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CASE REPORT
Elevated urine oxalate and renal calculi in a classic galactosemia
patient on soy-based formula
Julia A. Sabatino
1
| Danielle Starin
1
| Shamir Tuchman
2
| Carlos Ferreira
3
|
Debra S. Regier
1
1
Genetics and Metabolism, Rare Disease
Institute, Children's National Medical
Center, Washington, District of Columbia
2
Department of Nephrology, Children's
National Medical Center, Washington,
District of Columbia
3
National Human Genome Research
Institute, National Institutes of Health,
Bethesda, Maryland
Correspondence
Debra S. Regier, Department of Genetics
and Metabolism, Rare Disease Institute,
Children's National Medical Center,
111 Michigan Ave, NW, Washington DC
20010.
Email: dregier@childrensnational.org
Communicating Editor: Nancy Braverman
Abstract
Classic galactosemia results from a deficiency in the galactose-1-phosphate
uridylyltransferase (GALT) enzyme, which is essential for galactose metabolism.
Treatment focuses on lactose restriction and is achieved with a soy-based diet. Pre-
viously, renal calculi have not been documented in galactosemia patients. We pre-
sent a patient with galactosemia nutritionally dependent on soy-based formula via
G-tube, who developed renal calculi. Analysis of urinary stone risk factors revealed
elevated urine oxalate levels and stone analysis confirmed calcium oxalate compo-
sition. Initiation of lactose- and soy-free elemental formula returned urine oxalate
level to normal. Given the presence of a metabolic pathway for the conversion of
galactose to oxalate, and the high content of oxalate in soy-based formula, there is
the potential for elevated urine oxalate and a resulting risk of urinary calculi forma-
tion in patients with classic galactosemia. This potential can be effectively man-
aged with a lactose and soy-free elemental diet. This report describes the clinical
course and novel findings of calcium oxalate urinary calculi in a classic galacto-
semia patient dependent upon soy-based formula, with a discussion regarding the
multiple factors leading to increased stone formation in this patient.
KEYWORDS
galactose-1-phosphate uridylyltransferase, galactosemia, nephrocalcinosis, oxalate, soy, stone
1|INTRODUCTION
Galactosemia disorders encompass three known inborn errors
of galactose metabolism derived from deficiency in the
enzymes galactokinase (GALK1), galactose-1-phosphate
uridylyltransferase (GALT), and UDP-galactose 4-epimerase
(GALE).
1,2
Classic galactosemia is an autosomal recessive
disorder affecting 1 in 40 000-60 000 births, caused by com-
plete or partial deficiency of the GALT enzyme. Deficiency
in galactose metabolism poses an early and life threatening
challenge to a newborn since galactose and glucose are the
two component sugars of lactose, the primary carbohydrate in
both dairy and breast milk. Manifestations of life-threatening
symptoms appear within days of beginning feeding with
breast or formula milk. Early signs include feeding difficul-
ties, failure to thrive, vomiting, lethargy, bleeding abnormali-
ties, and jaundice (Reviewed in
1,3
). Life-threatening sepsis
and meningitis, often caused by Escherichia coli, and cata-
racts can develop.
The GALT enzyme is responsible for converting
galactose-1-phosphate to UDP-galactose in the galactose met-
abolic pathway.
2
Deficiency results in elevated galactose,
Received: 10 December 2018 Revised: 11 April 2019 Accepted: 23 May 2019
DOI: 10.1002/jmd2.12056
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
JIMD Reports. 2019;49:7–10. wileyonlinelibrary.com/journal/jmd2 7
galactose-1-phosphate, galactitol, and galactonate levels.
Newborn screening can detect galactosemia by measurement
of GALT enzyme activity and total galactose level. Confirma-
tory testing for classic galactosemia includes levels of erythro-
cyte galactose-1-phosphate and genetic testing for mutations
in the GALT locus on chromosome 9.
3
Treatment of classic galactosemia is urgent in the first few
days of life and includes immediate lactose restriction by
switching to soy-based formula. Lactose restriction results in
rapid clinical improvement.
1,3
However, galactose is obtained
through both dietary sources and by endogenous synthesis,
therefore even in patients with no lactose intake from the diet,
levels of erythrocyte galactose-1-phosphate remain elevated.
Long-term outcomes in patients with treated galactosemia
include mild growth delay, decreased bone density, delayed
speech development, verbal dyspraxia, cerebellar ataxia, and
dystonia (Reviewed in ref.
1
). These complications are consid-
ered diet independent and can appear in patients with well-
controlled erythrocyte galactose-1-phosphate level.
While not previously described in the galactosemia popu-
lation, nonambulatory patients are at increased risk for kid-
ney stones. The underlying mechanism appears to be the
decreased mineralization of bone, leading to increased uri-
nary excretion of calcium. In addition, low volume intake
can lead to increased stone formation, which can be seen in
nonambulatory individuals on G-tube feeding plans.
Here, we present a patient with classic galactosemia and
a history of E. coli meningitis as a neonate that lead to
severe, global delays. Following dependence on soy-based
formula via gastric tube (G-tube), he developed calcium oxa-
late urinary calculi. Previously galactosemia and renal cal-
culi have not been associated, however, we will demonstrate
a clinical course and metabolic pathway that intertwines
these conditions.
2|CLINICAL CASE
Our patient is a 14-year-old male with classic galactosemia with
significant neurologic injury caused by neonatal septicemia with
E. coli. He has severe mobility limitations, leading to wheelchair
confinement, and oral feeding intolerance, leading to depen-
dency on gastric-tube nutrition. He was placed on a soy-based
formula. Additionally, he is status postplacement of two ven-
triculoperitoneal shunts for hydrocephalus with a history of sei-
zures, kyphoscoliosis, and optic atrophy without cataracts.
Following a trauma event, he returned to care at a center
with metabolic specialists at age 9 years. GALT enzyme activ-
ity was tested to determine optimal dietary options and was con-
sistent with classic galactosemia (Gal-1-P Uridyltransferase
<2.0 μmol/hr/mmol Hb, reference range > 18.5 μmol/hr/mmol
Hb). Erythrocyte galactose-1-phospate was in the treatment
range. Soy-based formula was continued to meet his nutritional
needs at this time.
The patient represented at age 12 with repeated episodes of
urinary retention treated by catheterization. Repeated renal/
bladder ultrasounds and a noncontrast abdominal CT scan over
the subsequent 2 years indicated urinary calculi within the kid-
neys and bladder wall. The largest imaged stone was 1 cm in
diameter in the bladder. The patient presented with recurring
symptoms of stone passage and was treated for repeated uri-
nary tract infections/colonization with Enterococcus faecalis.
Throughout this time, renal/bladder ultrasounds continued
to demonstrate renal and bladder calculi, the patient's eryth-
rocyte galactose-1-phosphate was in the treatment range
(3.1 mg/100 mL RBC, reference range for treated galacto-
semia <15), and he remained on soy-based formula.
Given persistent urinary calculi formation, additional testing
was performed and showed minimal elevation of 25-hydroxy
vitamin D3 (56 ng/mL, normal range 10-44 ng/mL), and spot
random urine oxalate to creatinine ratio (99 mg/g creatinine
[Cr], reference range < 75 mg/g Cr). At this time, supplemen-
tation with cholecalciferol was discontinued. On follow-up, the
patient continued to demonstrate persisting urinary calculi on
ultrasound and an elevated urine oxalate to creatinine ratio
(259 mg/g Cr, reference range < 75 mg/g Cr).
Soybeans contain relatively high levels of oxalic acid.
4-7
Oxalate content of foods is not reported by food manufac-
turers and oxalate levels are also not standard in the food
nutrient analysis by the USDA for the food composition
database. For this reason, it is difficult to determine the exact
amount of oxalate in soy-based foods and formulas he was
receiving. Two studies measured oxalate content in soymilk
and showed a range from 0.02 to 1.4 mg/g protein.
5
Extrapo-
lating this range to the pediatric soy drink (since information
not available from the manufacturer) indicated he was
receiving 24-1680 g of oxalate per day. Cow's milk has been
estimated by an online resource as being low to very low
with a range of 0.004-0.02 g/g protein.
8
Thus, soy milk has
up to 3500-fold more oxalate per gram than cow's milk.
Based on the patient's unique dependence on purely soy-
based formula, a change to a lactose- and soy-free elemental
formula was performed as a trial. Following this change,
urine oxalate levels quickly fell within normal limits
(49 mg/g Cr). Additionally, retrieval and stone analysis dem-
onstrated calculi composition to be 50% calcium oxalate and
50% carbonate apatite.
3|DISCUSSION
Failure of the GALT enzyme in galactosemia leads to accumu-
lation of galactose in the body. This build up can be managed
effectively with restriction of lactose, although levels will not
be as low as in the general population (Reviewed in
1
). In cases
8SABATINO ET AL.
when the conversion of galactose to glucose is impaired, as in
galactosemia, excess galactose has been shown to favor an
alternative direct oxidative pathway.
9
The presence of this
alternative oxidative pathway in galactosemic patients was
proven by intravenous injection of a radioactive galactose
tracer, followed by measurement of radioactively labeled CO
2
in expired air.
10
This pathway purportedly leads to the forma-
tion of D-xylulose,
11
while the latter is eventually converted to
oxalate
10,12
(Figure 1). Activity of the first committed enzyme
in this proposed pathway, that is, galactose dehydrogenase,
has been found in mammalian liver-including human liver-
with 90% of the activity present in the soluble cellular fraction,
and 10% in the microsomal fraction.
11
The second branch of
the pathway, from D-xylulose to oxalate, was found in human
liver based on radioactive tracer studies and enzyme assays;
these studies suggested that the major regulation in the conver-
sion of carbohydrates to oxalate occurs at the level of the
enzymes participating in glycolate and glyoxylate metabo-
lism.
10
Although the final products of these two halves of the
oxidative pathway have been confirmed, the intermediate steps
remain hypothetical, especially until further delineation at the
molecular level can be established.
Additionally, this patient had an exclusively soy-based
diet. Since soy foods contain relatively high levels of oxa-
late;
5-7
thus, he had both increased intake and increased pro-
posed production of oxalate. Taylor and Curhan [11] showed
oxalate intakes were 214 mg/d in men, 185 mg/d in older
women, and 183 mg/d in younger women. Thus, this patient
had up to 8 times the average intake of oxalate for the
typical male.
Further, supplementation with calcium and vitamin D are
recommended in classic galactosemia patients to prevent
bone demineralization.
1
This may lead to increased urinary
calcium excretion due to impaired bone mineral accrual,
especially in patients that are not ambulatory. Together,
increased urine oxalate and calcium excretion heightens the
potential for calcium oxalate urinary calculi formation.
This case may represent a discrete subset of patients with
classic galactosemia, who are solely dependent on soy-based
formula. In addition, he had elevated risks for renal stones
due to decreased mobility and lack of weight-bearing exer-
cise. Thus, this sub-population of patients with galactosemia
are at an even higher than expected risk for stone formation.
We demonstrate that a simple intervention of a dietary
change to lactose- and soy-free elemental formula can effec-
tively reduce urine oxalate levels.
Although there are many long-term sequelae associated
with treated galactosemia, urinary calculi have not previ-
ously been documented. This case demonstrates a proposed
connection between galactosemia and urinary calculi forma-
tion and highlights the need to consider urinary calculi and
urine oxalate levels in the galactosemia patient population,
and particularly in those who are solely dependent on soy-
based formula and/or nonambulatory.
Galactose
Xylulose
Oxalate
Galactose-1-P
Glucose-1-P
UDPglucose
UDPgalactose
GALT
Glycolaldehyde
Xylulose-1-P
Glycolate
Glyoxylate
Calcium Oxalate
Glucose-6-P
GALE
GALK
Ca+2
Fructokinase
DHAP
Aldolase
Aldehyde dehydrogenase
Glycolate oxidase
Lactate dehydrogenase
FIGURE 1 Proposed mechanism for the formation of oxalate as an alternative pathway of galactose metabolism in Classic Galactosemia.
Blocked metabolism of galactose is shown by the deficiency in galactose-1-phosphate uridyltransferase (GALT). Galactose metabolism can proceed
by conversion to xylulose by the enzyme galactose dehyrogenase. Xylulose is converted to xylulose-1-phosphate by the enzyme fructokinase and
then to glycolaldehyde and dihydroxyacetone phosphate (DHAP) by an aldolase. Glycolaldehyde is first converted to glycolate by aldehyde
dehydrogenase and then to glyoxylate by glycolate oxidase before final conversion to oxalate by lactate dehydrogenase. The addition of calcium
results in the formation of calcium oxalate
SABATINO ET AL.9
4|CONCLUSIONS
Classic galactosemia is present in 1 in 40 000-60 000 new-
borns. Immediate lactose restriction is extremely important in
preventing life threatening multiorgan damage in these patients.
Patients with classic galactosemia are known to metabolize
excess galactose via an alternative oxidative pathway that gives
rise to D-xylulose, which in turn is converted to oxalate. When
utilizing a soy-based formula to treat patients with classic
galactosemia, elevated urine oxalate levels may indicate the
potential for urinary calculi formation and should be moni-
tored. Modification of the diet to lactose- and soy-free elemen-
tal formula can significantly reduce urine oxalate levels and
should be considered for galactosemia patients with elevated
kidney stone risk based on other risk factors.
AUTHOR CONTRIBUTIONS
Julia A Sabatino provided clinical care and drafted the man-
uscript. Danielle Starin provided clinical care and edited the
manuscript. Shamir Tuchman provided clinical care and
edited the manuscript. Carlos Ferreira provided extensive
discussion and laboratory knowledge and edited the manu-
script. Debra S Regier provided clinical care and wrote and
edited sections of the manuscript.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
A PATIENT CONSENT STATEMENT
The family of the patient described provided informed con-
sent for publication of this case.
ORCID
Carlos Ferreira https://orcid.org/0000-0002-2697-1046
Debra S. Regier https://orcid.org/0000-0001-7525-0088
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How to cite this article: Sabatino JA, Starin D,
Tuchman S, Ferreira C, Regier DS. Elevated urine
oxalate and renal calculi in a classic galactosemia
patient on soy-based formula. JIMD Reports. 2019;
49:7–10. https://doi.org/10.1002/jmd2.12056
10 SABATINO ET AL.
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