AM Bosch

Annet M. Bosch

B Panis

C Ficicioglu

CO Zlatunich

D Turck

DD Waggoner

FR Kaufman

GT Berry

HB Salt

HH Huidekoper

HH Mason

JB Holton

KC Gross

NL Jones

NL Potter

P Schadewaldt

PB Acosta

PJ Lee

RJ Merritt

S Schweitzer

S Schweitzer-Krantz

S Segal

SM Thompson

UN Wiesmann

Y Ai

PubMed

Bosch, A.M.

NARCIS 

Classic galactosemia: dietary dilemmas

Bosch, Annet M.

International Migration, Integration and Social Cohesion online publications

UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Classic galactosemia: dietary dilemmasBosch, A.M.DOI10.1007/s10545-010-9157-8Publication date2011Document VersionFinal published versionPublished inJournal of inherited metabolic diseaseLink to publicationCitation for published version (APA):Bosch, A. M. (2011). Classic galactosemia: dietary dilemmas. Journal of inherited metabolicdisease, 34(2), 257-260. https://doi.org/10.1007/s10545-010-9157-8General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:24 Jan 2024EDITORIALClassic galactosemia: dietary dilemmasAnnet M. BoschReceived: 15 March 2010 /Revised: 15 March 2010 /Accepted: 14 June 2010 /Published online: 13 July 2010# The Author(s) 2010. This article is published with open access at Springerlink.comIntroductionClassic galactosemia (McKusic 230400) is an inborn errorof galactose metabolism caused by a deficiency of theenzyme galactose-1-phosphate uridyltransferase (GALT,EC 2..7.712), resulting in accumulation of the metabolitesgalactitol and galactose-1-phosphate. Patients ingestinggalactose from breast milk or infant formula present in thefirst weeks of life with feeding difficulties, hepatocellulardysfunction, hypoglycemia, renal tubular dysfunction,cataract, and sepsis. Immediate removal of galactose fromthe diet results in a full recovery from this life-threateningneonatal crisis (Holton et al. 2001; Bosch 2006).Mason and Turner (1935) were the first to report thesuccessful use of a milk-free diet in an infant withgalactosemia. In the 1950s, different strategies to feedinfants a diet without galactose were discussed in theliterature (Salt et al. 1955; Jones and Leak 1959).Nowadays, initiating the diet is much easier, as infantformulas with a very limited amount of galactose arewidely available. Still, there are dilemmas in the treatmentof galactosemia, and the dietary treatment varies widelyaround the world. The most troubling issue is that despite acontinued galactose-restricted diet, and irrespective of aneonatal crisis, many patients suffer from long-termcomplications, such as reduced cognitive ability, languageimpairment, decreased bone mass, and hypergonadotrophichypogonadism in women (Kaufman et al. 1981; Waggoneret al. 1990; Schweitzer et al. 1993; Panis et al. 2004; Potteret al. 2008; Schadewaldt et al. 2010).InfancyIn the first weeks of life, the most important part ofmanaging patients with classic galactosemia is removingall galactose from the diet as soon as the diagnosis issuspected, immediately after starting the diagnosticinvestigations and without awaiting results, in order toprevent further life-threatening complications. Whereasclassic galactosemia is part of the newborn screeningprograms of many countries, most children will presentwith clinical symptoms, such as feeding problems,jaundice progressing to liver failure, and sepsis, beforethe screening results are available. Infants with classicgalactosemia must be prescribed a galactose-free formu-la. In The Netherlands, the recommended treatment issoy milk; in some other countries, infant formula on thebasis of casein hydrolysate and dextrine maltose ascarbohydrate source, such as Nutramigen®, is recom-mended. The safety of long-term use of soy milk has beenmuch debated; however, there is no clinical evidence forharmful effects of this product (Merritt and Jenks 2004; Turck2007). Both Nutramigen and soy formula still contain verysmall amounts of galactose, and recent studies demonstratedthat completely eliminating galactose from the diet byprescribing an elemental formula (Neocate®) instead ofNutramigen® or soy formula caused a significantly fasterdecrease of the high erythrocyte Gal-1-P values that arefound in infancy in these patients (Ficicioglu et al. 2005;Zlatunich and Packman 2008). As the time of diagnosis andCommunicated by: Gerard T. BerryCompeting interest: None declared.A. M. Bosch (*)Department of Pediatrics (H7-270), Academic Medical Center,University of Amsterdam,Meibergdreef 9,1105 AZ Amsterdam, The Netherlandse-mail: a.m.bosch@amc.uva.nlJ Inherit Metab Dis (2011) 34:257–260DOI 10.1007/s10545-010-9157-8the occurrence of the neonatal crisis do not seem to have asignificant effect on long-term outcome, it remains to beelucidated whether this rapid decrease would positivelyaffect outcome, and long-term studies need to be performedto clarify this before routinely putting these infants on thisexpensive and unpalatable formula (Schweitzer-Krantz2003).ChildhoodWith the introduction of solid foods, some galactose willinevitably be introduced into the diet, as many foods, suchas fruit and vegetables, bread, legumes, and offal, containtrace amounts of galactose (Gross and Acosta 1991; Acostaand Gross 1995). Bound galactose is found in manyvegetables as part of raffinose and stachyose. How muchof this bound galactose can be broken down in the gut isnot known. No significant contribution to the intake ofgalactose, or effect on biochemical parameters, has beendemonstrated (Wiesmann et al. 1995).There are major controversies concerning the dailyallowance of galactose during long-term treatment. ManyEuropean metabolic centers recommend a very strict diet,also restricting galactose containing fruits and vegetables.Other centers, e.g., in the UK, Germany, The Netherlands,and the USA, are more liberal, advising only a lactose-freediet. There is limited knowledge of the tolerance forexogenous galactose in patients with classic galactosemia.A newborn infant with galactosemia ingesting 300 ml offormula or breast milk per day in the first days of life,equivalent to >7,000 mg of galactose, will develop severeillness. As soon as the diagnosis is suspected, the galactoseintake will be restricted as much as possible. Patients on alactose-free diet with no restrictions of fruit and vegetableswill have a daily intake of galactose <30 mg (Berry et al.1993; Bosch et al. 2004a). On a diet enriched in fruit andvegetables, this intake increases to an average of 54 mg ofgalactose per day (Berry et al. 1993). In one study, threeadolescents ingested up to 600 mg of galactose per day for6 weeks without any effect on clinical or laboratoryparameters (Bosch et al. 2004a). Of importance is thestrong contrast between the exogenous intake of galactosein the lactose-restricted diet, with an average intake of54 mg of galactose per day with a diet enriched ingalactose-containing fruit and vegetables and the endogenousproduction of galactose in adult patients, amounting to1,000 mg per day (Berry et al. 2004, Huidekoper et al.2005). This fact is an argument not to restrict fruit andvegetables from the diet. Also, after the introduction of a lessrestricted diet in Australia, no increases in gal-1-p valueswere detected (Thompson et al. 2003). Furthermore, in theUK, where fruit and vegetables are not restricted from thediet, no new cataracts or liver diseases have been reported inthe literature. It has been demonstrated that the endogenousproduction of galactose is not affected by the exogenousintake from the diet. (Huidekoper et al. 2005)AdulthoodThere is no insight into galactose tolerance of adultspatients with classic galactosemia. Two remarkablepatients have been reported in the literature. A 38-year-old adult woman and a 34-year-old man, both withclassic galactosemia (Q188R homozygous), had bothdiscontinued their diet at the age of 3 years (Lee et al.2003; Panis et al. 2006). Her intake of galactose was2,690 mg per day, and his daily galactose intake was9,000 mg. In both patients, there were no signs of cataractor liver disease, and red cell galactose-1-phosphate andurine galactitol were within the range of treated galacto-semics. The female patient had started hormonal replace-ment therapy at 15 years of age because of primaryamenorrhoea. Her neuropsychological assessment showeda verbal IQ of 88 and a performance IQ of 78; tests ofattention, memory, and executive functions were belowthe tenth percentile for a normal population. The malepatient had an unremarkable neurologic examination anda normal educational attainment. His in vivo oxidation of[1-13C] galactose was evaluated and found to beseverely hampered and within the range for treatedpatients. These patients’ outcomes seem no worse thanin many patients with classic galactosemia treated with astrict diet. It is very well possible that the galactosetolerance of patients with classic galactosemia increaseswith age as a result of the age-related decrease ofendogenous galactose production (Berry et al. 2004;Schadewaldt et al. 2004). It might also be possible thatthese patients have a greater capacity to dispose ofgalactose by pathways yet unknown. Alternatively, otherfactors, such as an aldose reductase deficiency as reportedin the galactosemic mouse, may play a role (Ai et al. 2000;Segal 2004). In addition, it is not known whether red cellgalactose-1-phosphate or urinary galactitol reflect thelong-term toxicity of galactose in galactosemia. Long-term exposure to galactose could result in abnormalgalactosylation of glycoproteins and glycolipids, and thesepatients might well have had an even better cognitiveoutcome if they had continued their diet.Future perspectivesBased on the theory that exogenous galactose toleranceincreases in adulthood, partly due to the relative decrease in258 J Inherit Metab Dis (2011) 34:257–260endogenous production, relaxation of the galactose-restricted diet in adulthood might be considered (Berry etal. 2004; Schadewaldt et al. 2004). A slight relaxation, suchas a lactose-restricted diet without limitations in intake infruit and vegetables can very well be justified in the light ofthe available evidence and is the standard of care in manycountries. Increasing the daily galactose intake from 27 to54 mg per day is a minor increase when considering thefact that an adult will have an endogenous production up to1,000 mg per day (Berry et al. 2004; Huidekoper et al.2005). A further relaxation of the diet, however, will causea major increase of daily galactose intake. As milk andmilk-containing products such as yoghurt contain 2,400 and1,800 mg of galactose per 100 mg, respectively, the intakeof even one glass of milk rapidly increases the daily intaketo more than 4,800 mg per day, more than four times thedaily endogenous production. Therefore, full dietary relax-ation should probably be strongly discouraged until thepathophysiology behind the long-term complications hasbeen elucidated and it is clear whether or not this is relatedto galactose intake. Long-term studies, preferably afterdeveloping a more valid biochemical marker forgalactose toxicity, evaluating the biochemical and clinicaleffects of exogenous galactose in adults as well as inchildren, are necessary before any further relaxation ofthe diet can be considered.Even though a lifelong diet will affect the daily lives ofthe patients, a lactose-free diet without restriction of fruitand vegetables is a palatable and not very complicated diet.Studies have demonstrated that patients with classicgalactosemia have a severely hampered quality of life(Bosch et al. 2004b). However, it has been demonstratedthat this is the result of the late complications that are foundin many patients and not a result of the diet (Bosch et al.2009). As the late complications may result fromcontinuous intoxication by galactose from endogenousproduction, dietary relaxation might well increase thelong-term complications by rapidly increasing galactoseload and thus affect patients’ quality of life even more.Open Access This article is distributed under the terms of the CreativeCommons Attribution Noncommercial License which permits anynoncommercial use, distribution, and reproduction in any medium,provided the original author(s) and source are credited.ReferencesAcosta PB, Gross KC (1995) Hidden sources of galactose in theenvironment. Eur J Pediatr 154(suppl 2):s87–s92Ai Y, Zheng Z, O’Brien-Jenkins A, Bernard DJ et al (2000) A mousemodel of galactose-induced cataracts. Hum Mol Genet 9(12):1821–1827Berry GT, Palmieri M, Gross KC et al (1993) The effect of fruit andvegetables on urinary galactitol excretion in galactose-1-phosphate uridyltransferase deficiency. J Inherit Metab Dis16:91–100Berry GT, Moate PJ, Reynolds RA et al (2004) The rate of de novogalactose synthesis in patients with galactose-1-phosphateuridyltransferase deficiency. Mol Genet Metab 81:22–30Bosch AM (2006) Classical galactosaemia revisited. J Inherit MetabDis 29(4):516–525Bosch AM, Bakker HD, Wenniger-Prick LJ, Wanders RJ, WijburgFA (2004a) High tolerance for oral galactose in classicalgalactosaemia: dietary implications. Arch Dis Child 89(11):1034–1036Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HS, WijburgFA, Last BF (2004b) Living with classical galactosemia:health-related quality of life consequences. Pediatrics 113(5):423–428Bosch AM, Maurice-Stam H, Wijburg FA, Grootenhuis MA (2009)Remarkable differences: the course of life of young adultswith galactosaemia and PKU. J Inherit Metab Dis 32(6):706–712Ficicioglu C, Hussa C, Yager C, Segal S (2005) Effect of galactosefree formula on galactose-1-phosphate in two infants withclassical galactosemia. J Inherit Metab Dis 28(2):163–168Gross KC, Acosta PB (1991) Fruit and vegetables are a source ofgalactose: implications of planning the diets of patients withgalactosemia. J Inherit Metab Dis 14:253–258Holton JB, Walter JH, Tyfield LA (2001) Galactosemia. In: ScriverCR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW et al(eds) The metabolic and molecular basis of inherited disease, 8thedn. McGraw-Hill, New York, pp 1553–1583Huidekoper HH, Bosch AM, van der Crabben SN, Sauerwein HP,Ackermans MT, Wijburg FA (2005) Short-term exogenousgalactose supplementation does not influence rate of appearanceof galactose in patients with classical galactosemia. Mol GenetMetab 84(3):265–272Jones NL, Leak D (1959) The treatment of congenital galactosaemia.Arch Dis Child 34:307–311Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C,Koch R (1981) Hypergonadotropic hypogonadism in femalepatients with galactosemia. N Engl J Med 304:994–998Lee PJ, Lilburn M, Wendel U, Schadewaldt P (2003) A woman withuntreated galactosaemia. Lancet 362(9382):446Mason HH, Turner ME (1935) Chronic galactemia, report of case withstudies on carbohydrates. Am J Dis Child 50(2):359–374Merritt RJ, Jenks BH (2004) Safety of soy-based infant formulascontaining isoflavones: the clinical evidence. J Nutr 134:1220s–1224sPanis B, Forget PP, van Kroonenburgh MJ, Vermeer C, Menheere PP,Nieman FH, Rubio-Gozalbo ME (2004) Bone metabolism ingalactosemia. Bone 35(4):982–987Panis B, Bakker JA, Sels JP, Spaapen LJ, van Loon LJ, Rubio-Gozalbo ME (2006) Untreated classical galactosemia patient withmild phenotype. Mol Genet Metab 89(3):277–279Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD(2008) Correlates of language impairment in children withgalactosaemia. J Inherit Metab Dis 31(4):524–532Salt HB, Ross CAC, Gerrard JW (1955) Low-lactose milk forcongenital galactosemia. Lancet 265(6875):1177–1178Schadewaldt P, Amalanathan L, Hammen HW, Wendel U (2004) Agedependence of endogenous galactose formation in Q188Rhomozygous galactosemic patients. Mol Genet Metab 81:31–44Schadewaldt P, Hoffmann B, Hammen HW, Kamp G, Schweitzer-KrantzS, Wendel U (2010) Longitudinal assessment of intellectualachievement in patients with classical galactosemia. Pediatrics 125(2):374–381J Inherit Metab Dis (2011) 34:257–260 259Schweitzer S, Shin Y, Jacobs C, Brodehl J (1993) Long-term outcomein 134 patients with galactosemia. Eur J Pediatr 152:36–43Schweitzer-Krantz S (2003) Early diagnosis of inherited metabolicdisorders towards improving outcome: the controversial issue ofgalactosaemia. Eur J Pediatr 162(Suppl 1):S50–S53Segal S (2004) Another aspect of the galactosemic enigma. Letter tothe editor. Mol Genet Metab 81:253–254Thompson SM, Netting MJ, Jerath S, Wiley V (2003) Effect of a lessrestricted diet in galactosemia. J Inherit Metab Dis 26(suppl2):214Turck D (2007) Soy protein for infant feeding: what do we know?Curr Opin Clin Nutr Metab Care 10(3):360–365Waggoner DD, Buist NRM, Donnell GN (1990) Long-term prognosisin galactosemia: Results of a survey of 350 cases. J Inherit MetabDis 13:802–818Wiesmann UN, Rose-Beutler B, Schluchter R (1995) Leguminosae inthe diet: the raffinose-stachyose question. Eur J Pediatr 154(suppl2):s93–s96Zlatunich CO, Packman S (2008) Galactosaemia: early treatment withan elemental formula. Eur J Pediatr 167(5):595–596260 J Inherit Metab Dis (2011) 34:257–260

English

UvA-DARE

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Classic galactosemia: dietary dilemmas
Bosch, A.M.
Published in:
Journal of inherited metabolic disease
DOI:
10.1007/s10545-010-9157-8
Link to publication
Citation for published version (APA):
Bosch, A. M. (2011). Classic galactosemia: dietary dilemmas. Journal of inherited metabolic disease, 34(2), 257-
260. https://doi.org/10.1007/s10545-010-9157-8
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),
other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating
your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask
the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,
The Netherlands. You will be contacted as soon as possible.
Download date: 04 Feb 2021
EDITORIAL
Classic galactosemia: dietary dilemmas
Annet M. Bosch
Received: 15 March 2010 /Revised: 15 March 2010 /Accepted: 14 June 2010 /Published online: 13 July 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Introduction
Classic galactosemia (McKusic 230400) is an inborn error
of galactose metabolism caused by a deficiency of the
enzyme galactose-1-phosphate uridyltransferase (GALT,
EC 2..7.712), resulting in accumulation of the metabolites
galactitol and galactose-1-phosphate. Patients ingesting
galactose from breast milk or infant formula present in the
first weeks of life with feeding difficulties, hepatocellular
dysfunction, hypoglycemia, renal tubular dysfunction,
cataract, and sepsis. Immediate removal of galactose from
the diet results in a full recovery from this life-threatening
neonatal crisis (Holton et al. 2001; Bosch 2006).
Mason and Turner (1935) were the first to report the
successful use of a milk-free diet in an infant with
galactosemia. In the 1950s, different strategies to feed
infants a diet without galactose were discussed in the
literature (Salt et al. 1955; Jones and Leak 1959).
Nowadays, initiating the diet is much easier, as infant
formulas with a very limited amount of galactose are
widely available. Still, there are dilemmas in the treatment
of galactosemia, and the dietary treatment varies widely
around the world. The most troubling issue is that despite a
continued galactose-restricted diet, and irrespective of a
neonatal crisis, many patients suffer from long-term
complications, such as reduced cognitive ability, language
impairment, decreased bone mass, and hypergonadotrophic
hypogonadism in women (Kaufman et al. 1981; Waggoner
et al. 1990; Schweitzer et al. 1993; Panis et al. 2004; Potter
et al. 2008; Schadewaldt et al. 2010).
Infancy
In the first weeks of life, the most important part of
managing patients with classic galactosemia is removing
all galactose from the diet as soon as the diagnosis is
suspected, immediately after starting the diagnostic
investigations and without awaiting results, in order to
prevent further life-threatening complications. Whereas
classic galactosemia is part of the newborn screening
programs of many countries, most children will present
with clinical symptoms, such as feeding problems,
jaundice progressing to liver failure, and sepsis, before
the screening results are available. Infants with classic
galactosemia must be prescribed a galactose-free formu-
la. In The Netherlands, the recommended treatment is
soy milk; in some other countries, infant formula on the
basis of casein hydrolysate and dextrine maltose as
carbohydrate source, such as Nutramigen®, is recom-
mended. The safety of long-term use of soy milk has been
much debated; however, there is no clinical evidence for
harmful effects of this product (Merritt and Jenks 2004; Turck
2007). Both Nutramigen and soy formula still contain very
small amounts of galactose, and recent studies demonstrated
that completely eliminating galactose from the diet by
prescribing an elemental formula (Neocate®) instead of
Nutramigen® or soy formula caused a significantly faster
decrease of the high erythrocyte Gal-1-P values that are
found in infancy in these patients (Ficicioglu et al. 2005;
Zlatunich and Packman 2008). As the time of diagnosis and
Communicated by: Gerard T. Berry
Competing interest: None declared.
A. M. Bosch (*)
Department of Pediatrics (H7-270), Academic Medical Center,
University of Amsterdam,
Meibergdreef 9,
1105 AZ Amsterdam, The Netherlands
e-mail: a.m.bosch@amc.uva.nl
J Inherit Metab Dis (2011) 34:257–260
DOI 10.1007/s10545-010-9157-8
the occurrence of the neonatal crisis do not seem to have a
significant effect on long-term outcome, it remains to be
elucidated whether this rapid decrease would positively
affect outcome, and long-term studies need to be performed
to clarify this before routinely putting these infants on this
expensive and unpalatable formula (Schweitzer-Krantz
2003).
Childhood
With the introduction of solid foods, some galactose will
inevitably be introduced into the diet, as many foods, such
as fruit and vegetables, bread, legumes, and offal, contain
trace amounts of galactose (Gross and Acosta 1991; Acosta
and Gross 1995). Bound galactose is found in many
vegetables as part of raffinose and stachyose. How much
of this bound galactose can be broken down in the gut is
not known. No significant contribution to the intake of
galactose, or effect on biochemical parameters, has been
demonstrated (Wiesmann et al. 1995).
There are major controversies concerning the daily
allowance of galactose during long-term treatment. Many
European metabolic centers recommend a very strict diet,
also restricting galactose containing fruits and vegetables.
Other centers, e.g., in the UK, Germany, The Netherlands,
and the USA, are more liberal, advising only a lactose-free
diet. There is limited knowledge of the tolerance for
exogenous galactose in patients with classic galactosemia.
A newborn infant with galactosemia ingesting 300 ml of
formula or breast milk per day in the first days of life,
equivalent to >7,000 mg of galactose, will develop severe
illness. As soon as the diagnosis is suspected, the galactose
intake will be restricted as much as possible. Patients on a
lactose-free diet with no restrictions of fruit and vegetables
will have a daily intake of galactose <30 mg (Berry et al.
1993; Bosch et al. 2004a). On a diet enriched in fruit and
vegetables, this intake increases to an average of 54 mg of
galactose per day (Berry et al. 1993). In one study, three
adolescents ingested up to 600 mg of galactose per day for
6 weeks without any effect on clinical or laboratory
parameters (Bosch et al. 2004a). Of importance is the
strong contrast between the exogenous intake of galactose
in the lactose-restricted diet, with an average intake of
54 mg of galactose per day with a diet enriched in
galactose-containing fruit and vegetables and the endogenous
production of galactose in adult patients, amounting to
1,000 mg per day (Berry et al. 2004, Huidekoper et al.
2005). This fact is an argument not to restrict fruit and
vegetables from the diet. Also, after the introduction of a less
restricted diet in Australia, no increases in gal-1-p values
were detected (Thompson et al. 2003). Furthermore, in the
UK, where fruit and vegetables are not restricted from the
diet, no new cataracts or liver diseases have been reported in
the literature. It has been demonstrated that the endogenous
production of galactose is not affected by the exogenous
intake from the diet. (Huidekoper et al. 2005)
Adulthood
There is no insight into galactose tolerance of adults
patients with classic galactosemia. Two remarkable
patients have been reported in the literature. A 38-year-
old adult woman and a 34-year-old man, both with
classic galactosemia (Q188R homozygous), had both
discontinued their diet at the age of 3 years (Lee et al.
2003; Panis et al. 2006). Her intake of galactose was
2,690 mg per day, and his daily galactose intake was
9,000 mg. In both patients, there were no signs of cataract
or liver disease, and red cell galactose-1-phosphate and
urine galactitol were within the range of treated galacto-
semics. The female patient had started hormonal replace-
ment therapy at 15 years of age because of primary
amenorrhoea. Her neuropsychological assessment showed
a verbal IQ of 88 and a performance IQ of 78; tests of
attention, memory, and executive functions were below
the tenth percentile for a normal population. The male
patient had an unremarkable neurologic examination and
a normal educational attainment. His in vivo oxidation of
[1-13C] galactose was evaluated and found to be
severely hampered and within the range for treated
patients. These patients’ outcomes seem no worse than
in many patients with classic galactosemia treated with a
strict diet. It is very well possible that the galactose
tolerance of patients with classic galactosemia increases
with age as a result of the age-related decrease of
endogenous galactose production (Berry et al. 2004;
Schadewaldt et al. 2004). It might also be possible that
these patients have a greater capacity to dispose of
galactose by pathways yet unknown. Alternatively, other
factors, such as an aldose reductase deficiency as reported
in the galactosemic mouse, may play a role (Ai et al. 2000;
Segal 2004). In addition, it is not known whether red cell
galactose-1-phosphate or urinary galactitol reflect the
long-term toxicity of galactose in galactosemia. Long-
term exposure to galactose could result in abnormal
galactosylation of glycoproteins and glycolipids, and these
patients might well have had an even better cognitive
outcome if they had continued their diet.
Future perspectives
Based on the theory that exogenous galactose tolerance
increases in adulthood, partly due to the relative decrease in
258 J Inherit Metab Dis (2011) 34:257–260
endogenous production, relaxation of the galactose-
restricted diet in adulthood might be considered (Berry et
al. 2004; Schadewaldt et al. 2004). A slight relaxation, such
as a lactose-restricted diet without limitations in intake in
fruit and vegetables can very well be justified in the light of
the available evidence and is the standard of care in many
countries. Increasing the daily galactose intake from 27 to
54 mg per day is a minor increase when considering the
fact that an adult will have an endogenous production up to
1,000 mg per day (Berry et al. 2004; Huidekoper et al.
2005). A further relaxation of the diet, however, will cause
a major increase of daily galactose intake. As milk and
milk-containing products such as yoghurt contain 2,400 and
1,800 mg of galactose per 100 mg, respectively, the intake
of even one glass of milk rapidly increases the daily intake
to more than 4,800 mg per day, more than four times the
daily endogenous production. Therefore, full dietary relax-
ation should probably be strongly discouraged until the
pathophysiology behind the long-term complications has
been elucidated and it is clear whether or not this is related
to galactose intake. Long-term studies, preferably after
developing a more valid biochemical marker for
galactose toxicity, evaluating the biochemical and clinical
effects of exogenous galactose in adults as well as in
children, are necessary before any further relaxation of
the diet can be considered.
Even though a lifelong diet will affect the daily lives of
the patients, a lactose-free diet without restriction of fruit
and vegetables is a palatable and not very complicated diet.
Studies have demonstrated that patients with classic
galactosemia have a severely hampered quality of life
(Bosch et al. 2004b). However, it has been demonstrated
that this is the result of the late complications that are found
in many patients and not a result of the diet (Bosch et al.
2009). As the late complications may result from
continuous intoxication by galactose from endogenous
production, dietary relaxation might well increase the
long-term complications by rapidly increasing galactose
load and thus affect patients’ quality of life even more.
Open Access This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
References
Acosta PB, Gross KC (1995) Hidden sources of galactose in the
environment. Eur J Pediatr 154(suppl 2):s87–s92
Ai Y, Zheng Z, O’Brien-Jenkins A, Bernard DJ et al (2000) A mouse
model of galactose-induced cataracts. Hum Mol Genet 9
(12):1821–1827
Berry GT, Palmieri M, Gross KC et al (1993) The effect of fruit and
vegetables on urinary galactitol excretion in galactose-1-
phosphate uridyltransferase deficiency. J Inherit Metab Dis
16:91–100
Berry GT, Moate PJ, Reynolds RA et al (2004) The rate of de novo
galactose synthesis in patients with galactose-1-phosphate
uridyltransferase deficiency. Mol Genet Metab 81:22–30
Bosch AM (2006) Classical galactosaemia revisited. J Inherit Metab
Dis 29(4):516–525
Bosch AM, Bakker HD, Wenniger-Prick LJ, Wanders RJ, Wijburg
FA (2004a) High tolerance for oral galactose in classical
galactosaemia: dietary implications. Arch Dis Child 89
(11):1034–1036
Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HS, Wijburg
FA, Last BF (2004b) Living with classical galactosemia:
health-related quality of life consequences. Pediatrics 113
(5):423–428
Bosch AM, Maurice-Stam H, Wijburg FA, Grootenhuis MA (2009)
Remarkable differences: the course of life of young adults
with galactosaemia and PKU. J Inherit Metab Dis 32(6):706–
712
Ficicioglu C, Hussa C, Yager C, Segal S (2005) Effect of galactose
free formula on galactose-1-phosphate in two infants with
classical galactosemia. J Inherit Metab Dis 28(2):163–168
Gross KC, Acosta PB (1991) Fruit and vegetables are a source of
galactose: implications of planning the diets of patients with
galactosemia. J Inherit Metab Dis 14:253–258
Holton JB, Walter JH, Tyfield LA (2001) Galactosemia. In: Scriver
CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW et al
(eds) The metabolic and molecular basis of inherited disease, 8th
edn. McGraw-Hill, New York, pp 1553–1583
Huidekoper HH, Bosch AM, van der Crabben SN, Sauerwein HP,
Ackermans MT, Wijburg FA (2005) Short-term exogenous
galactose supplementation does not influence rate of appearance
of galactose in patients with classical galactosemia. Mol Genet
Metab 84(3):265–272
Jones NL, Leak D (1959) The treatment of congenital galactosaemia.
Arch Dis Child 34:307–311
Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C,
Koch R (1981) Hypergonadotropic hypogonadism in female
patients with galactosemia. N Engl J Med 304:994–998
Lee PJ, Lilburn M, Wendel U, Schadewaldt P (2003) A woman with
untreated galactosaemia. Lancet 362(9382):446
Mason HH, Turner ME (1935) Chronic galactemia, report of case with
studies on carbohydrates. Am J Dis Child 50(2):359–374
Merritt RJ, Jenks BH (2004) Safety of soy-based infant formulas
containing isoflavones: the clinical evidence. J Nutr 134:1220s–
1224s
Panis B, Forget PP, van Kroonenburgh MJ, Vermeer C, Menheere PP,
Nieman FH, Rubio-Gozalbo ME (2004) Bone metabolism in
galactosemia. Bone 35(4):982–987
Panis B, Bakker JA, Sels JP, Spaapen LJ, van Loon LJ, Rubio-
Gozalbo ME (2006) Untreated classical galactosemia patient with
mild phenotype. Mol Genet Metab 89(3):277–279
Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD
(2008) Correlates of language impairment in children with
galactosaemia. J Inherit Metab Dis 31(4):524–532
Salt HB, Ross CAC, Gerrard JW (1955) Low-lactose milk for
congenital galactosemia. Lancet 265(6875):1177–1178
Schadewaldt P, Amalanathan L, Hammen HW, Wendel U (2004) Age
dependence of endogenous galactose formation in Q188R
homozygous galactosemic patients. Mol Genet Metab 81:31–44
Schadewaldt P, Hoffmann B, Hammen HW, Kamp G, Schweitzer-Krantz
S, Wendel U (2010) Longitudinal assessment of intellectual
achievement in patients with classical galactosemia. Pediatrics 125
(2):374–381
J Inherit Metab Dis (2011) 34:257–260 259
Schweitzer S, Shin Y, Jacobs C, Brodehl J (1993) Long-term outcome
in 134 patients with galactosemia. Eur J Pediatr 152:36–43
Schweitzer-Krantz S (2003) Early diagnosis of inherited metabolic
disorders towards improving outcome: the controversial issue of
galactosaemia. Eur J Pediatr 162(Suppl 1):S50–S53
Segal S (2004) Another aspect of the galactosemic enigma. Letter to
the editor. Mol Genet Metab 81:253–254
Thompson SM, Netting MJ, Jerath S, Wiley V (2003) Effect of a less
restricted diet in galactosemia. J Inherit Metab Dis 26(suppl
2):214
Turck D (2007) Soy protein for infant feeding: what do we know?
Curr Opin Clin Nutr Metab Care 10(3):360–365
Waggoner DD, Buist NRM, Donnell GN (1990) Long-term prognosis
in galactosemia: Results of a survey of 350 cases. J Inherit Metab
Dis 13:802–818
Wiesmann UN, Rose-Beutler B, Schluchter R (1995) Leguminosae in
the diet: the raffinose-stachyose question. Eur J Pediatr 154(suppl
2):s93–s96
Zlatunich CO, Packman S (2008) Galactosaemia: early treatment with
an elemental formula. Eur J Pediatr 167(5):595–596
260 J Inherit Metab Dis (2011) 34:257–260


Springer - Publisher Connector

EDITORIAL
Classic galactosemia: dietary dilemmas
Annet M. Bosch
Received: 15 March 2010 /Revised: 15 March 2010 /Accepted: 14 June 2010 /Published online: 13 July 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Introduction
Classic galactosemia (McKusic 230400) is an inborn error
of galactose metabolism caused by a deficiency of the
enzyme galactose-1-phosphate uridyltransferase (GALT,
EC 2..7.712), resulting in accumulation of the metabolites
galactitol and galactose-1-phosphate. Patients ingesting
galactose from breast milk or infant formula present in the
first weeks of life with feeding difficulties, hepatocellular
dysfunction, hypoglycemia, renal tubular dysfunction,
cataract, and sepsis. Immediate removal of galactose from
the diet results in a full recovery from this life-threatening
neonatal crisis (Holton et al. 2001; Bosch 2006).
Mason and Turner (1935) were the first to report the
successful use of a milk-free diet in an infant with
galactosemia. In the 1950s, different strategies to feed
infants a diet without galactose were discussed in the
literature (Salt et al. 1955; Jones and Leak 1959).
Nowadays, initiating the diet is much easier, as infant
formulas with a very limited amount of galactose are
widely available. Still, there are dilemmas in the treatment
of galactosemia, and the dietary treatment varies widely
around the world. The most troubling issue is that despite a
continued galactose-restricted diet, and irrespective of a
neonatal crisis, many patients suffer from long-term
complications, such as reduced cognitive ability, language
impairment, decreased bone mass, and hypergonadotrophic
hypogonadism in women (Kaufman et al. 1981; Waggoner
et al. 1990; Schweitzer et al. 1993; Panis et al. 2004; Potter
et al. 2008; Schadewaldt et al. 2010).
Infancy
In the first weeks of life, the most important part of
managing patients with classic galactosemia is removing
all galactose from the diet as soon as the diagnosis is
suspected, immediately after starting the diagnostic
investigations and without awaiting results, in order to
prevent further life-threatening complications. Whereas
classic galactosemia is part of the newborn screening
programs of many countries, most children will present
with clinical symptoms, such as feeding problems,
jaundice progressing to liver failure, and sepsis, before
the screening results are available. Infants with classic
galactosemia must be prescribed a galactose-free formu-
la. In The Netherlands, the recommended treatment is
soy milk; in some other countries, infant formula on the
basis of casein hydrolysate and dextrine maltose as
carbohydrate source, such as Nutramigen®, is recom-
mended. The safety of long-term use of soy milk has been
much debated; however, there is no clinical evidence for
harmful effects of this product (Merritt and Jenks 2004; Turck
2007). Both Nutramigen and soy formula still contain very
small amounts of galactose, and recent studies demonstrated
that completely eliminating galactose from the diet by
prescribing an elemental formula (Neocate®) instead of
Nutramigen® or soy formula caused a significantly faster
decrease of the high erythrocyte Gal-1-P values that are
found in infancy in these patients (Ficicioglu et al. 2005;
Zlatunich and Packman 2008). As the time of diagnosis and
Communicated by: Gerard T. Berry
Competing interest: None declared.
A. M. Bosch (*)
Department of Pediatrics (H7-270), Academic Medical Center,
University of Amsterdam,
Meibergdreef 9,
1105 AZ Amsterdam, The Netherlands
e-mail: a.m.bosch@amc.uva.nl
J Inherit Metab Dis (2011) 34:257–260
DOI 10.1007/s10545-010-9157-8
the occurrence of the neonatal crisis do not seem to have a
significant effect on long-term outcome, it remains to be
elucidated whether this rapid decrease would positively
affect outcome, and long-term studies need to be performed
to clarify this before routinely putting these infants on this
expensive and unpalatable formula (Schweitzer-Krantz
2003).
Childhood
With the introduction of solid foods, some galactose will
inevitably be introduced into the diet, as many foods, such
as fruit and vegetables, bread, legumes, and offal, contain
trace amounts of galactose (Gross and Acosta 1991; Acosta
and Gross 1995). Bound galactose is found in many
vegetables as part of raffinose and stachyose. How much
of this bound galactose can be broken down in the gut is
not known. No significant contribution to the intake of
galactose, or effect on biochemical parameters, has been
demonstrated (Wiesmann et al. 1995).
There are major controversies concerning the daily
allowance of galactose during long-term treatment. Many
European metabolic centers recommend a very strict diet,
also restricting galactose containing fruits and vegetables.
Other centers, e.g., in the UK, Germany, The Netherlands,
and the USA, are more liberal, advising only a lactose-free
diet. There is limited knowledge of the tolerance for
exogenous galactose in patients with classic galactosemia.
A newborn infant with galactosemia ingesting 300 ml of
formula or breast milk per day in the first days of life,
equivalent to >7,000 mg of galactose, will develop severe
illness. As soon as the diagnosis is suspected, the galactose
intake will be restricted as much as possible. Patients on a
lactose-free diet with no restrictions of fruit and vegetables
will have a daily intake of galactose <30 mg (Berry et al.
1993; Bosch et al. 2004a). On a diet enriched in fruit and
vegetables, this intake increases to an average of 54 mg of
galactose per day (Berry et al. 1993). In one study, three
adolescents ingested up to 600 mg of galactose per day for
6 weeks without any effect on clinical or laboratory
parameters (Bosch et al. 2004a). Of importance is the
strong contrast between the exogenous intake of galactose
in the lactose-restricted diet, with an average intake of
54 mg of galactose per day with a diet enriched in
galactose-containing fruit and vegetables and the endogenous
production of galactose in adult patients, amounting to
1,000 mg per day (Berry et al. 2004, Huidekoper et al.
2005). This fact is an argument not to restrict fruit and
vegetables from the diet. Also, after the introduction of a less
restricted diet in Australia, no increases in gal-1-p values
were detected (Thompson et al. 2003). Furthermore, in the
UK, where fruit and vegetables are not restricted from the
diet, no new cataracts or liver diseases have been reported in
the literature. It has been demonstrated that the endogenous
production of galactose is not affected by the exogenous
intake from the diet. (Huidekoper et al. 2005)
Adulthood
There is no insight into galactose tolerance of adults
patients with classic galactosemia. Two remarkable
patients have been reported in the literature. A 38-year-
old adult woman and a 34-year-old man, both with
classic galactosemia (Q188R homozygous), had both
discontinued their diet at the age of 3 years (Lee et al.
2003; Panis et al. 2006). Her intake of galactose was
2,690 mg per day, and his daily galactose intake was
9,000 mg. In both patients, there were no signs of cataract
or liver disease, and red cell galactose-1-phosphate and
urine galactitol were within the range of treated galacto-
semics. The female patient had started hormonal replace-
ment therapy at 15 years of age because of primary
amenorrhoea. Her neuropsychological assessment showed
a verbal IQ of 88 and a performance IQ of 78; tests of
attention, memory, and executive functions were below
the tenth percentile for a normal population. The male
patient had an unremarkable neurologic examination and
a normal educational attainment. His in vivo oxidation of
[1-13C] galactose was evaluated and found to be
severely hampered and within the range for treated
patients. These patients’ outcomes seem no worse than
in many patients with classic galactosemia treated with a
strict diet. It is very well possible that the galactose
tolerance of patients with classic galactosemia increases
with age as a result of the age-related decrease of
endogenous galactose production (Berry et al. 2004;
Schadewaldt et al. 2004). It might also be possible that
these patients have a greater capacity to dispose of
galactose by pathways yet unknown. Alternatively, other
factors, such as an aldose reductase deficiency as reported
in the galactosemic mouse, may play a role (Ai et al. 2000;
Segal 2004). In addition, it is not known whether red cell
galactose-1-phosphate or urinary galactitol reflect the
long-term toxicity of galactose in galactosemia. Long-
term exposure to galactose could result in abnormal
galactosylation of glycoproteins and glycolipids, and these
patients might well have had an even better cognitive
outcome if they had continued their diet.
Future perspectives
Based on the theory that exogenous galactose tolerance
increases in adulthood, partly due to the relative decrease in
258 J Inherit Metab Dis (2011) 34:257–260
endogenous production, relaxation of the galactose-
restricted diet in adulthood might be considered (Berry et
al. 2004; Schadewaldt et al. 2004). A slight relaxation, such
as a lactose-restricted diet without limitations in intake in
fruit and vegetables can very well be justified in the light of
the available evidence and is the standard of care in many
countries. Increasing the daily galactose intake from 27 to
54 mg per day is a minor increase when considering the
fact that an adult will have an endogenous production up to
1,000 mg per day (Berry et al. 2004; Huidekoper et al.
2005). A further relaxation of the diet, however, will cause
a major increase of daily galactose intake. As milk and
milk-containing products such as yoghurt contain 2,400 and
1,800 mg of galactose per 100 mg, respectively, the intake
of even one glass of milk rapidly increases the daily intake
to more than 4,800 mg per day, more than four times the
daily endogenous production. Therefore, full dietary relax-
ation should probably be strongly discouraged until the
pathophysiology behind the long-term complications has
been elucidated and it is clear whether or not this is related
to galactose intake. Long-term studies, preferably after
developing a more valid biochemical marker for
galactose toxicity, evaluating the biochemical and clinical
effects of exogenous galactose in adults as well as in
children, are necessary before any further relaxation of
the diet can be considered.
Even though a lifelong diet will affect the daily lives of
the patients, a lactose-free diet without restriction of fruit
and vegetables is a palatable and not very complicated diet.
Studies have demonstrated that patients with classic
galactosemia have a severely hampered quality of life
(Bosch et al. 2004b). However, it has been demonstrated
that this is the result of the late complications that are found
in many patients and not a result of the diet (Bosch et al.
2009). As the late complications may result from
continuous intoxication by galactose from endogenous
production, dietary relaxation might well increase the
long-term complications by rapidly increasing galactose
load and thus affect patients’ quality of life even more.
Open Access This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
References
Acosta PB, Gross KC (1995) Hidden sources of galactose in the
environment. Eur J Pediatr 154(suppl 2):s87–s92
Ai Y, Zheng Z, O’Brien-Jenkins A, Bernard DJ et al (2000) A mouse
model of galactose-induced cataracts. Hum Mol Genet 9
(12):1821–1827
Berry GT, Palmieri M, Gross KC et al (1993) The effect of fruit and
vegetables on urinary galactitol excretion in galactose-1-
phosphate uridyltransferase deficiency. J Inherit Metab Dis
16:91–100
Berry GT, Moate PJ, Reynolds RA et al (2004) The rate of de novo
galactose synthesis in patients with galactose-1-phosphate
uridyltransferase deficiency. Mol Genet Metab 81:22–30
Bosch AM (2006) Classical galactosaemia revisited. J Inherit Metab
Dis 29(4):516–525
Bosch AM, Bakker HD, Wenniger-Prick LJ, Wanders RJ, Wijburg
FA (2004a) High tolerance for oral galactose in classical
galactosaemia: dietary implications. Arch Dis Child 89
(11):1034–1036
Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HS, Wijburg
FA, Last BF (2004b) Living with classical galactosemia:
health-related quality of life consequences. Pediatrics 113
(5):423–428
Bosch AM, Maurice-Stam H, Wijburg FA, Grootenhuis MA (2009)
Remarkable differences: the course of life of young adults
with galactosaemia and PKU. J Inherit Metab Dis 32(6):706–
712
Ficicioglu C, Hussa C, Yager C, Segal S (2005) Effect of galactose
free formula on galactose-1-phosphate in two infants with
classical galactosemia. J Inherit Metab Dis 28(2):163–168
Gross KC, Acosta PB (1991) Fruit and vegetables are a source of
galactose: implications of planning the diets of patients with
galactosemia. J Inherit Metab Dis 14:253–258
Holton JB, Walter JH, Tyfield LA (2001) Galactosemia. In: Scriver
CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW et al
(eds) The metabolic and molecular basis of inherited disease, 8th
edn. McGraw-Hill, New York, pp 1553–1583
Huidekoper HH, Bosch AM, van der Crabben SN, Sauerwein HP,
Ackermans MT, Wijburg FA (2005) Short-term exogenous
galactose supplementation does not influence rate of appearance
of galactose in patients with classical galactosemia. Mol Genet
Metab 84(3):265–272
Jones NL, Leak D (1959) The treatment of congenital galactosaemia.
Arch Dis Child 34:307–311
Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C,
Koch R (1981) Hypergonadotropic hypogonadism in female
patients with galactosemia. N Engl J Med 304:994–998
Lee PJ, Lilburn M, Wendel U, Schadewaldt P (2003) A woman with
untreated galactosaemia. Lancet 362(9382):446
Mason HH, Turner ME (1935) Chronic galactemia, report of case with
studies on carbohydrates. Am J Dis Child 50(2):359–374
Merritt RJ, Jenks BH (2004) Safety of soy-based infant formulas
containing isoflavones: the clinical evidence. J Nutr 134:1220s–
1224s
Panis B, Forget PP, van Kroonenburgh MJ, Vermeer C, Menheere PP,
Nieman FH, Rubio-Gozalbo ME (2004) Bone metabolism in
galactosemia. Bone 35(4):982–987
Panis B, Bakker JA, Sels JP, Spaapen LJ, van Loon LJ, Rubio-
Gozalbo ME (2006) Untreated classical galactosemia patient with
mild phenotype. Mol Genet Metab 89(3):277–279
Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD
(2008) Correlates of language impairment in children with
galactosaemia. J Inherit Metab Dis 31(4):524–532
Salt HB, Ross CAC, Gerrard JW (1955) Low-lactose milk for
congenital galactosemia. Lancet 265(6875):1177–1178
Schadewaldt P, Amalanathan L, Hammen HW, Wendel U (2004) Age
dependence of endogenous galactose formation in Q188R
homozygous galactosemic patients. Mol Genet Metab 81:31–44
Schadewaldt P, Hoffmann B, Hammen HW, Kamp G, Schweitzer-Krantz
S, Wendel U (2010) Longitudinal assessment of intellectual
achievement in patients with classical galactosemia. Pediatrics 125
(2):374–381
J Inherit Metab Dis (2011) 34:257–260 259
Schweitzer S, Shin Y, Jacobs C, Brodehl J (1993) Long-term outcome
in 134 patients with galactosemia. Eur J Pediatr 152:36–43
Schweitzer-Krantz S (2003) Early diagnosis of inherited metabolic
disorders towards improving outcome: the controversial issue of
galactosaemia. Eur J Pediatr 162(Suppl 1):S50–S53
Segal S (2004) Another aspect of the galactosemic enigma. Letter to
the editor. Mol Genet Metab 81:253–254
Thompson SM, Netting MJ, Jerath S, Wiley V (2003) Effect of a less
restricted diet in galactosemia. J Inherit Metab Dis 26(suppl
2):214
Turck D (2007) Soy protein for infant feeding: what do we know?
Curr Opin Clin Nutr Metab Care 10(3):360–365
Waggoner DD, Buist NRM, Donnell GN (1990) Long-term prognosis
in galactosemia: Results of a survey of 350 cases. J Inherit Metab
Dis 13:802–818
Wiesmann UN, Rose-Beutler B, Schluchter R (1995) Leguminosae in
the diet: the raffinose-stachyose question. Eur J Pediatr 154(suppl
2):s93–s96
Zlatunich CO, Packman S (2008) Galactosaemia: early treatment with
an elemental formula. Eur J Pediatr 167(5):595–596
260 J Inherit Metab Dis (2011) 34:257–260


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Classic galactosemia: dietary dilemmas
Bosch, A.M.
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Journal of inherited metabolic disease
DOI:
10.1007/s10545-010-9157-8
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Citation for published version (APA):
Bosch, A. M. (2011). Classic galactosemia: dietary dilemmas. Journal of inherited metabolic disease, 34(2), 257-
260. https://doi.org/10.1007/s10545-010-9157-8
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Download date: 08 Feb 2021
EDITORIAL
Classic galactosemia: dietary dilemmas
Annet M. Bosch
Received: 15 March 2010 /Revised: 15 March 2010 /Accepted: 14 June 2010 /Published online: 13 July 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Introduction
Classic galactosemia (McKusic 230400) is an inborn error
of galactose metabolism caused by a deficiency of the
enzyme galactose-1-phosphate uridyltransferase (GALT,
EC 2..7.712), resulting in accumulation of the metabolites
galactitol and galactose-1-phosphate. Patients ingesting
galactose from breast milk or infant formula present in the
first weeks of life with feeding difficulties, hepatocellular
dysfunction, hypoglycemia, renal tubular dysfunction,
cataract, and sepsis. Immediate removal of galactose from
the diet results in a full recovery from this life-threatening
neonatal crisis (Holton et al. 2001; Bosch 2006).
Mason and Turner (1935) were the first to report the
successful use of a milk-free diet in an infant with
galactosemia. In the 1950s, different strategies to feed
infants a diet without galactose were discussed in the
literature (Salt et al. 1955; Jones and Leak 1959).
Nowadays, initiating the diet is much easier, as infant
formulas with a very limited amount of galactose are
widely available. Still, there are dilemmas in the treatment
of galactosemia, and the dietary treatment varies widely
around the world. The most troubling issue is that despite a
continued galactose-restricted diet, and irrespective of a
neonatal crisis, many patients suffer from long-term
complications, such as reduced cognitive ability, language
impairment, decreased bone mass, and hypergonadotrophic
hypogonadism in women (Kaufman et al. 1981; Waggoner
et al. 1990; Schweitzer et al. 1993; Panis et al. 2004; Potter
et al. 2008; Schadewaldt et al. 2010).
Infancy
In the first weeks of life, the most important part of
managing patients with classic galactosemia is removing
all galactose from the diet as soon as the diagnosis is
suspected, immediately after starting the diagnostic
investigations and without awaiting results, in order to
prevent further life-threatening complications. Whereas
classic galactosemia is part of the newborn screening
programs of many countries, most children will present
with clinical symptoms, such as feeding problems,
jaundice progressing to liver failure, and sepsis, before
the screening results are available. Infants with classic
galactosemia must be prescribed a galactose-free formu-
la. In The Netherlands, the recommended treatment is
soy milk; in some other countries, infant formula on the
basis of casein hydrolysate and dextrine maltose as
carbohydrate source, such as Nutramigen®, is recom-
mended. The safety of long-term use of soy milk has been
much debated; however, there is no clinical evidence for
harmful effects of this product (Merritt and Jenks 2004; Turck
2007). Both Nutramigen and soy formula still contain very
small amounts of galactose, and recent studies demonstrated
that completely eliminating galactose from the diet by
prescribing an elemental formula (Neocate®) instead of
Nutramigen® or soy formula caused a significantly faster
decrease of the high erythrocyte Gal-1-P values that are
found in infancy in these patients (Ficicioglu et al. 2005;
Zlatunich and Packman 2008). As the time of diagnosis and
Communicated by: Gerard T. Berry
Competing interest: None declared.
A. M. Bosch (*)
Department of Pediatrics (H7-270), Academic Medical Center,
University of Amsterdam,
Meibergdreef 9,
1105 AZ Amsterdam, The Netherlands
e-mail: a.m.bosch@amc.uva.nl
J Inherit Metab Dis (2011) 34:257–260
DOI 10.1007/s10545-010-9157-8
the occurrence of the neonatal crisis do not seem to have a
significant effect on long-term outcome, it remains to be
elucidated whether this rapid decrease would positively
affect outcome, and long-term studies need to be performed
to clarify this before routinely putting these infants on this
expensive and unpalatable formula (Schweitzer-Krantz
2003).
Childhood
With the introduction of solid foods, some galactose will
inevitably be introduced into the diet, as many foods, such
as fruit and vegetables, bread, legumes, and offal, contain
trace amounts of galactose (Gross and Acosta 1991; Acosta
and Gross 1995). Bound galactose is found in many
vegetables as part of raffinose and stachyose. How much
of this bound galactose can be broken down in the gut is
not known. No significant contribution to the intake of
galactose, or effect on biochemical parameters, has been
demonstrated (Wiesmann et al. 1995).
There are major controversies concerning the daily
allowance of galactose during long-term treatment. Many
European metabolic centers recommend a very strict diet,
also restricting galactose containing fruits and vegetables.
Other centers, e.g., in the UK, Germany, The Netherlands,
and the USA, are more liberal, advising only a lactose-free
diet. There is limited knowledge of the tolerance for
exogenous galactose in patients with classic galactosemia.
A newborn infant with galactosemia ingesting 300 ml of
formula or breast milk per day in the first days of life,
equivalent to >7,000 mg of galactose, will develop severe
illness. As soon as the diagnosis is suspected, the galactose
intake will be restricted as much as possible. Patients on a
lactose-free diet with no restrictions of fruit and vegetables
will have a daily intake of galactose <30 mg (Berry et al.
1993; Bosch et al. 2004a). On a diet enriched in fruit and
vegetables, this intake increases to an average of 54 mg of
galactose per day (Berry et al. 1993). In one study, three
adolescents ingested up to 600 mg of galactose per day for
6 weeks without any effect on clinical or laboratory
parameters (Bosch et al. 2004a). Of importance is the
strong contrast between the exogenous intake of galactose
in the lactose-restricted diet, with an average intake of
54 mg of galactose per day with a diet enriched in
galactose-containing fruit and vegetables and the endogenous
production of galactose in adult patients, amounting to
1,000 mg per day (Berry et al. 2004, Huidekoper et al.
2005). This fact is an argument not to restrict fruit and
vegetables from the diet. Also, after the introduction of a less
restricted diet in Australia, no increases in gal-1-p values
were detected (Thompson et al. 2003). Furthermore, in the
UK, where fruit and vegetables are not restricted from the
diet, no new cataracts or liver diseases have been reported in
the literature. It has been demonstrated that the endogenous
production of galactose is not affected by the exogenous
intake from the diet. (Huidekoper et al. 2005)
Adulthood
There is no insight into galactose tolerance of adults
patients with classic galactosemia. Two remarkable
patients have been reported in the literature. A 38-year-
old adult woman and a 34-year-old man, both with
classic galactosemia (Q188R homozygous), had both
discontinued their diet at the age of 3 years (Lee et al.
2003; Panis et al. 2006). Her intake of galactose was
2,690 mg per day, and his daily galactose intake was
9,000 mg. In both patients, there were no signs of cataract
or liver disease, and red cell galactose-1-phosphate and
urine galactitol were within the range of treated galacto-
semics. The female patient had started hormonal replace-
ment therapy at 15 years of age because of primary
amenorrhoea. Her neuropsychological assessment showed
a verbal IQ of 88 and a performance IQ of 78; tests of
attention, memory, and executive functions were below
the tenth percentile for a normal population. The male
patient had an unremarkable neurologic examination and
a normal educational attainment. His in vivo oxidation of
[1-13C] galactose was evaluated and found to be
severely hampered and within the range for treated
patients. These patients’ outcomes seem no worse than
in many patients with classic galactosemia treated with a
strict diet. It is very well possible that the galactose
tolerance of patients with classic galactosemia increases
with age as a result of the age-related decrease of
endogenous galactose production (Berry et al. 2004;
Schadewaldt et al. 2004). It might also be possible that
these patients have a greater capacity to dispose of
galactose by pathways yet unknown. Alternatively, other
factors, such as an aldose reductase deficiency as reported
in the galactosemic mouse, may play a role (Ai et al. 2000;
Segal 2004). In addition, it is not known whether red cell
galactose-1-phosphate or urinary galactitol reflect the
long-term toxicity of galactose in galactosemia. Long-
term exposure to galactose could result in abnormal
galactosylation of glycoproteins and glycolipids, and these
patients might well have had an even better cognitive
outcome if they had continued their diet.
Future perspectives
Based on the theory that exogenous galactose tolerance
increases in adulthood, partly due to the relative decrease in
258 J Inherit Metab Dis (2011) 34:257–260
endogenous production, relaxation of the galactose-
restricted diet in adulthood might be considered (Berry et
al. 2004; Schadewaldt et al. 2004). A slight relaxation, such
as a lactose-restricted diet without limitations in intake in
fruit and vegetables can very well be justified in the light of
the available evidence and is the standard of care in many
countries. Increasing the daily galactose intake from 27 to
54 mg per day is a minor increase when considering the
fact that an adult will have an endogenous production up to
1,000 mg per day (Berry et al. 2004; Huidekoper et al.
2005). A further relaxation of the diet, however, will cause
a major increase of daily galactose intake. As milk and
milk-containing products such as yoghurt contain 2,400 and
1,800 mg of galactose per 100 mg, respectively, the intake
of even one glass of milk rapidly increases the daily intake
to more than 4,800 mg per day, more than four times the
daily endogenous production. Therefore, full dietary relax-
ation should probably be strongly discouraged until the
pathophysiology behind the long-term complications has
been elucidated and it is clear whether or not this is related
to galactose intake. Long-term studies, preferably after
developing a more valid biochemical marker for
galactose toxicity, evaluating the biochemical and clinical
effects of exogenous galactose in adults as well as in
children, are necessary before any further relaxation of
the diet can be considered.
Even though a lifelong diet will affect the daily lives of
the patients, a lactose-free diet without restriction of fruit
and vegetables is a palatable and not very complicated diet.
Studies have demonstrated that patients with classic
galactosemia have a severely hampered quality of life
(Bosch et al. 2004b). However, it has been demonstrated
that this is the result of the late complications that are found
in many patients and not a result of the diet (Bosch et al.
2009). As the late complications may result from
continuous intoxication by galactose from endogenous
production, dietary relaxation might well increase the
long-term complications by rapidly increasing galactose
load and thus affect patients’ quality of life even more.
Open Access This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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Journal of Inherited Metabolic Disease

Hidden sources of galactose in the environment.

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