Clinical

and in
By

Biochemical Galactosemia
KURT

Observations

J.

ISSELIIACIIER,

M.D.*

I
tary

IS

flOW

well
in 40 up to of occurs believed.

known
represents the cases the cases investigations the not have

that
an metabolism been have on condition as present

the
inborn of

disease,
and galactose. reported timet and discovered disease. a rare as was in

ga- diarrhea
herediness.

together Jaundice is

with a very

lethargy common

and

drowsifinding as

lactosenmia, error than unreported course although More literature mtmore

iii

the disease progresses and is usually associated enlargement of the liver and spleen. The thewith
is in cases may a and tend to the the occur If the detect cataract becomrme period initially later disease in the clinical of four evidence formation. increasingly continues. A Both frequent due stages is to fatty cirrhosis often neonatal condition to of eight mental sympprominent ocsignificantly as infiltraensues. tion, In and it soon tends but severe death thereafter. beyond can usually

many hepatomegaly

been this is

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the

fulminating period cxweeks, reor

Thus, probably heretofore

one,

infrequently

It
view cuss ical alice mnethods omm the

is the
the in defect of detail

purpose
clinical the considered this of

of this
aspects recently to and, disease.
FEATURES

communication
of galactosemia, elucidated be to the finally, basic to to emphasize the to dis-

to re- one
tardation toms galactose when detection tions biochemdisturbcomment

ingestion

condition, diagnosis, possibly of the

CLINICAL

newer currence blood toxic elevated.

is

the This

development
levels

of
are

hypoglycemia readily escape

determinacomnes with in the

galactose

factors

contributing

syndrome
total to the blood

may
sugar

mmianifestations

if are earliest

only clue

performed. diagnosis sugar (galactose) of a reducing

The

The usually and gestion tures retardation, and pear ingestion

From holic Medicine, Service, Mass.
*

synmptoms

which
themselves to or early Afflicted at birth, readily
Institute

occur
causally galactose. nutritional infants but after develop
of Md., School, General

in
shortly

galactosemia
after to main failure, osteoporosis usually apof related

the birth urine. the inmented feamental the

finding

manifest are known of imiclude cataracts. normal they

time Diseases, Harvard Massachusetts in Boston, work Natiomial was Institutes Natiommal

This
by enzyme

sugar,
yeast glucose and test

unlike
also oxidase. papers utilize be negative. the

glucose,
is not The (e.g. the It galactosuria glucose

is
a substrate

not

ferfor in-

be

milk

The

recently oxidase incon-

troduced Tes-Tape#{174}) reaction emphasize

clinical which will thus that

Clitmistix#{174},

hepato-splenomegaly,

is important is

a few

days vonmiting

milk to andstant sion

Meta-

and
urinalysis

can

be
of

absent
a the may of

on
patient

the
not

routine
who, have mriilk. because been

admisof able In of is reason alconorally

Arthritis the and Hospital,

and Departmemmt time

persistent
of to

vomiting, much the to galactosuria,

Bethesda, Medical

absorb intravenously

ingested the galactose For

Medical Boston,

trast or ways

tolerance this

administered impaired.

Instructor Assistant

Medicine, Mass. supported of

Harvard Massachusetts in Health part

Medical General by a grant

School,

significantly

and
Hospital, This the

itmm Medicine,

the
has
from

performance
often of hazard, of been the

of

the

galactose
This because as test of

tolerance
necessary is the as not the for frequent

test
the withpos-

considered disease. hypoglycemnia

(A-1392). imidividual
references

diagnosis out occurrence

t
reports

Extensive

may

bibliographies citing be found by consulting

case 1 to 3. 527

however,

well

528

THE

AMERICAN

JOURNAL

OF

CLINICAL

NUTRITION

[\l.

5,

No.

sible tose. enzymuatic which ance

(leleterious More test obviates test. recently

effects has the been need

of a newer for

the described the

additional and more

glac- or specific by There toler- that

somatic the is patients

development prolonged! ample UD allow P for glucose

in

in use

general, of as

is imidicated possess

imnpaired! duets. herein, the which of galacgalactosystemn5

galactose-free

(vide
galactose

infra)

evidence, with

galactosemia

enzyme,

Galactose-4-epimiierase, emmdogenous and the central hemice synthesis perniit nervous

The
of all simple alanine, addition acid, butyric of these mo-acid cases,

other
pattern with aliphatic

usual
and a has chain

urine
been type; glutamine, lysine,

abnormalities
The essentially of i.e. cystine, tyrosine and in detected the serine, and

consist
amsimilar neutral, glycine, valine; glutamic amino-isothe

would tose lipid in and with in

gest experiencing

albuminuria

amino-aciduria.6 predominance

from
formation

elsewhere.

It has

been

frequently
may quantities any significant to two in of

observed
later galactose years

that patients
life of
without in-

threonine, phenylanine, methyl acids histidine, have

galactosemia varying

side
factors:

effects. (a)

This the and

of ingested

been

urines is probably provement these patients that in to than

related in later body in are so the with

imin (b) is the far the

patients.45
NUTRITIONAL THERAPY

tolerance increasing the neonatal

to age;
ratio

galactose

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fact

years

Fortunately, this disease

one is the

of

the

striking

features improvement

of galactose smaller

weight the pronounced.

or

surface period

area when

remarkable

which
advanced, even tions gain arrhea. size. disappear malities cease. somewhat appear which mental most damage rigid for this institution

occurs
all disappear only. and The Cirrhosis,

when
diets. of One the

these
If

patients
the disease may with observes nausea, spleen has

are
is dietary rapid vomiting return been

placed
not regress restricweight and to normal known

onsymptoms
too and

galactose-free

symptoms readily of and

BIOCHEMICAL

STUDIES

completely

(A)

Normal

Galactose
knowledge concerning its utilization

Metabolism
has the in the of been metabolism body. gained of Most in galof

cessation liver if

Considerable direcent years

present,
m

the in
dis1).

actose to

and

ingested
the

dietary
main

galactose
carbohydrate

is in
milk,

the

form
which

of

The
above present, instances The

urinary
likewise often they is major improvement been nervous despite diet. and be of or a substitutes important. diagnosis

abnorpromptly regress may symptom the by system the It is prompt most

lactose,

mentioned Cataracts, and completely.2 usually retardation. authors may adherence reason of by that not to that therapy diets resorting available It diets development. ingestion galactose there that is at central is and galactose that has shows It the in if some

the

intestine
These sugars

is split
galactose differ

into
only

its
and in

two
glucose the

component
(Fig. orientation

monosaccharides,

no has

,OH

observed

H\

,OH

central galactose-free are so readily to milk any

improve a early can

?
HCOH
I

HCOH
I

?
I

HOCH
instituted number such soy with bean normal feels benefit in function, a the
and

HOCH HOCH

Galactose-free in as that growth that and body, evidence infancy commercially Nutramigen#{174}, these preparation.

I
of HCOH

DextriMaltose#{174} been are amply compatible Although may poorly nervous present

I
HC

HC

demonstrated Platt7 be of special synthesized no definite system

I
CH2OH
-

I
CH2OH
a
of time

Glucose
Comparison

-0 -Ga/ccfose
of

clinical Fig.

1.

structure

a-D-glucose

a-D-galactose.

Septemnber-October

1957

1
hydroxyl The
,

ISSELBACHER

529

of

the

hydrogen carbon
immto

and atom.

groups galactose and

about may be of manner a result amid their in

-

theabove incame who

reactions. from the in subjects We demonstrated the upon

A observations that red

clue

iii of

this

direction -phosphate

fourth
corporated

Schwarz ci al.,3 cells of of in galactommii!k or of

galactolipids to glucose for greatly of Le!oir, this energy. enters

muco-polybut most

galactose-l blood the ingestion

saccharides is then whereby pool the The phosphate sine triphosphate galactokinase.
(I) Galactose

(chondroitin utilized galactose has been

sulfate) derivatives The the elucidated Kalckar direction

it accumulated semic galactose. servations of was shown incubated

converted! be

which
exact as glucose energy

can

were
vitro

able

to

confirm erythrocytes
containing

these
which

obit

with in

experiments

the
in in

galactosenmic
a medium contrast to This

when
galactose

investigations first step (Reaction

showed
in of consists a-galactose-l the 1 -phosphate, similarly phosphorylation galactose

a significant
incubated.

accumulation
normal suggested

of galactosered that cell the to block P-Gal that all contrast, while of enzymes the three

I). (ATP)

This and

requires a specific

adenoenzyme,

defect
in might transferase. In normal the

in

galactosemia
of and involve studies cell referred from is to it able

could
galactose-I that

be

due
such

to
a

a block

conversion reasonably further red

-phosphate the enzyme

glucose-i-phosphate, + ATP
-

Galactose-1-P

ADP

Downloaded from www.ajcn.org by guest on August 23, 2011

The
to

galactose-1 which
the to the time

-phosphate
by

is then
a second

converted
reaction In is while this

was to m their This

observed catalyze
j

glucose-I

-phosphate

(II)
dine reaction ferred the The called nmore
(II)

involves
galactose-I nucleotide

specific
-phosphate to -phosphate this unidyl

nucleotide,
transunidine at has is liberated. reaction transferase

un- reactions
erythrocytes normal di- and I transferase with

diphosphoglucose

(UDPGlucose). yield

galactosemic to

patients, content

respect

III,

showed
activity. in far. any inhibitors activity. the due many been the of for as were all three shown absence an been In liver traces liver deficiency the was transferase off red

a striking
over These co-factors to 20 cases nor account

absence
observation of did galactosemic they for

of
has red the galactosemia

P-Gal

phospho-galactose same enzyme simply,

(UDPGalactose) glucose-I catalyzing

phospho-galactose

been confirmed been studied thus or, did not lack demonstrable of transferase that be is, since had of time, their

cells lack

contain

P-Gal

transferase.
+ UDPGlucose + Glucose1 -phosphate

Galactose-1-phosphiate U DPGalactose

It
an of the galactose cells activity.

was
of adaptive the

initially
enzyme

rcamight patients

soned simply that tested riods lost a

absence to

phenomenon; for extended gradually However, had mnonths normal Also, patient at birth with noted in the in transferase the the liver, amounts patients by at biopsy recomactivity biopsy.6 been were with mnore that by in demthe disred pehave when off cxrerethe

Imi nucleotides which present that cofactor a 4-keto enzyme waldenase tions
it

a is

third are still time.

reaction interconverted incompletely It the has

(III) in understood recently nucleotide and an of mnechanism called been the it

the a been

two manner at (DPN)

uridine the observed is The galactoobserva-

galactosemic might who

diphosphopyridine for sugar has but on is the perhaps

.

erythrocytes ammiined spect cently, transferase onstrating cord blood

t6

patients long found enzymes. in existed of as to

reaction may previously in better view be

is believed
ml

that galactose they to it

IS be one the afflicted

intermediate. recent of

called the

probable

reaction

UDPGalactose-4-

epimerase

of also

infant

DPN
(III) UDPGalactose m IjDPGlucose

ease. cells which of galactoof the

The has normally enzymes. of only to

enzymatic contains two tissue of

defect investigated

significant galactosemic obtained transferase

(B) In semia the

The studies it defect

Enzymatic on seemed mimight the

Defect possible reasonable involve one

in

Galactosemia of presume or mnore

causes to

analysis that vealed the pared

normnal

obtained

531)

TUE

AMERICAN

JOURNAL

OF

CLINICAL

NUTRITION

I \ol.

5,

No.

(C)

Possible

Alternate

Routes

of

Galactose

Metabolism
Observations
gTOUp5

have investigators galactose in have from is of that 30 retained of Schwarz some et

been to can been to and the of based SO per not

made suggest be patients.3 on cent of

by that nietabolized the the

several adto

test has been developed which can readily be perfornied on blood specinmens. This test, the details of which have heeim dieScribed! elsewhere,8 far no is false both positives
however, normal with

of

sI)ecific have

and been
if the

sensitive. detected.
patient within has

Thims Erbeen three

mmiiliisteredl some conclusions anywhere galactose urinary servations of course degree

galactosemic

may These rors transfused fact that ingested for the expect galactose

occur,

blood

accounted From would retained with male with this was it galactose definite

months prior the transferase by

give oba false

to

the assay. content of

result.
t6

In the of

such a situation, dommor cells may having permits

without

excretion

sugar. one this

negative

In semia,
sis to

a
be

newborn the
made

suspected method
cord blood) to activity (on

galactoa diagnoexposing

enzymatic to the
in of

would
Recent galactose semia tion ability per that cent 3 of

be

in the
studies in a

form
24-year-old

of galactose-l

-phosphate.
C4-labeled galactoinvestigapatients only was

performed a more Although galactose to of the the normal,

the
nosis.

infant

possible
order

hazards
arrive might at

of
the be

galactose
diagascribed

administration Traces

have this to per

permitted metabolize compared cent

Downloaded from www.ajcn.org by guest on August 23, 2011

to

admixtures

of

maternal

blood one month in addition tolerance aspects of

and

warrants

administered

a second test method may shown enzymatic useful than the galactose dating the the Genetic hereditary
Factors

onetherefore

later. The prove niore test in elucigalactoseimmia.

could duronic mechanism

this cent of

be

accounted acid. of
the

for

in his

urine

as

a glucosi-

In view of our glucosiduronic

very strongly must studies that have

knowledge of acid formation,

at been least converted

(E)

suggests

:3 per

galactose

It is hereditary
has

quite evident disease but been

show of of a It is traits Dr. Variation that based would metabolic our attention Factors the on have two be the cases conceivable

that galactosemia the exact genetic Although

in siblings, tolerance demonstrated that one the that galactose with one disease Post of the of alleles, for that a the trait. Toxicity still has may more Institute the University) be of the

is pattern disease
parents By test in the parents tolerance Ho!-

to
tides).

a glucose
These

metabolite observed

(via
would

the

urine
indicate

nucleoin galacexists

not

established.
any clinical galactose usually of assay of Richard this (Columbia inheritance

the
their

either
tosemia possible galactose probably tose see this the

the
is

enzymatic
or or not for be Any a major clinical to otherwise that such accessory

defect
there

that occurs never means a zel and for majority

frequently

manifestations.

incomplete metabolism.

alternate could metabolism, pronounced subsequent disease

pathway pathway route one would in ingestion.* manifestations for

Komrower9 lowering

galac- showed never test. of pick However, Human the up

a refinement able readily. for has d!isease in which another thus far to

transferase

galactose

(D)

New

Spectrophotometric

Test

for

Galactosemia It nosis intravenous tioned an ment infant of above, in galactose has of been galactosemia galactose this whom test there metabolism. customary by to means tolerance is not is a As confirm of without marked a result the test. the oral

suggested2#{176} diag- might or case one

multiple to pattern as in look

As men- deranged escaped hazard in impairof (F)

Possible of Recent

the discovery of tosemia a relatively

*

the

enzymatic defect in simple spectrophotometric

of this of manuscript, galactose (Isselbacher,

galaclight pronounced occur repeatedly

Galactosemia animal studies possibly It when has have shed contributing disturbances been (rats animals considerable to which observed or chicks) the

Simice suchm beeti (in

the

submission

evidence metabolism

on in

factors physiologic galactosemia. that

for has

atm accessory obtained press)).

pathway imi this laboratory

J.: K.

Science

SepteiiilnrOctobcr

l.)57J

ISSELBAC1

IER

531

are and nod mnals

placedl uniformly of has 14

on show to

3O per a develop 21

cent
typical

galactose
quivering cataracts Examination

diets
within

they
syndrome a of

ficiency ase
As petheutilized

of

specific

enzyimme, uridyl
galactose

P-Gal
cannot be

trammsferproperly

fredluently

(phospho-galactose
a consequence,

transferase).

days.2t23

lenticular2m
galactose-l galactosemic

and
-phosphate, red

hepatic
the just cells. with which

tissues24
accumulation as is the

of

such
of case in

demomistrated

ani- in be

and galactose-l -phosphate accumulates the tissues. The latter accumulation causally related to the toxic manifestations
clinically.

may

theobserved

It
or in

is tempting
inhibit turn seen with one could this

to
or lead

specmore to

ulate
might zyme physiologic and

that
interfere systems clinically. et

this

hexose-phosphate

accumulation

In spite galactose
enthese thea

of the utilization specific

known has

enzymatic been shown

defect some to occur in

new this

patients. and

Reference is made to the use of enzymatic blood assay for

The advantages

disturbances 1mm line

experimentally reasoning

the of

diagnosis

of galactosemia.

procedure
presented.

over

the

galactose

tolerance

Schwarz lation
is tion of

of

have galactose-1
with cells. a

shown -phosphate
reduced

that in

the
oxygen

accumutest the red cells

consumnp-

are

associated these

REFERENCES

Downloaded from www.ajcn.org by guest on August 23, 2011

1. TOVNSEND,

Hansen
nucleotide fed levels content tose-fed nmethods duction glucose. The galactosemia as being
22

et

a!.

have
in They

studied
the found and similar using been the studies specific able livers the

the
of

uridine
galactose2.

E. H., P. S. : Gaiactosemia
: additionmal review
AND
six

MASON,

H.
its literature Pediatrics of a

H.,
relatioti

AND

STRONG,

amid of cases.
CANNON,

to amid 7: 760, with J.

Laetinecs presentation

patterns greatly increased. rats we in have the and not hepatic reduced In

cirrhosis
of

chicks.2t

UDPglucose UDPgalactose on to of find UPDin by it should found associated as in

7.

1951.
notes Med. 252: on

RITTER, with 747,

J.

A.,

E. J. : Galactosemia
case England

cataracts: 1955.

report New

galacenzymatic any re- 3.

physiopathology.

KOMROWER, GOLBERG,

concentration which often considered to the the

C.. M., SCHWARZ, L. A clinical

Arch.

V., and
Dis.

HOLZEL,

A.,

AND

biochemical
Childhood

study

of 1956.

galactosemia.

31 : 254,
WOLSON,

hypoglycemia has causally of that immore this do most not pronounced disease.
SUMMARY AND

occurs clinical manifes-

4.

also related disease. of

been

many be5. in
6.

tations recalled galactosemia with

However symptoms immdiseases occur

A., KOMROWER, G. K. : Amino-aciduria in Med. J. 1 : 194, 1952. HsIA, D. V., HSIA, H., GREEN, GELLIS, S. S. : Amimio-aciduria
HOLZEL,

M.,

AND

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galactosemia.

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S.,
in

KAY,

M.,

AND

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AND FLYNN,

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Al.

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CUSWORTH,
\.:

D.
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C.,

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E.,

hypoglycemia,

Amino-aciduria

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Arch. sophmisticaMed. in 1957. imexosepimosJ. maim

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B. S.:
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and M.: feediimg Biochemical Science Time and metabolism Metabolism, B.

CONCLUSIONS

tion 1:179,

Galactosemia ease normally. tritional cirrhosis, mnation. galactose and Effective i mmstitution disappearamice diagnosis The is disease mmmcmiis pronmptly
of

constitutes galactose outstanding retardation studies galactosunia, is The failure, mental Laboratory tolerance,

a cannot

hereditary be metabolized are with and reveal cataract

disnufor-

8. 9.

KALCKAR,

mutations 125: 105, of

in

which

and
LELOIR,

microorganisms. Phosphorus McElroy

features

hepato-splenomegaly

phates
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I (ed.
Johns

by
Hopkimms of

Glass),

a decreased

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LELOIR,

albuminuria 1)OsSible by Conmplete

occur

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derivative.

Baltimore, 1951, p. 67. L. E.: Enzymatic diphosphate glucose

Arch. Biochem.
BRAGANCA,

transfornmation imito 33: 186, 1951.

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aimiimmo-aciduria. treatmiiemit a
of

the II.

KALCKAR, PETERSEN,

H.
A.:
of
)ti

M.,
inc

B.,
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AND

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and galacttm

time

for-

may
and froimm the

if dietary

time

itiatit

urid

se. Nature a C/rem.

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E.
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P.,

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KURAHASHI,

AND

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cyte 62:34, 14.

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Defect in the uptake of galactoseliver nucleotides in congenital galactosemia. Science 125: 113, 1957. EISENBERG, F., JR., ISSELBACHER, K. J., AND KALCKAR, H. M.: Studies in the metabolism carbon-14-labelled galactose in a galactosemic individual. Science 125: 116, 1957. 1-phosphate

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