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Agro FOOD Industry Hi Tech - vol 24(6) - November/December 2013 Intolerances hypersensitivity (2,6). food intolerance, isanon-immunemediated food and non-allergicfoodhypersensitivity, previouslycalled reactions mediatedbyclassical immunemechanisms emotional reactions,butshould insteadberestrictedto used non-specificallytoinclude intolerancesorpsycho- into twogroups(2).Theterm “foodallergy”isoften and others(2,6).Foodhypersensitivity canbesubdivided blamed onenvironmentalfactors,behavioraldisorders, additives, sideeffectstodrugs,psychologicalreactions of adversereactionstofoodsuchas and isnowusedastheumbrellatermtocoverallkinds (4, 5).Theterm“hypersensitivity”havebeenproposed causes suchasirritantsandpsychosomaticresponses pharmacological and,althoughstillunclear,include non-immunological reactionsmaydependonenzymatic, based onthepathogenicmechanismsinvolved.The mediated (foodallergy)andnon-immune-mediated reactions, thelatterbeingsubdividedintoimmune- food comprisetwomaingroups,toxicandnon-toxic According tothisclassification,adversereactions food allergybasedonpathogeneticmechanisms. Paper onFoodAllergyestablishedaclassificationof Allergology andClinicalImmunology(EAACI)Position reactions tofood.In1995theEuropeanAcademyof Various termshavebeenusedtodescribetheadverse and-effectrelation canbeproven(3). immunopathologic processcanbeshownandacause- hypersensitivity, definedasaneventinwhichadefinite food additives,<20%areduetotrueallergyor mechanisms. Ofalladversereactionstofoodsand idiosyncratic, metabolic,andneuropsychologic by immunologic,pharmacologic,toxic,infectious, this subject(2).Suchreactionsmaybemediated of patientsarethereforedeservinginvestigationson result offoodhypersensitivity.Increaseinthenumber variety ofphysicalandpsychologicalsymptomsarethe medical interesthavealsopopularizedclaimsthata intolerance intheirlifetime(1).Increasingpublicand of individualsexperienceoneormoreepisodesfood and havebeennotedfortwomillenniums.Atleast30% Adverse reactionstofoodhavebeenseenfrequently INTRODUCTION Bornova, Izmir,Turkey Ege UniversityFacultyofAgriculture,DepartmentDairyTechnology *Corresponding author İLYAS ERDEMTONGUÇ*,CEMKARAGÖZLÜ and dairyproducts:areview Galactosemia, diet were discussed. galactosemia has been given and dietary treatments, especiallydairy products consumption for galactosemia patients complications, including cataracts and mental retardation, can be prevented. In this review brief information on resolve andmanyofthelong-term will removal oflactoseandgalactosefromthediet,symptoms birth andtreatedby products. If untreated, the disorder can causeliverfailure,kidneydysfunction, sepsis, anddeath. If itisdiagnosedsoon after glucose. Individualswithgalactosemiaare intolerant of dietarylactose and galactose, primarily found in milk and milk ABSTRACT: Galactosemia is a rare, autosomal recessive condition in which resulting the inability to convert galactose to KEYWORDS: Foodallergies,foodintolerance,galactose,galactosemia,dairyproducts. phosphate (PO4) uridyltransferase(GALT),and UDPgalactose- involving threeenzymes, galactokinase(GALK),galactose-1- to uridyldiphosphate(UDP)-glucose byaseriesofreactions lactase intheintestine.Galactose isthenfurthermetabolized Dietary lactoseishydrolyzedto glucose andgalactoseby retardation, canbeprevented (12). long-term complications,including cataractsandmental from thediet,symptomswill resolveandmanyofthe after birthandtreatedbyremovaloflactosegalactose kidney dysfunction,sepsis,anddeath.Ifitisdiagnosedsoon products. Ifuntreated,thedisordercancauseliverfailure, dietary lactoseandgalactose,primarilyfoundinmilk 1956 (12,14).Individualswithgalactosemiaareintolerantof 1-phosphate uridyltransferase(GALT)enzymebyKalckarin was enzymaticallydefinedasadeficiencyofthegalactose- galactose-1-phosphate inredbloodcells,andthecondition Komrower etal.(1956),demonstratedtheaccumulationof found intheurineofanaffectedpatient(9).Inmid1950s, originally describedtheconditionin1935,whengalactosewas first describedbyvonReuss1908(12,13).MasonandTurner Genetic TestingSymposium)(12).Classicalgalactosemiawas Genetics ResourceCenter;2002NewbornScreeningand estimated at1:53,000(NationalNewbornScreeningand mostcases ascertainedbynewbornscreening,iscurrently in Japan(11).TheincidencetheUnitedStates,with reported between1:30-40,000inEurope(10)and1:1,000,000 inherited enzymedeficiencywithvariableworldwideincidence 1 in60,000newborns(9).Galactosemiaisarelativelyrare metabolize galactosetoglucose.Itoccursinapproximately carbohydrate metabolismthatresultsintheinabilityto Galactosemia isanautosomalrecessiveinbornerrorof pathological situations(7). of galactoseinbloodandureacanbethesignssome beets, andothergumsmucilages.Recognizableamount lactose isformed.Galactosefoundindairyproducts,sugar through adehydrationreaction, When combinedwithglucose isomers aregiveninFigure1. Chemical structuresofgalactose in watercomparedtoglucose. with lesssweetnessandsolubility Galactose isamonosaccharide GALACTOSEMIA structure ofgalactose(8) Figure 1.Chemical İlyas Erdem Tonguç

Agro FOOD Industry Hi Tech - vol 24(6) - November/December 2013 Intolerances 61 of galactosemia with a known pathophysiology. Galactitol, pathophysiology. with a known of galactosemia reduction, by aldose free galactose of by reduction produced Adolescents and adults of lens fibers. produces swelling maygalactose in their diet higher amounts of who include function with ability to cataracts that interfere rarely develop and intraocular lens from lensectomy and may benefit visually more devastating A less well known, but placement. during vitreous hemorrhage complication is ophthalmologic (17). the acute neonatal syndrome Ovarian failure is common in femalesHypergonadotropic hypogonadism has not been reported in males (12,with galactosemia but from severe primary ovarian failure16, 18)The spectrum varies in order to achieve secondaryrequiring hormone support to premature menopause. Pregnanciessexual characteristics have been reported (12, 16,without hormonal intervention ovarian dysfunction is unknown, but it19)The mechanism of that chronic exposure to galactose- has been hypothesized may directly damage the ovaries1-phosphate and galactitol require monitoring(20). Females with classical galactosemia and progestinof gonadotropin levels and initiation of estrogen support as needed (12, 21). Neurologic sequelae Cerebral oedemas ofCerebral oedema is one of the common sequela havegalactosemia in newborn infants. Animal models oedema maysuggested that the mechanism of cerebral be due to elevations in brain galactitol concentrations andand alterations in glucose, adenosine triphosphate, (22, 12). phosphocreatine levels increase osmolality Cognitive impairment quotientMany studies have reported that mean intelligence and adults(IQ) scores are reduced in galactosemic children have resulted(12, 16, 23, 24, 25). Differences between studies in screeningfrom a variety of factors. For example, differences of dietaryand diagnostic practices mean that the initiation countries (12).treatment may vary systematically among Speech difficulty One studySpeech difficulty is common in galactosemia. reported that 56% of patients with galactosemia over 3 years of age have difficulties with speech, with 92 % of these patients described as having delayed vocabulary (16). Galactosemic patients with speech difficulty had significantly lower developmental quotient (DQ) and IQ scores than patients without speech difficulties (16, 26). Lower DQ/IQ scores and speech pathology could independently reflect more severe neuropathology (12). Motor function disorders Despite early treatment initiation and optimal dietary compliance, approximately 10-20% of galactosemia patients develop more severe and progressive ataxia and tremor (12, 16, 27). Seizures Seizures have been described rarely in galactosemia.Two siblings with galactosemia developed seizures in adulthood (27), but galactosemia,to related are seizures these that doubts are there given the low prevalence of reported seizures (12). TREATMENT AND THE IMPORTANCE OF DIET AND DAIRY PRODUCTS IN GALACTOSEMIA In galactosemia treatment, diet based therapy have been used for almost fifty years. In such treatment foods, containing Lactose is metabolized by lactase in the intestine to Lactose is metabolized by lactase in the intestine galactose and glucose. Galactose is metabolized in the liver via galactose and glucose. Galactose is metabolized required include (1) the pathway shown in the figure. The enzymes (GALT),and galactokinase, (2) galactose-1-PO4 uridyltransferase enzyme in classic (3)UDP galactose-4-epimerase. The defective galactose, as galactosemia is GALT (2). Galactose-1-PO4 and in patients with well as galactitol and galactonate, are elevated classic galactosemia (9). Fıgure 2. Eyes Cataracts have been reported in up to 30% of patients with galactosemia, and they usually resolve with galactose restriction (16). Cataracts are one of the few complications Non-neurologic sequelae Growth Growth is generally delayed in most patients withgalactosemia, but final height-for-age is not significantlyless than the general population, although females may be more likely to have short stature (16). Ridel et al. (2005), has classified the sequelae of galactosemia in two groups as non-neurologic and neurologic. HEALTH CONDITIONS CAUSED BY GALACTOSEMIA The gold standard for diagnosis is the demonstration of nearThe gold standard for diagnosis is the demonstration Transfusion of redtotal absence of GALT activity in red cells. this determination.cells from a normal donor can interfere with Measurement of accumulated galactose-1-phosphate in red cells has diagnostic utility even if dietary galactose has been withdrawn, although benign variants can also have increased gal-1-P levels, particularly if the infant is still consuming galactose. Examination of the urine for reducing substances lacks both sensitivity and specificity but can certainly raise sufficient clinical suspicion in a symptomatic infant to trigger further evaluation and empiric treatment (12, 15). 4-epimerase (GALE). Although galactosemia and galactosuria and galactosemia Although (GALE). 4-epimerase these enzymes, one of of any by a deficiency caused can be of greatest clinical the condition classic galactosemia, in GALT (9). is caused by a defect importance, galactose and galactose- with GALT deficiency, In individuals as the reduction product, in tissues, as well 1-PO4 accumulate are galactonate, which the oxidation product, galactitol, and (9). pathways for galactose alternate metabolic derived from the conversion of galactose toGalactokinase catalyzes is then converted to glucose- galactose-1-PO4. Galactose-1-PO4 involving GALT and UDP galactose- 1-PO4 by a two-step reaction the transfer of UDP to galactose- 4-epimerase. GALT catalyzes UDP-galactose is then converted1-PO4 to form UDP galactose. galactose-4-epimerase. Galactoseto UDP-glucose by UDP and glycolipids, using UDP- is incorporated into glycoproteins for galactosylation reactions.galactose as the substrate 62

Agro FOOD Industry Hi Tech - vol 24(6) - November/December 2013 Intolerances in nutrition. Dairy products are known for their critical role in nutrition.Dairyproductsareknownfortheircriticalrole daily dietsregardingtotheimportanceofmilkproducts cannot consumeseriousamountofessentialnutrientsintheir galactose containingproductswhichmeansthatthey Individuals sufferingfromgalactosemiacannotconsume to theothercarbohydrateintolerancerelateddisorders. cause serioushealthproblems,andevendeath,compared which canonlybetreatedwithadietandifnot Galactosemia isanautosomalrecessivelyinheriteddisorder characterized (12). term complicationsintermsofbonehealtharenotwell density hasbeenreported(28,29),althoughthelong difficult toachievewithoutsupplements(12).Lowbone restriction ofdairyproducts,adequatecalciumintakeis of nutritionforthehumanbodyunavailable.Withdietary galactosemia makesoneofthemostimportantsources Removing milkanddairyproductsfromthedietdueto The galactosecontentofsomefoodsaregiveninTable1. low ornogalactosecontentsholudbeaddedtodiet(12). infant grows,cereals,fruits,vegatablesandmeatwithvery to reduceorattempteliminategalactoseinthediet.As complicated. Anideal,standardpracticehasbeenapplied infant formulasareweaned,nutritionalissuesbecomemore initiated asneeded.Oncesolidfoodsareinitiated,andwhen antibiotics, andtreatmentofcoagulopathyshouldbe Supportive carewithintravenousfluids,phototherapy, and galactose-containingformulasshouldbewithdrawn. newborn screeningresultsshouldbeevaluatedpromptly, daily diet.Symptomaticinfantsorwithhighlysuspicious lactose andgalactoseareeliminatedorwithdrawnfromthe Table 1.Galactose contentofsomefoods(21) with galactosemia. Some of these studies report significantly with galactosemia. Someofthesestudiesreport significantly on food,specifically dairyproductsdeveloped forpeople there areverylimitedamountof researchespresentfocusing dairy products,specificallymentioning, probiotics.Currently, from theprobioticmicroorganisms foundinthefermented food products,aforementioned individualscannotbenefit Furthermore, regardingthefunctional valuesoffermented compensated bytakingfoodsupplements orformulas. are mostlydevoidofvariousnutrientswhichcannotbefully immune system.Peoplewhocannotconsumedairyproducts mentally andphysicallyahealthylifeenhancingthe healthy nutrition,foragrowth,maintainingboth products inthedietisabiggap,sotospeak,regarding milk anddairyproducts.Absenceofdrinking of allkindsfoodcontaininglactoseandgalactose,ergo an appropriatediet,specificallyspeaking,bytheremoval above, galactosemia,byitsnature,canonlybetreated lives andpreventpermanentdamages.Asmentioned diagnosis andtreatmenthasavitalimportance.Itcansave Galactosemia isacriticalhealthdisorderwhereearly CONCLUSION cultures hasanabilitytometabolizegalactose(33). kefir culture,itwasfoundthatyoghurtandacidophilusmilk predetermined criticalvalue.Also,inthestudy,alongside milk-infant foodmixtureswerefoundedtobelowerthanthe in ordertoenhancesensorialproperties.Galactoselevelsof Galactose freestrawberryflavorwasaddedtotheproducts fermented withacidophilousmilk,ayranandkefircultures. free infantfood(Neocate,Galactomin19)ina1:1ratiowere UHT milkandmixturesoflactosefreegalactose UHT milkwasusedascontrolgroupandwithlactosefree suffering patientswereproduced.Inthestudy,conventional and fermenteddairybeveragessuitableforgalactosemia were comparedduetotheirgalactosehydrolysislevels from galactosemia.Inanotherstudy(33),differentcultures nutriments aresuitableforuseinthedietofpatientssuffering means thatthekefir-likeproductsbasedonmixedmilkwith lactose hydrolysedmilkandgalactosefreenutrimentswhich lower thanthevalue200mg/100cm After 48hoffermentation,galactosecontentwasfound free UHTmilkwasabovecriticalvalueof200mg/100cm (31,32). Theydeterminedthatthegalactoseleveloflactose youth 250(–400mg),adults300(–500mg)galactose/day mg), infants150(–200schoolchildren200(–300 with galactosemiahavebeenverified:babies50(–200 following thedailygalactoseintakelimitvaluesforpatients many yearsofexperiencedoctorsanddieticians,the was measuredduringandafterfermentation.Basedon for thefermentationandlevelofgalactosereduction 2:1 ratio.Forfermentationtraditionalkefirculturewasused free nutriments(PregominAS,Nutrilon)werefermentedina of lactosehydrolysedmilksupplementedwithgalactose studies (31),lactosehydrolysedmilkandtwotypesofmixture number ofstudiesconcerningthismatter.Inonethese developing galactosefreedairyproducts.Therearelimited strategy maybefittedforgalactosemiasufferingindiviualsby hereditary lactasedefciencyandgalactosemia(30).Asimilar (Ig) E-mediatedallergy,secondarylactoseintolerance, allergic diseasesinterminfants,includingImmunoglobulin successful useinmanagingseveralseriousdigestiveand Soy protein-basedinfantformulashavealonghistoryofsafe, available inthemarketsforindividualswithceliacdisease. is similarwithgalactosemia.Thereareglutenfreeproducts patterns andsocialconditionsareconcernedceliacdisease products leadstoagroupofseriousdeficiencies.Ifnutrition in healthygrowthandnotconsuminganymilkdairy 3 in the mixtures of inthemixturesof 3 . important results for the benefit of patients with galactosemia. However, none of these researches include any results of clinical tests regarding the consumption of these products by galactosemia patients. We sincerely, recommend that the studies on this subject should be extended widely as well as be supported by clinical trials for the evaluation regarding the safety of these products.

REFERENCES

1. Chandra, K., R., , Am J Clin Nutr; 66:526S-9S (1997) 2. Lied,A., G., Turk J Gastroenterol,18 (1): 5-13 (2007) 3. Chandra, R., K., Gill, B., Kumari, S., ClinRev Allergy Immunol, 13:293-314 (1995). 4. Bruijnzeel-Koomen, C., Ortolani, C., Aas, K., Bindslev-Jensen, C., Björkstein, B., Moneret-Vautrin, D., Wuthrich, B., Allergy, 50,:623 (1995). 5. Brandtzaeg, P., Environ Toxicol Pharmacol 4:9-24 (1997). 6. Johansson, S., G., Hourihane, J., O., Bousquet, J., Bruijnzeel- Koomen, C., Dreborg, S., Haahtela, T., Kowalski, M.,L., Mygind, N., Ring, J., Van Cauwenberge, P., Hage-Hamsten, M. and Wuthrich, B., Allergy; 56: 813-24 (2001). 7. Ophardt, C., E., Virtual Chembook, Elmhurst College, available at http://www.elmhurst.edu/~chm/vchembook/543galactose. html (2003). 8. Metin, M., Süt Teknolojisi, E.Ü Mühendislik Fakültesi Yayınları, Vol N° 33, 192 (1998) 9. Grange, D., K., Encyclopedia of Gastroenterology, P. 83-87 (2004). 10. Murphy, M., McHugh, B., Tighe, O., et al., Eur J Hum Genet; 7:549-54 (1999). 11. Hirokawa, H., Okano, Y., Asada, M., Fujimoto, A., Suyama, I., Isshiki, G, Eur J Hum Genet, 7:757-64 (1999). 12. Ridel, R., K., Leslie, N., D. and Gilbert, D., L, Pediatric Neurology, Vol.33, No.3, 153-161(2005). 13. Von Reuss, A., Zuckerausscheidung in säuglinsalter. Wein MedWschr, 58:799-800 (1908). 14. Komrower, G., M., Schwartz, R., P., Holzel, A., Golberg, A., Arch Dis Child 31:254-64 (1956). 15. Flanagan, J., M., Tighe, O., O’Neil, l., C., Naughten, E., Mayne., P., D., Croke, D., T., Molec Genet Metab, 81:133-6 (2004). 16. Waggoner, D., Buist, N. and Donnell, G., J Inher Metab Dis,13:802-18 (1990). 17. Levy HL, Brown AE, Williams SE, de Juan E Jr., J Pediatr, 129:922-5 (1996). 18. Kaufman, F., Kogut, M., Donnell, G., Goebelsmann, U., March, C. ,Koch, R., N Engl J Med, 304:994-8 (1981). 19. De Jongh, S., Vreken, P., Lijst, L., Wanders, R., Jakobs, C., Bakker, H., J InherMetab Dis, 22:754-5 (1999). 20. Gibson , J., Eur J Pediatr, 154:S14-20 (1995). 21. Liu, G., Hale, E., G. and Hughes, C., L., Reproductive Toxicology, Volume 14, Issue 5, 377-384 (2000). 22. Knull, H., Wells, W. and Kozak, L., Science, 176:815-6 (1972). 23. Lo, W., Packman, S., Nash, S., et al., Pediatrics, 73:309-12 (1984). 24. Schweitzer, S., Shin, Y., Jakobs, C., Brodehl, J., Eur J Pediatr ,152:36-43 (1993). 25. Wang, Z., I., Berry, G., T., Dreha, S., F., Zhao, H., Segal, S., Zimmerman, R., A., Ann Neurol, 50:266-9 (2001). 26. Nelson, D., Waggoner, D., Donnell, G., Tuerck, J., Buist, N.,. Pediatrics, 88:346-50 (1991). 27. Friedman, J., Levy, H. and Boustany, R.,. Neurology;39: 741-2 (1989). 28. Kaufman, F., Loro, M., Azen, C., Wenz, E., Gilsanz, V., J Pediatr 123:365-70 (1993). 29. Panis, B., Forget, P., P., Van Kroonenburgh, M., J., et al., Bone 35:982-7 (2004) 30. Cordle, C.,. AgroFOOD industry hi tech, 18(2):27-30 (2007). 31. Varga, Z., Palvolgyi, M., Juhasz-Roman, M. and Toth-Markus, M., Acta Alimentaria, Volume 35(3):295-304 (2006). 32. Tonguç., İ., E., Laktoz ve Galaktoz İntoleranslı Bireylerin Tüketimine Yönelik Fermente Süt Ürünlerinin Geliştirilmesi ve Kalite Özelliklerinin Belirlenmesi, Ege Üniversitesi Fen Bilimleri Enstitüsü, PhD Theses, 163 p. (2012).