Galactosemia

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The Metabolism of Galactose by Patients 
with Congenital Galactosemia* 
STANTON SEGAL, M.D., ALBERTA BLAIR, B.S. and HENRY ROTH, M.D. 
Bethesda, Maryland 
C 
ONGENITAL galactosemia is a genetically 
transmitted disease characterized by in- 
ability to metabolize the sugar, n-galactose. 
Continued ingestion of this sugar in infancy re- 
sults in a toxic syndrome manifested by failure 
to thrive, cataracts, jaundice, hepatosplenomeg- 
aly and mental retardation [I-5]. This clinical 
syndrome is associated with an increase in the 
blood galactose concentration and tissue galac- 
tose-l-phosphate content, galactosuria, amino- 
aciduria and proteinuria [ 1,6]. After the original 
description of the syndrome by Mason and 
Turner [7], numerous clinical reports of cases 
appeared in the 1940’s [8-701. This period was 
followed by a decade of intensive biochemical 
investigation which led to recognition of the 
specific enzymatic defect, a deficiency of the 
enzyme galactose-1 -phosphate uridyl trans- 
ferase [7 71, and to development of a specific 
diagnostic technic for assaying the activity of this 
enzyme in red blood cells [72]. Modification of 
the latter procedure then permitted its applica- 
tion to a definitive genetic analysis of the pattern 
of transmission of this disorder [ 731. 
Attention now has been focused on another 
aspect of the disease, namely, the extent to which 
galactosemic patients are capable of metab- 
olizing galactose, and the factors which may be 
influential in governing or modifying the proc- 
ess. In the past, estimation of the extent of 
galactose metabolism has been based on the 
rate of disappearance of the sugar from the blood 
after the oral administration of relatively large 
quantities. Several investigators have also at- 
tempted to quantify the ability of galactosemic 
patients to metabolize galactose by determining 
the fraction of ingested galactose excreted in the 
urine [2,8]. Whereas normal persons excrete 
little or none of the galactose ingested, galacto- 
semic subjects excrete 15 to 60 per cent of the 
sugar in the urine over a 24-hour period. The 
assumption has been that the remainder was 
stored in the body or metabolized. In order to 
assess more accurately and more specifically the 
quantitative extent of gaIactose metabolism by 
galactosemic patients, a technic has been devised 
in which galactose, radioactively-labelled with 
C14, is injected intravenously, and the extent of 
its oxidation to radioactive carbon dioxide is 
determined by measuring the appearance of 
the latter in the expired air during the 5-hour 
period following the injection. This report de- 
scribes the results of these experiments in twelve 
patients. (Preliminary results have been de- 
scribed [ 147). 
METHODS AND MATERIALS 
The Patients. The clinical characteristics of the 
patients at the time of these studies are described in 
Table I. The ages of the patients ranged from six to 
thirty years. Because the experimental procedure in- 
volved collection of expired air in Douglas bags 
through breathing valves, and required the coopera- 
tion of the patient, no attempt was made to include 
patients under six years of age. Five patients were 
postpubertal, by clinical criteria. All but one had or 
had previously had cataracts. Intelligence quotients, 
determined by standard procedures, were normal in 
only two patients. Four patients showed signs of 
generally retarded physical development. Each 
patient was maintained on an absolutely galactose- 
free diet for at least one week prior to the experiments; 
in no case could galactose be detected in the urine. 
All the subjects were shown to be lacking the enzyme, 
galactose-l-phosphate uridyl transferase, in red cells 
according to the diagnostic technic of Anderson et al. 
[72], and hemolysates of the peripheral blood were 
incapable of oxidizing Cr4-galactose to Ct40s in the 
diagnostic test routinely used in this laboratory [75]. 
* From the Clinical Endocrinology Branch, National Institute of Arthritis and Metabolic Diseases, National 
Institutes of Health, Bethesda, Maryland. Presented at the Annual Meeting of the American Federation for Clinical 
Research, Atlantic City, N. J., May 1963. Manuscript received March 6, 1964. 
62 AMERICAN JOURNAL OF MEDICINE 
Congenital Galactosemia jl’~,qc~l P/ ni. 
TABLE I 
6.3 
CH:\RACTERISTICS OF GALACTOSEMIC P.4TIENTS .4’l- TIIE TIME 01; S’I [.I))’ 
-i- 
I 
- 
Escellcnt 
t;xrell~-Ilt 
Fair 
Poor 
Fair 
F,xcellcnt 
Fair 
Poor 
Fair 
L.xcellcnt 
Fair 
Fair 
Fair 
Fair 
Patient cataracts* 
+ 
+ 
0 
+ 
: 
+ 
R 
+ 
: 
R 
+ 
R 
I.Q. Growthj Puhert) 
85 Good 0 
70 Good 0 
76 j Poor 0 
.I. 0‘1) 
B. A. 
I,. I’. 
1:. I\. 
P. R. 
P. Hr. 
I,. Br. 
L. .J. 
6 
7 
7 
9 
9 
11 
10 
11 
11 
15 
15 
16 
17 
30 
Good 
P00r 
Poor 
Poor 
Good 
Good 
Good 
Good 
Good 
Good 
Good 
0 
0 
0 
0 
0 
0 
z + 
: 
32 
61 
96 
40 
59 
75 
90 
72 
65 
H. ‘I‘. 
.I. s. 
.T. D. 
‘r. B. 
L - - 
* R = removed. 0 = absent. f = present. 
t Poor = less than third percentile. 
,+ Excellent = all milk and milk nroducts excluded. Fair = milk and milk nroducts not eaten directlv but ingested 
1 
in prepared food. Poor = milk and milk products in diet. 
TABLE II 
PRESENTING CLINICAL FINDINGS IN INFANCY OF THE GALACTOSEMIC PATIENTS INVESTIGATED 
- 
- 
Jaundice 
! 
, 
Patient 
Age 
At Onset At Diagnosis 
Hepato- 
spleno- Vomiting 
megaly 
Hypogly- 
cemi.1 
Diarrhea 
+ 
+ 
: 
++ 
+ 
+ 
+ 
: 
+ 
.I. O’D 
B. A. 
I.. F. 
E. 1%‘. 
P. R. 
P. Br. 
I.. Br. 
I.. .I. 
H. T. 
J. s. 
J. D. 
T. B. 
2 days 
2.5 wk 
P0stoatal 
3 “lo. 
2 wk. 
Postnatal 
1 “I”. 
2 wk. 
3 days 
2.5 mo. 
I wk. 
Postnatal 
3 ma. 
1.5 ma. 
4 mo. 
If 5 yr.t 
* yr.S 
2 5 mo. 
4 yr. 
3 In”. 
2 “lo. 
5 In”. 
3 wk. 
13 “lo. 
i - - 
* Due to ins&n administration. 
t Galactose-free diet starred at 3 m”. without diagnosis. 
f Calacrose-free diet started at 15 ma without diagnosis. 
‘The clinical findings during infancy in these cases 
(Table II) have been compiled from parents’ state- 
ments, hospital records and published reports. All the 
patients exhibited the characteristic clinical syndrome 
of congenital galactosemia. One patient (T. B.) had 
been the subject of the first report of galactosemia in 
the American literature by Mason and Turner 171. 
The clinical findings in infancy of three others (J. D., 
J. S. and 1~. J.) have been published [8-701. Gener- 
ally, the syndrome appeared during the postnatal 
period, while milk was ingested, and several weeks 
elapsed between the initial onset and the time of 
diagnosis. 
v o L . 38 , JANUARY 1965 
Volunteer subjects over the age of eighteen served 
as normal control subjects. Institutional policies pre- 
clude administration of radioisotopes to normal 
children, who therefore were not available as sub- 
jects. However, on the basis of available data, older 
normal control subiects might, if anything, be ex- 
pected to metabolize galactose less rapidly than young 
children [76,77]. Therefore, the metabolic data ob- 
tained from this group of normal subiects are re- 
garded as valid standards against which to compare 
the results obtained from the galactosemic patients. 
Plan of the Experiments. Twenty-one intravenous 
tests of Ci4-galactose metabolism were performed in 
64 Congenital Galactosemia-Segal et al. 
twelve galactosemic patients, in addition to eight ex- 
periments involving normal control subjects. Each 
experiment was performed after an overnight fast, 
which was continued throughout the 5-hour period 
of study. Galactose-l-C14 was injected as rapidly as 
possible into an antecubital vein and,at various inter- 
vals after the injection, 4-minute samples of expired 
air were collected in Douglas bags for assay of WO2. 
The galactosemic patients were given from 1 to 3 
gc. of galactose-l-CY4, either as a tracer dose (less than 
0.6 mg.) or mixed with larger amounts of unlabeled 
galactose (in 20 per cent solution). The normal con- 
trol studies were performed using 5 PC. of the radio- 
active sugar. Urine was collected for 24 hours for 
assay of radioactivity. 
Materials. Galactose-1-W (specific activity = 4.72 
PC. per mg.) was purchased from the National Bureau 
of Standards and was chromatographically pure. A 
solution containing 1 pc. per ml. in normal saline 
solution, suitable for intravenous administration, was 
prepared by the Radiopharmaceutical Service of the 
National Institutes of Health. Unlabeled galactose was 
purchased from the Pfanstiehl Co. and was prepared 
for intravenous administration as an aqueous solution 
containing 20 gm. per 100 ml. These solutions were 
sterile and pyrogen-free. 
Methods. The amounts of carbon dioxide and C140s 
excreted by the galactosemic patients in the expired 
air were analyzed by a modification [ 791 of the method 
of Fredrickson and Ono [18]. Since the metabolism 
of galactose normally is extensive, the Q401 excreted 
by the normal subjects was determined by the method 
of Fredrickson and Ono [ 781 without the intermediate 
step of BaC03 precipitation. CL40~ was assayed in 
hyamine using a liquid scintillation spectrometer 
counting at 60 per cent efficiency. The cumulative 
excretion of Cl402 was calculated by integration of 
the area under the excretion curve, according to 
Berlin, Tolbert and Lawrence [ZO]. Blood was as- 
sayed for radioactivity by methods previously de- 
scribed [27], as was urine Cl4 12.21. Glucose was iso- 
lated from blood as gluconate [23] and galactose as 
mucic acid [24]; both were assayed for Cl4 as pre- 
viously described [24J. 
RESULTS 
Cl402 Excretion After Tracer Doses of C14-galac- 
tose. The excretion of G402 by subjects given 
tracer amounts (less than 0.6 mg.) of galactose- 
l-G4 is shown in Figure 1, in which the fraction 
of the injected Cl4 excreted per minute is plotted 
as a function of time. The curve tracing the solid 
circles is an average of curves obtained from 
three normal control subjects. The lower curve, 
tracing the open circles, represents the average 
of curves obtained from six galactosemic pa- 
tients. Comparison of the cumulative excretion 
of C140z by these two groups shows that the 
normal subjects excreted approximately 30 per 
cent of the administered Cl4 during the 5-hour 
period, whereas the galactosemic patients ex- 
creted only 5 per cent of the administered dose. 
The curve tracing the solid triangles describes 
the excretion of Cl402 by a thirty year old galac- 
tosemic patient (T. B.), (Table I) under the same 
conditions ; he excreted 19 per cent of the 
dose. The curve tracing the open triangles is an 
average of two similar curves obtained in 
sibling patients (P. Br. and L. Br.) aged ten and 
eleven, who excreted about 40 per cent of the 
dose. These three patients, whose metabolism of 
galactose differs so strikingly from that of the 
remaining patients with galactosemia, have been 
designated as “galactosemic.” 
The Metabolism of Larger Amounts of Galactose. 
Because of the unexpected ability shown by 
these three unusual “galactosemic” patients to 
metabolize small tracer doses of galactose, it 
seemed important to test their responses to 
larger galactose loads. Accordingly, 1 gm. of 
galactose was administered. The results of these 
studies are shown in Figure 2. The curve which 
follows the solid circles represents two normal 
subjects, while the curve which follows the open 
circles represents three galactosemic patients 
who metabolized only 5 per cent of the tracer 
dose in the earlier experiments. The excretion of 
Cl402 by these latter subjects was essentially the 
same after 1 gm. dose as after the tracer dose. 
The three “galactosemic” patients who metab- 
olized significant amounts of the tracer dose 
(solid and open triangles) handled the 1 gm. 
load even more efficiently; the initial rate of 
qxidation was much faster and the peak excre- 
tion was reached at an earlier time (compare 
Fig. 2 with Fig. 1). Whereas T. B. excreted 19 
per cent of the tracer dose, he excreted 26 per 
cent of the label given in 1 gm. A possible ex- 
planation for these observations would be that 
in these three patients the system for metab- 
olizing galactose has a lower affinity for the 
sugar than that in the normal subjects and thus 
more sugar must be available to achieve maxi- 
mum metabolic rates. 
In Figure 3 the metabolism of 10 and 20 gm. 
loads in normal subjects are compared with a 
2 and a 10 gm. load in a “galactosemic” patient 
(T. B.). It can be seen that this patient can 
metabolize a 2 gm. load as well as the normal 
subject can metabolize a 10 gm. load; however, 
he cannot metabolize 10 gm. as well as the 
AMERICAN JOURNAL OF MEDICINE 
Congenital Galactosemia-- -,S~<~NI rt al. 
FIG. 1. The excretion of CYOZ in expired air by normal 
subjects and patients with congenital galactosemia after 
intravenous administration of tracer quantities of galac- 
tose-1 -cn. 
FIG. 2. The excretion of U402 in expired air by normal 
subjects and patients with galactosemia after intra- 
venous administration of 1 gm. quantities of galactose 
containing galactose-1 -CY4. 
Fro 3. Comparison of the excretion of CnOz in expired 
air after administration to normal subjects and patient 
T. B. of various quantities of galactose added to C”- 
labeled sugar. 
VOL. 38, JANUARY 1965 
normal subject (19 per cent cscrcrion ol‘ C?- 
given compared to 23 per cent). hlthouqh the 
patient (T. B.) possesses a considerat)le capacity 
to metabolize galactose, it is still not entirely- 
normal. Patient T. B. was subjected to a loadin,? 
experiment in which milk plus supplemental 
galactose was given orally so that he ingested 
40 gm. of the sugar per day. On the morning of 
the seventh day, in a fasting state, the galactose 
level in the blood was assayed (as the difference 
between total reducing and glucose oxidase 
reacting material). No circulating galactosc was 
detectable. It was previously reported [2,5] that 
when T. B. was seven years old, the addition of a 
glass of milk with each meal (approximately 
10 to 15 gm. of galactose per day) did not 
produce galactosuria. Indeed, after a single in- 
jection of 10 gm., we have found less than 8 
per cent of the Cl4 in the urine after 24 hours. 
Loading experiments could not be performed 
in the two other patients who showed the ability 
to metabolize tracer doses of galactose. How- 
ever, from the results of the experiments in 
which 1 gm. was given, these patients (P. Br. 
and L. Br.) would be expected to have an even 
greater capacity for handling the sugar than 
T. B. 
Factors Injuencing the Ability to Metabolize 
Galactose. In Table III are summarized the 
Cl402 excretion data from all the studies. The 
patients are listed in order of increasing age, and 
are identified as to sex and race. There appears 
to be no correlation between increasing ability 
to metabolize galactose and age. There subjects 
(H. T., .J. S. and J. D.) aged fourteen, sixteen and 
seventeen years, respectively, metabolize the 
sugar no better than patients aged seven or nine 
years. Clearly the patients here fall into two 
distinct groups, those who excrete from 0 to 8 
per cent of the dose and those whose metabolism 
of galactose falls in the normal or near normai 
range. There is no age correlation in the latter 
group, P. Br. and L. Br. being children and 
T. B. an adult. One patient (L. .J.) was studied 
twice, first at age eleven and then at age fifteen. 
Althoughthe excretion was higher at age fifteen, 
he still remains in the group who metabolize 
little galactose under our test situation. Five 
subjects were postpubertal when studied (see 
Table I), while eight were examined in the 
prepubertal state. (L. J. was studied both before 
and after puberty.) According to these data, 
puberty, like age, appears to play no significant 
role, since there are patients who metabolize 
66 Congenital Galactosemia-Segal et al. 
TABLE III 
THE OXIDATION OF &‘-LABELED GALACTOSE BY 
GALACTOSEMIC PATIENTS 
Age (yr.) 
Sex and Race 
Galactose-1 -Cl4 
gm. /AC. 
Adminis- 
tered Cl4 
in Expired 
Air after 
5 Hours 
(%) 
Galoxtosemic Patient 
J. O’D. 
B. A. 
L. F. 
E. W. 
P. R. 
P. Br. 
6, M, W 
7, M, W 
7, F, W 
9,M,W 
9, F, W 
11 
10, F, N 
L. J. 
L. Br. 
11, M, w 
15 
11, M, N 
H. T. 14, M, W 
J. S. 16,M,W 
J. D. 17, M, W 
T. B. 30, M, N 
- 
0.00042 2 
1.0 2 
0.00042 2 
0.00042 2 
0.00042 2 
1.0 1 
0.00042 2 
1.0 2 
0.00042 2 
0.00042 2 
0.00042 2 
1.0 3 
0.00042 2 
1.0 2 
0.00053 2.5 
1.0 2.5 
0.00053 2.5 
1.0 2.5 
2.0 2.5 
10.0 2.5 
Normal Subjects 
- 
1 
8 
8 
0 
3 
7 
45 
42 
1 
5 
36 
35 
5 
2 
3 
5 
19 
26 
28 
19 
* No. of patients. 
galactose well and those who metabolize it 
poorly in both groups. 
The group of galactosemic subjects is pre- 
dominantly male, 3 to 1. This preponderance of 
males has been noted previously in larger series 
[26,27] and remains unexplained. Whatever the 
reason for this may be, it appears that among 
galactosemic patients, neither sex has a greater 
proportion of individuals capable of metab- 
olizing galactose: one of three females and two 
of nine males metabolized galactose well. 
Again, there is complete overlapping of the 
“metabolizers” and “nonmetabolizers” with 
respect to sex. 
The only correlation evident from these ob- 
servations appears to be that all three patients 
who metabolize galactose to a considerable 
extent are Negro. Also to be noted is the fact 
that P. Br. and L. Br. are siblings. The present 
data are not extensive enough to permit the 
conclusion that the differences observed are 
racially determined (although this conclusion is 
perhaps suggested). L. Br. and P. Br. may have 
fallen into the same group not because they are 
Negro, but simply because they are members 
of the same family. 
The Pathway of Galactose Metabolism in Patients 
Metabolizing the Sugar. The known pathways of 
galactose metabolism are shown in Figure 4. 
Galactose is phos+horylated to galactose-l- 
phosphate (Gal-l-P) which then reacts with 
uridinediphosphoglucose (UDPGlu) to form 
uridinediphosphogalactose (UDPGal) plus glu- 
cose-l-phosphate. UDPGal then undergoes epi- 
merization at the fourth carbon, changing the 
spatial position of the hydroxyl group, thereby 
converting the UDPGal to UDPGlu. The latter 
is then cleaved to form glucose-l-phosphate, 
which then enters into the glucose pathway to 
carbon dioxide. The enzyme at B (in Fig. 4), 
P-Gal transuridylase or galactose-1 -phosphate 
uridyl transferase, is the deficient enzyme in 
galactosemia. An alternate pathway has been 
described in the rat [28] which can circumvent 
the block at B. In this pathway Gal-l-P reacts 
with uridinetriphosphate to form UDPGal, 
which then reacts with epimerase at C. The net 
result of this somewhat intricate scheme of re- 
actions is the conversion of galactose to glucose. 
The conversion of infused C14-galactose to 
circulating blood glucose has been demonstrated 
in normal subjects [24]. A study was therefore 
carried out to ascertain whether the Cl402 
excreted by patient T. B. after the administra- 
tion of C14-galactose was derived from the oxida- 
tion of circulating C14-glucose. The conversion of 
galactose to C14-glucose would indicate that the 
pathway was analogous to that of the normal 
and not some unknown pathway perhaps in- 
CONVENTIONAL 
I) GALACTOSE A ,GAL.I-P 
2) GAL-I.P+ URIDINEOIPHOSPHOGLUCOSE AUOPGAL + GLUCOSE-1.P 
3) UDPGAL C c UDPGLUCOSE 0 GLUCOSE.1.P 
ALTERNATE 
GAL-l-P + URIDINE TRIPHOSPHATE _,UOPGAL+ P.P 
FIG. 4. Galactose metabolic pathway. A = galacto- 
kinase; B = P-Gal transuridylase; C = UDPGal-4- 
epimerase ; D = UDPGlu pyrophosphorylase; E = 
UDPGal pyrophosphorylase. 
AMERICAN JOURNAL OF MEDICINE 
Congenital Galactosemia--Se~~Nl rl fil. 
volT,.ing tllc direct oxidation of galactose. The 
results of such an experiment are shown in 
Tablo IV, in which the conversion of Ci4-galac- 
tose to blood glucose is compared in two normal 
subjects and patient T. B. Fifteen minutes after 
injection, T. B.‘s blood glucose was as highly 
labeled as that of the normal control subjects. 
Another type of experiment was performed in 
order to learn whether the metabolism of galac- 
tose in patients L. Br. and T. B. involved the 
epimerase reaction (C in Fig. 4). It is known 
that the epimerase reaction is highly sensitive 
to the intracellular concentration of reduced 
diphosphopyridine nucleotide, DPNH [29,30], 
and that the elevated DPNH levels produced by 
ethanol administration will impede the con- 
version of C14-galactose to Cl402 in normal sub- 
jects [24]. Therefore, a comparison was made of 
CWZ excretion in a control state and after the 
oral administration of ethanol. Figure 5 shows 
the results obtained in an eleven year old pa- 
tient (L. Br.). After the administration of 10 
ml. of ethanol, galactose metabolism was in- 
hibited to the same extent as in normal subjects 
[2.d]. A parallel (although less striking) response 
to ethanol ingestion was observed in T. B. 
Thus, it seems that these “galactosemic” pa- 
tients have a pathway for galactose metabolism 
which involves conversion of galactose to glucose 
and involves the epimerase reaction. The exact 
mechanism whereby this is accomplished re- 
mains obscure. 
1 ‘rinary Excretion of Cl4 after Galactose- l-C’4 
TABLE IV 
DISTRIBUTION OF Cl4 IN BLOOD AFTER 5 PC. 
GALACTOSE-1 -cl4 ADMINISTRATION 
FIG. 5. The effect of ethanol on C’Y& excretion of 
patient L. Br. after the administration of 1 gm. of galac- 
tose containing galactose-1 -tY. 
Administration. Urinary Cl4 excretion during 
the 24-hour period after injection of the isotope 
was measured. Between 1 and 5 per cent of the 
administered tracer dose or 1 gm. dose was 
excreted in the urine by all the galactosemic 
patients, regardless of whether or not they were 
able to metabolize the sugar. Similar fractions 
of administered doses are excreted by normal 
subjects via this route. In patients unable to 
metabolize the sugar, much of the label was 
probably sequestered in tissue as galactose-l- 
phosphate. Therefore, measurement of the frac- 
tion of a tracer dose of radioactively labeled 
galactose excreted in the urine does not help to 
distinguish normal subjects from persons unable 
to metabolize the sugar. 
COMMENTS 
T 
Time A.fter 
Cl4 in Blood (d.p.m./lOO ml.) 
Injection 
(min.) 
I I 
Total Galac- Glucose 
C’4 tose Cl4 C” 
L 
Normal Subjects 
, I 1 I 
M. B. 30 48 400 ) 2,723 18,485 
121 21,000 223 7,305 
.l. F. j 15 43,400 3,402 12,904 
96 20,600 657 5,980 
“Gdactosemic” Patient 
A standardized metabolic test, in which the 
oxidation of galactose-l-Cl4 to Cr40z was meas- 
ured over a 5-hour period, has been applied to 
twelve patients, children and adults, each of 
whom had a history of galactose intoxication 
during early infancy, and exhibited one or more 
residual physical findings documenting the 
presence of galactose intoxication earlier in life. 
Every one of the patients fulfilled the definitive 
laboratory criteria for the diagnosis of con- 
genital galactosemia : absence of galactose- 
l-phosphate uridyl transferasein the red blood 
cells [ 121 and complete inability of hemolysates 
to oxidize galactose-l-Cl4 to G402 in vitro [ 151. 
The results indicate that the majority of patients 
with this condition were able to metabolize only 
a very small fraction of the administered galac- 
VOL. 38, JANUARY 1965 
68 Congenital Galactosemia-&gal et al. 
tose during the test period (0 to 8 per cent). The 
curves obtained for these latter patients suggest 
that the slight amount of galactose metabolism 
observed during the 5-hour test period continues 
beyond this period. It is possible that over an 
extended period of time (say, 24 to 48 hours), the 
cumulative metabolism of the administered 
tracer dose of galactose might reach substantial 
proportions, approaching those seen in normal 
subjects during the 5-hour period. 
The results also indicate that within a group 
of subjects with typical galactosemia in infancy, 
a subgroup can be distinguished in childhood, 
the members of which possess metabolic path- 
ways for galactose metabolism in tissues other 
than red blood cells. Although one of the pa- 
tients able to metabolize considerable amounts 
of the sugar is a thirty year old adult, galactose 
ingestion studies performed when he was seven 
years old [25] suggest he was capable of metab- 
olizing the sugar even at that age. 
On reviewing the clinical histories (Table 
II), there is no clear-cut evidence that the 
syndrome of galactose toxicity during infancy 
differed in any way with respect to severity or 
time of onset in this subgroup as compared with 
the majority of galactosemic patients (those who 
metabolize the sugar poorly). Indeed, patient 
T. B. (who can metabolize galactose) was the 
first American patient described [7] with what 
might be called the classic symptoms of the 
disease, and the description of his disease served 
as the prototype for recognition of the disease in 
the patients J. D., J. S. and L. J. studied here, 
as well as all others. Why members of this sub- 
group were affected by the toxicity syndrome at 
all is problematic. There are two possible ex- 
planations that suggest themselves immediately: 
(1) this metabolic capability did not arise until 
some time after infancy, or (2) although present 
at birth, it was not sufficient to handle the rela- 
tively large proportions of dietary galactose 
during infancy. 
The ability of three of twelve galactosemic 
patients to metabolize galactose cannot be cor- 
related with age, puberty or sex. The only ap- 
parent correlation is the fact that these three 
patients are Negro. Any definitive statement 
concerning this, however, must await the study 
of more Negro patients with galactosemia. 
An interesting observation resulting from these 
experiments is that most galactosemic subjects 
do not develop an increased capacity for metab- 
olizing galactose as they progress from childhood 
to adult life. It has been stated in the literature 
that galactose tolerance improves in galac- 
tosemic patients as they grow older [28], and 
that there is a relative lack of acute symptoms 
[27]. In explanation of this observation, the 
hypothesis has been advanced that as these pa- 
tients grow older, alternate pathways of galac- 
tose metabolism develop which circumvent the 
inherited block in metabolism. Isselbacher [28] 
showed that in the liver of the maturing normal 
rat, the alternate pathway involving the enzyme 
UDPGal pyrophosphorylase increases in activity 
(Fig. 4.) (Despite this, however, actual galactose 
utilization in older rat liver decreases with age 
[ 761.) The present findings clearly establish 
that alternate pathways do not develop in most 
older galactosemic subjects. 
This does not, however, alter the fact that 
acute symptoms resulting from galactose in- 
gestion are observed less frequently in older 
patients with galactosemia. Patient J. D., age 
seventeen, who metabolizes little galactose, 
related that until the age of twelve or thirteen 
the ingestion of milk or ice cream resulted in 
immediate nausea and vomiting, whereas after 
this period he could ingest milk without having 
any symptoms. Perhaps the best explanation for 
the relative lack of toxicity in older patients is a 
change in tissue sensitivity to whatever toxic 
factor accumulates as a result of the inability to 
metabolize galactose. 
The physician is frequently faced with the 
problem of deciding whether or not small 
amounts of galactose may be added to the diets 
of older galactosemic patients without causing 
damage to the patient. Before this question can 
be answered definitively, further study of the 
clinical and metabolic aspects of galactose 
toxicity is required. However, in the light of the 
limited information presently available, galac- 
tose should not be added to the diet on the as- 
sumption (shown to be erroneous by the data 
reported here and elsewhere [ 761) that the older 
patient possesses an increased ability to metab- 
olize this sugar. 
The diagnostic tests used for this disease 
deserve some comment. It was pointed out that 
the red cells of all twelve patients lack the 
transferase enzyme and are incapable of oxi- 
dizing galactose-l-C4 to Cr40z in vitro. Both of 
these assays correlate perfectly with the presence 
of the galactose toxicity syndrome in infancy. 
Since, however, some patients are able to 
metabolize galactose to carbon dioxide in vZUO, 
AMERICAN JOURNAL OF MEDICINE 
Congenital Galactosemia-Sqal et al. 60 
the results of the erythrocyte tests do not 
necessarily reflect the capacity of the intact 
organism to metabolize the sugar. 
It is apparent that although the red cells of 
the metabolizing patients do not oxidize galac- 
tose-1 -C4, some tissue or tissues within the body 
must be capable of metabolizing galactose. An 
examination has been made into the metabolic 
capability of several tissues from patient T. B. 
[37]. Red cells, white cells, skin cells in tissue 
culture, small intestinal mucosa and liver speci- 
mens obtained by punch biopsy were analyzed 
by the galactose-l-Cl4 oxidation test. Of these 
tissues, only liver was capable of the oxidation in 
an almost normal fashion. The latter finding is 
paralleled by that reported here showing the 
rapid conversion of galactose to circulating 
blood glucose, a process most extensively carried 
out by liver tissue. The effect of ethanol on 
galactose oxidation suggests that the epimerase 
reaction is involved in the pathway, but the 
exact biochemical sequence involved, as well as 
the genetic and metabolic regulatory mecha- 
nisms resulting in a phenotypic difference among 
the various tissues, remains to be investigated. 
SUMMARY 
Galactose-1 -Cl4 oxidation has been studied in 
twelve subjects fulfilling the diagnostic criteria 
of congenital galactosemia. Nine patients, aged 
six to seventeen years, were found to metabolize 
the sugar poorly, without any increase in this 
capacity with increasing age. Three patients, 
two children and one adult, all Negro, were 
found to metabolize 1 gm. of galactose to a 
normal extent. This metabolism involves the 
conversion of galactose to blood glucose and 
takes place in the liver, which can metabolize 
the sugar although other tissues cannot. The 
results indicate that in most galactosemic pa- 
tients alternate metabolic pathways for metab- 
olizing galactose do not develop. Although 
enzymologic red cell diagnostic procedures are 
consistent with the presence of the galactosemic 
syndrome, they do not necessarily reflect the 
in vivo capacity for metabolizing galactose. 
Acknowledgment: We gratefully acknowledge 
the cooperation of the following physicians who 
contributed to these studies by the referral of 
patients: James Sidbury Jr., Vincent L. 
O’Donnell, Ruth Harris, George Guest, 
Angelo Di George, EugeneGoldstein and 
Thomas Eagan. 
VOL. 38, JANUARY 1965 
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