwise been a cause of symptoms, cept matic previously
holding was

studied no
that

as it may fracture in
not

have of the been

been tarsal boy

related bones

to a tratssome G. ). Breathreports

tase Amino
Gaull2

in

biopsies analyses
\Vaisman11

revealed of cerebral
indicates

activity. tissue
cysta-

acid
and

by

(J.
purely

mentioned

in other

and

may

have

coincidental,

thionine that the

is much enzyme

is

diminished, lacking

in

suggesting brain, too.

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740
The large children amounts described of

HOMOCYSTINURIA here and The in only

may be

IN very
to

TWO did (A

SIBLINGS not small increase peak in the was prior calctilated hour The after so that he methionine, before to in one or father taking urine to of the in the excretion became a small the in-

excreted
compared

cystine mother. position gestion cystine, would nauseated

homocystine

present

those children of

in

Gaulls of White
fluids

series,
et al.

the small one

an

younger amount of three

underesti-

of the be

homocystine twenty-fotir 3.6 and mg.) vomited

of methionine;

as homo-

homocystine the may of taken. phenylalanine lack

found of that

cerebnospinal

mate;
samples

suggests

cystine some been

in all sulfhydryl lost during

three cornthe

pounds preparation cautions

seem

have

amount of methionine unsuccessful. Althotigh excreted no load. three scnibed however, could to
in

the test was subsequently there after parent ingestion was the of of detest which from not
or

samples, despite the preThe situation here would

to phenylketonuria, in

107 A similar

mg

of peak

homocystine was

comparable

reaction noted

which cerebrospinal

is as
synthetase

elevated as in
requires

in

the
pyri-

methionine

fluid as be

well

Cystathionine

children with homocystinuria by White et a!. The idiosyncrasy, was be carried excretion mg/24
normal

doxal
sibility

phosphate was due by of

of certain

co-enzyme. entertained required in

The that very

posthis large as pheas a 24 mg

less

marked out, increased This on be

and following was

Whether

the

therefore may

substance amounts
suggested

homocystine 24.3
a

1.4 found
not

to an atypical apoenzyme, Scniver in explaining the vitamin

seizure

hours.
individual.

nornenon
cause

B-6 collecting were

dependency
states of

nausea methionine the any not

tress

and carrier event tolerate

after its

vomiting load state as some ingested heterozygotes

oral

ingestion a manifestation uncertain, not individuals and had by have

of but

the of in do some

infancy.3

may remains

Therefore, hours, both of pynidoxine was collected in both the was (After amino determined.
homocystine

after patients

urine given

for 200

it is probably normal

of importance

hydrochloride orally. Urine over the subsequent 24 hours and content. No found then The during change in G. hours; desirable excreted S. in either analyzed for acid amount of the period the 388 total mg mg. the patient.

inasmuch presumed more, other

methionine
administration.

individuals,
excreted

no
Further-

disin or of clear

amino dosage

acids may has and restriction

given cause not it of of

mouth

comparable
14

vomiting yet is been not

excretion

was pynidoxine

J.
been

Dietary demonstrable whether to prevent

treatment value, dietary accumulation

of homocystine/24 It would have observations nary amino period ously of both

G., 155 to extend

methionine

on the excretion rate of unacid oven a more prolonged pynidoxine patients the This which agent ingestion, began to but cunion its this by
effort

homocysteine

experience

or supplementation able. Carson found benefit to a 4-year-old cystine

likely,

with cystine is desirno clinical evidence of receiving additional period.

any dietary

severe headaches withdrawal of reinstitution. curtailed aspect The an to zyme loading hours methionine

would cease and recur on symptom study inherited In an a partial

out. In

for
however,

a 10-month
that

It

is quite
treatment

unexplained

must period be

be of effective. not
cases

started rapid This

early brain is

in quite

life

during in order is apparent

the to in probby the to and treatHope-

a more prolonged of the problem. disease the is presumably recessive presence the
carried

of

growth

phenylketonuria. ably
many

Homocystinunia disease
in the

autosomal establish defect tests following

gene. of

a rare
found

as evidenced
last

enthe 24

2 years. will infancy dietary

in
were

parents, of

methionine22 gm homoof

fully, detect make

ment.

screening the possible disorder

procedures in early experimental

serve

ingestion
.

(155

mole/1.73M2),

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ARTICLES

741 5. Carson, N. A. J., Dent, C. E., Field, C. M. B., Gaul1, C. E.: hlomocystinuria. A cliniand pathological review of ten cases. J. Pediat., 66:565, 1965. 6. Page, L. B. and Culver, P. J. : A Syllabus of Laboratory Examination in Clinical Diagnoand cal
sis. 7. Spackman, in 8. Perry, content the T. Cambridge, Massachusetts:
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SUMMARY
1 . Two 14 found: mental blotchiness tional holding fancy. vascular both of lability and 21
features ty pica!

cases are

of
of

homocystinunia in the the of seizures, skin. prominent disorder optical pes and

at which

ages the were

described,

subluxation retardation, of the was

lenses, cavus, emobreath-

Harvard W. H., apparatus amino T. : The and acid. amino

UniMoore, for use Anal. acid

versity

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D.

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Additionally,

H.,

S. : Automatic
Chem., 30:1190, L., of Invest., L., and

recording of 1958. Jones, human R.

attacks had been Neither had suffered occlusive episode. the children described and
and

present in inany apparent Prominent in was narrowing

were

chromatography

genof
9.

normal

individuals
Bray,

cerebrospinal and in mental

1961. C., Field, C.,

fluid
defectives. Love, thrombosis

in

eralized osteoporosis joint spaces.

2. Homocystine

J.

Clin.

40:136,

McDonald,

F.,

methionine

and
and
1964.

Davies,
the

found

to be

elevated fluid.

in urine,

plasma

and
10.

B. : Homocystinuria, blood platelets.

Lancet,

1:745,

cerebrospinal

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HOMOCYSTINURIA: A REPORT IN TWO SIBLINGS Charles Kennedy, Vivian E. Shih and Lewis P. Rowland Pediatrics 1965;36;736
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1965 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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