Galactosemia

Background

This is a rare inherited disorder of metabolism. There are two main variants, classic and Duarte. It is inherited as an autosomal recessive trait, meaning both parents must carry the defective gene. Galactose is a sugar, commonly formed when lactose, found in dairy products such as milk, cheese, butter, is broken down into galactose and glucose. In these patients, the enzyme normally responsible for metabolizing galactose is deficient or missing. This results in an accumulation of galactose which may infiltrate various organs including the liver and the lens. Over time, progressive liver and kidney failure may occur. Cataracts may occur. Progressive neurologic deterioration may also occur.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

GEOGRAPHY

Galactosaemia in black South African children.

Ojwang PJ, Manickum T, Deppe WM.

Department of Chemical Pathology, Faculty of Medicine, University of Natal, Durban, South Africa.

East Afr Med J 1999 May;76(5):247-50 Abstract quote
OBJECTIVE: To evaluate the clinical and biochemical features of all black children confirmed to have galactosaemia from the KwaZulu Natal Province of South Africa.

DESIGN: Prospective laboratory study.

SUBJECTS: These included all black children with the presenting clinical features suggestive of the diagnosis of galactosaemia.

SETTING: Department of Chemical Pathology, King Edward VIII Hospital, Durban, South Africa.

METHOD: In each case, urine was screened for the presence of a reducing substance using urinary dipstick followed by thin layer chromatography to establish the presence of galactosaemia. The diagnosis of galacotosaemia was then confirmed by analysis of galactose-1 phosphate uridyl transferase (GALT) activity in the erythrocytes using the established Beutler enzyme assay procedure. Age and sex-matched samples were used as controls for GALT activity. The presenting clinical features of each patient on admission were also recorded.

INTERVENTIONS: Patients confirmed to have galactosaemia were immediately placed on a galactose free diet.

RESULTS: The age distribution of affected individuals varied from six weeks to 27 months with 60% of the children being males. The most common presenting clinical features were jaundice in 77% of the patients, failure to thrive 62%, and cataracts 54%. Four patients had complete absence of GALT activity. Two infants who displayed acute toxicity symptoms and positive urine galactose, exhibited normal GALT activity.

CONCLUSION: GALT deficiency is the most common form of galactosaemia in black children in the KwaZulu Natal region. Cases of galactokinase or epimerase enzyme deficiency appear to be present. Further investigation is required to establish the occurrence and prevalence of the latter in affected individuals in this region.

EPIDEMIOLOGIC ASSOCIATIONS

Large-scale molecular screening for galactosemia alleles in a pan-ethnic population.

Suzuki M, West C, Beutler E.

Department of Molecular and Experimental Medicine (MEM215), The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.

Hum Genet 2001 Aug;109(2):210-5 Abstract quote
DNA samples from 4,796 subjects from diverse ethnic groups were screened for five frequently encountered galactose-1-phosphate uridyl transferase (GALT) mutations: S135L (cDNA nt 404C-->T, as numbered from the initiator ATG codon, with A=1); Q188R (cDNA nt 563A-->G); K285 N (cDNA nt 855G-->T); the Duarte variant, N314D (cDNA nt 940A-->G); and the Los Angeles variant, which contains L218L (cDNA nt 652C-->T) and N314D.

Among Whites, the gene frequency of the Q188R mutation was 0.29%, and that of the K285 N mutation was 0.062%. Only one S135L mutation was encountered among 505 African-Americans (gene frequency 0.10%). The pan-ethnic gene frequencies of the Duarte and the Los Angeles variants were 5.1% and 2.7%, respectively. Both of these frequencies were significantly less among African-Americans and Asians than among Whites and Hispanics. Native Americans revealed a higher incidence of the both variants.

Based upon the gene frequency of the Q188R mutation in the White population, the birth incidence of classic galactosemia is estimated at one patient per 47,000 in the White population. This prevalence would be increased by inbreeding.

It agrees well with the results from newborn screening programs and is only minimally higher than that reported in most studies, suggesting that most, if not all, infants with the galactosemia genotype are born and survive sufficiently long to be screened.

DISEASE ASSOCIATIONS CHARACTERIZATION

PREMATURE OVARIAN FAILURE

Risk factors for premature ovarian failure in females with galactosemia.

Guerrero NV, Singh RH, Manatunga A, Berry GT, Steiner RD, Elsas LJ 2nd.

Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

J Pediatr 2000 Dec;137(6):833-41 Abstract quote
The risk for premature ovarian failure (POF) in females with galactosemia can be predicted by analyzing 3 areas of risk pathology: the patient's molecular genotype for galactose-1-phosphate uridyltransferase (GALT), alternate pathways for galactose metabolism, and the patient's environment at diagnosis and during treatment.

STUDY DESIGN: Retrospective cross-sectional information was collected on 53 females with classic galactosemia, and their ovarian function was analyzed by determination of serum follicle-stimulating hormone and luteinizing hormone levels and by clinical observation. The associations were analyzed between POF and the mutations in GALT, the highest erythrocyte galactose-1-phosphate (Gal-1-P) level at diagnosis, the age at which dietary treatment was initiated, mean erythrocyte Gal-1-P level during treatment, and whole-body carbon 13-labeled galactose oxidation to (13)CO(2).

RESULTS: The most prevalent mutation, Q188R, had a significant effect of genotype category (Q188R/Q188R, Q188R/Other, Other/Other) on POF (P =.04, Fisher exact test and an odds ratio of 8.3). Mean erythrocyte Gal-1-P level during treatment was a significant risk factor for POF (P =.04). Also, all patients studied with less than 5% total body oxidation of galactose to (13)CO(2) had POF, whereas those with more than 5% did not have POF (P =.008, Fisher exact test).

CONCLUSION: The development of POF in females with galactosemia is more likely if the patient's genotype is Q188R/Q188R, if the mean erythrocyte Gal-1-P is >3.5 mg/dL during therapy, and if the recovery of (13)CO(2) from whole-body (13)C-galactose oxidation is reduced below 5% of administered (13)C-galactose.

PATHOGENESIS CHARACTERIZATION

GENERAL

Insights into the Pathogenesis of Galactosemia.

Leslie ND.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039.
Annu Rev Nutr 2003 Apr 9 Abstract quote
In humans, the absence of galactose-1-phosphate uridyltransferase (GALT) leads to significant neonatal morbidity and mortality which are dependent on galactose ingestion, as well as long long-term complications of primary ovarian failure and cognitive dysfunction, which are diet independent.

The creation of a knockout mouse model for GALT deficiency was aimed at providing an organism in which metabolic challenges and gene manipulation could address the enigmatic pathophysiologic questions raised by humans with galactosemia. Instead, the mouse represents a biochemical phenotype without evidence of clinical morbidity. The similarities and differences between mice and humans with galactosemia are explored from metabolite, enzyme, and process points of view.

The mouse both produces and oxidizes galactose in a manner similar to humans. It differs in brain accumulation of galactitol. Future directions for exploration of this enigmatic condition are discussed.

MOLECULAR DEFECT IN THE GALT ENZYME

Galactosemia: deletion in the 5' upstream region of the GALT gene reduces promoter efficiency.

Trbusek M, Francova H, Kozak L.

Department of Biochemical and Molecular Genetics, Research Institute of Child Health, Cernopolni 9, 662 62 Brno, Czech Republic.
Hum Genet 2001 Jul;109(1):117-20 Abstract quote
Galactosemia is a metabolic disorder caused by a defect in the galactose-1-phosphate uridyltransferase (GALT) enzyme. In previous studies, we have shown that the presence of a deletion in the 5' upstream (promoter) region of the GALT gene is associated with the Duarte (D2) allele.

In the present study, by using a promoter fusion assay we provide direct evidence that a GTCA deletion located in position -119/-116 of the GALT gene (considered in relation to the translational start site) decreases transcription of a reporter gene to about 55% compared with a normal "healthy" promoter transfected into human hepatocyte HepG2 cells. This result coincides well with previously published biochemical data showing 50% GALT-gene activity in Duarte (D2) galactosemia patients.

By transfecting the same promoters (normal and deleted) into mouse NIH/3T3 cells, we show that the GTCA motif in the promoter region of the GALT gene was conserved throughout evolution.

We conclude that the -119/-116delGTCA promoter mutation is a crucial factor in reduction of Duarte allele enzyme activity.

Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R).

Kozak L, Francova H, Fajkusova L, Pijackova A, Macku J, Stastna S, Peskovova K, Martincova O, Krijt J, Bzduch V.

Research Institute of Child Health, Department of Biochemical and Molecular Genetics, Cernopolni 9, CZ-662 62 Brno, Czech Republic.
Hum Mutat 2000 Feb;15(2):206 Abstract quote
A study of the galactose-1-phosphate uridyltransferase (GALT) gene from 37 unrelated galactosemia families is reported here. A total of 16 sequence variations in eleven mutated alleles was found.

The two most common molecular defects were the mutations Q188R (46.0%) and K285N (25.7%). Six novel mutations in the GALT gene, X380R, Y209S, E340K, L74fsdelCT, Q169K and L256/P257delGCC, were detected.

Three mutations, V151A, L195P and R204X that were previously described in other populations, were also found. The mutation X380R, which breaks the stop codon of the GALT gene, causes elongation of the GALT enzyme's protein chain. A deletion of four nucleotides in the 5' promoter region, in a position 116 - 119 nucleotides upstream from the initiate codon (5'UTR-119delGTCA), was revealed in Duarte (D2) alleles, in addition to N314D, IVS4nt-27g-->c, IVS5nt+62g-->a, and IVS5nt-24g-->a. An unusual molecular genotype was observed on 2 types of classical galactosemia alleles, with six variations from the normal nucleotide sequence presented in cis (mutation V151A or E340K plus five Duarte (D2) characteristic variations).

In summary, galactosemia is a heterogeneous disorder at the molecular level, and mutation N314D, appears to be an ancient genetic variant of the GALT gene.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

BONE MINERAL DENSITY

Bone mineral density in patients with classic galactosaemia.

Rubio-Gozalbo ME, Hamming S, van Kroonenburgh MJ, Bakker JA, Vermeer C, Forget PP.

Department of Pediatrics, Academic Hospital Maastricht, Netherlands.
Arch Dis Child 2002 Jul;87(1):57-60 Abstract quote
BACKGROUND: Diminished bone mineral density (BMD) is a well known complication in women with classic galactosaemia caused by premature ovarian failure. Diminished BMD in prepubertal patients of either sex has, however, only been reported once. Aim: To assess BMD in children with classic galactosaemia.

METHODS: Eleven treated patients (five males, six females, aged 2-18 years) had BMD determined by dual energy x ray absorptiometry. Two measurements were performed, an areal measurement of the total body and a volumetric measurement of the femoral neck. Results were expressed as Z scores. Dietary calcium intake, blood calcium, phosphate, vitamin D, parathormone, and markers of bone formation (bone alkaline phosphatase, osteocalcin) and bone resorption (NTX) were determined.

RESULTS: All patients had a significantly diminished BMD. Mean Z score of the volumetric BMD was -1.76 (range -0.7 to -3.3), and of the areal BMD -0.99 (range -0.5 to -1.4). Dietary calcium intake and calcium, phosphate, parathormone, bone alkaline phosphatase, vitamin D metabolites, and osteocalcin (free and carboxylated) were normal in all patients. NTX levels in blood were significantly lower (p < 0.001) than in control subjects.

CONCLUSION: BMD in this group of children of both sexes with classic galactosaemia under dietary treatment was decreased. Lower NTX levels in galactosaemics point to an apparent decreased bone resorption.

PROTON MAGNETIC RESONANCE SPECTROSCOPY

Proton magnetic resonance spectroscopy of brain metabolites in galactosemia.

Wang ZI, Berry GT, Dreha SF, Zhao H, Segal S, Zimmerman RA.

Department of Radiology, The Children's Hospital of Philadelphia, PA 19104, USA.
Ann Neurol 2001 Aug;50(2):266-9 Abstract quote
Brain edema may occur in infants with galactosemia and has been associated with accumulation of galactitol. Proton magnetic resonance spectra were obtained from 12 patients (four newly diagnosed neonates and eight patients on galactose-restricted diets, age range 1.7-47 years) and control subjects to measure brain galactitol levels in vivo and correlate them with urinary galactitol excretion.

The results demonstrate that a markedly elevated brain galactitol level may be present only in newborn infants with galactosemia who exhibit massive urinary galactitol excretion.

LABORATORY MARKERS

SCREENING

Analysis of common mutations in the galactose-1-phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia.

Dobrowolski SF, Banas RA, Suzow JG, Berkley M, Naylor EW.

Neo Gen Screening, Inc., Bridgeville, Pennsylvania.

J Mol Diagn 2003 Feb;5(1):42-7 Abstract quote
Classical galactosemia is a genetic disease caused by mutations in the galactose-1-phosphate uridyl transferase (GALT) gene. Prospective newborn screening for galactosemia is routine and utilizes the universally collected newborn dried blood specimen on filter paper.

Screening for galactosemia is achieved through analysis of total galactose (galactose and galactose-1-phosphate) and/or determining the activity of the GALT enzyme. While this approach is effective, en vironmental factors and the high frequency of the Duarte D2 mutation (N314D) does lead to false positive results.

Using DNA derived from the original newborn dried blood specimen and Light Cycler technology a panel of five assays able to detect the four most frequently encountered classical galactosemia alleles (Q188R, S135L, K285N, and L195P) and the N314D Duarte variant mutation are described. The five assays are performed simultaneously using common conditions. Including DNA preparation, set-up, amplification, and analysis the genotype data for all five loci is obtained in less than 2 hours.

The assays are easily interpreted and amenable to high-throughput newborn screening. Mutational analysis is useful to reduce false positive results, differentiate D/G mixed heterozygotes from classical galactosemia, and to clearly identify a very high percentage of those affected by classical galactosemia.

Pitfalls in diagnosing galactosemia: false negative newborn screening following red blood cell transfusion.

Sokol RJ, McCabe ER, Kotzer AM, Langendoerfer SI.

Section of Pediatric Gastroenterology and Nutrition, University of Colorado School of Medicine, Denver 80262.
J Pediatr Gastroenterol Nutr 1989 Feb;8(2):266-8 Abstract quote
Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose-1-phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions.

We describe an infant with galactosemia who received packed red cell transfusions in the first few days of life and was misdiagnosed after an initial positive screening test result. Although the patient was thought to have cytomegaloviral hepatitis, a percutaneous liver biopsy helped direct the evaluation toward identifying the galactosemia carrier state in both parents.

This case report illustrates the need for careful consideration of the patient's history of transfusion of blood products when evaluating newborn screening results.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

CLASSIC Typical presentation includes:
Enlarged liver
K idney failure
Cataract
Brain damage

DUARTE
Occurs when the gene for classic galactosemia and the Duarte variant gene are inherited from either parent

Galactose-1-phosphate uridyltransferase enzyme activity is approximately 25%-50% of that found in children born with no galactosemia gene

Usually lack the usual complications of classic disease

VARIANTS

CATARACTS

Pregnancy-exaggerated galactosemia and congenital cataracts.

Ramakrishnan S, Sulochana KN, Punitham R, Kar B, Ravishankar K, Vasanthi SB, Lakshminarayanan P.

Biochemistry Research Department, Medical Research Foundation, Chennai, India.

Indian J Pediatr 1998 Nov-Dec;65(6):919-24 Abstract quote
One child in a family and two children in another family had galactosemia and congenital cataract. Two of them had total soft cataracts while in one, cataract was less soft. In addition, they had mild lactosuria.

The mothers of the affected children had significant lactosuria and mild galactosuria without cataracts. Fathers did not have galactosuria or lactosuria. Clinically unaffected siblings in one family had mild galactosuria and lactosuria. Pregnancy-exaggerated galactosemia was suspected in these two mothers who gave birth to children with congenital cataract. As an extension of this work, 5001 pregnant women were screened for galactose in urine just before the delivery of babies. Mild galactosuria was present in 54 (1.08%). Three children had congenital cataract and one had changes in posterior pole and cornea.

Restriction of lactose by reducing intake of milk and milk products during pregnancy by mothers with galactosuria is recommended to avoid the birth of children with congenital cataract.

PROGNOSIS CHARACTERIZATION

GENERAL

Galactosemia: a treatable metabolic disorder.

Afzal M.

Department of Paediatrics, Combined Military Hospital, Gujranwala.
J Coll Physicians Surg Pak 2003 Feb;13(2):114-5 Abstract quote
Galactosemia is a rare metabolic disorder. It has good prognosis, if detected in neonatal period or early infancy. Two cases of classic galactosemia are presented.

One case was detected in neonatal period. Early intervention has led to normal development till now.

The second case was diagnosed at 1 year of age. Elimination of milk from diet is quite simple and effective treatment modality.

TREATMENT CHARACTERIZATION

GENERAL

DIETARY RESTRICTIONS

Galactose content of baby food meats: considerations for infants with galactosemia.

Weese SJ, Gosnell K, West P, Gropper SS.

Department of Nutrition and Food Science, Auburn University, Auburn, AL 36849, USA.
J Am Diet Assoc 2003 Mar;103(3):373-5 Abstract quote
Treatment of galactosemia requires a galactose-restricted diet. Although meats are not traditionally thought of as a dietary carbohydrate source, small amounts may be present in free form and/or bound to proteins or lipids.

The purpose of this study was to determine the free and bound galactose contents of baby food meats. Galactose was assayed using high-performance liquid chromatography.

The free galactose content of baby food meats ranged from 0 to 0.031 mg/100 g. No statistically significant differences in free galactose content were found among the meats. Bound galactose was found in all analyzed baby food meats, ranging from 0.065 to 0.148 mg/100 g. The mean galactose content of BeechNut chicken (St. Louis, MO) was significantly less than that found in Gerber (Fremont, MI) and Heinz (Pittsburgh, PA) brands of chicken, beef, and turkey, and Gerber lamb and veal.

Based on current recommendations, all examined baby food meats would be acceptable for infants with galactosemia.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Internet Links

Last Updated 4/28/2003

PATHOGENESIS	CHARACTERIZATION
GENERAL
Insights into the Pathogenesis of Galactosemia. Leslie ND. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039.	Annu Rev Nutr 2003 Apr 9 Abstract quote In humans, the absence of galactose-1-phosphate uridyltransferase (GALT) leads to significant neonatal morbidity and mortality which are dependent on galactose ingestion, as well as long long-term complications of primary ovarian failure and cognitive dysfunction, which are diet independent. The creation of a knockout mouse model for GALT deficiency was aimed at providing an organism in which metabolic challenges and gene manipulation could address the enigmatic pathophysiologic questions raised by humans with galactosemia. Instead, the mouse represents a biochemical phenotype without evidence of clinical morbidity. The similarities and differences between mice and humans with galactosemia are explored from metabolite, enzyme, and process points of view. The mouse both produces and oxidizes galactose in a manner similar to humans. It differs in brain accumulation of galactitol. Future directions for exploration of this enigmatic condition are discussed.
MOLECULAR DEFECT IN THE GALT ENZYME
Galactosemia: deletion in the 5' upstream region of the GALT gene reduces promoter efficiency. Trbusek M, Francova H, Kozak L. Department of Biochemical and Molecular Genetics, Research Institute of Child Health, Cernopolni 9, 662 62 Brno, Czech Republic.	Hum Genet 2001 Jul;109(1):117-20 Abstract quote Galactosemia is a metabolic disorder caused by a defect in the galactose-1-phosphate uridyltransferase (GALT) enzyme. In previous studies, we have shown that the presence of a deletion in the 5' upstream (promoter) region of the GALT gene is associated with the Duarte (D2) allele. In the present study, by using a promoter fusion assay we provide direct evidence that a GTCA deletion located in position -119/-116 of the GALT gene (considered in relation to the translational start site) decreases transcription of a reporter gene to about 55% compared with a normal "healthy" promoter transfected into human hepatocyte HepG2 cells. This result coincides well with previously published biochemical data showing 50% GALT-gene activity in Duarte (D2) galactosemia patients. By transfecting the same promoters (normal and deleted) into mouse NIH/3T3 cells, we show that the GTCA motif in the promoter region of the GALT gene was conserved throughout evolution. We conclude that the -119/-116delGTCA promoter mutation is a crucial factor in reduction of Duarte allele enzyme activity.
Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R). Kozak L, Francova H, Fajkusova L, Pijackova A, Macku J, Stastna S, Peskovova K, Martincova O, Krijt J, Bzduch V. Research Institute of Child Health, Department of Biochemical and Molecular Genetics, Cernopolni 9, CZ-662 62 Brno, Czech Republic.	Hum Mutat 2000 Feb;15(2):206 Abstract quote A study of the galactose-1-phosphate uridyltransferase (GALT) gene from 37 unrelated galactosemia families is reported here. A total of 16 sequence variations in eleven mutated alleles was found. The two most common molecular defects were the mutations Q188R (46.0%) and K285N (25.7%). Six novel mutations in the GALT gene, X380R, Y209S, E340K, L74fsdelCT, Q169K and L256/P257delGCC, were detected. Three mutations, V151A, L195P and R204X that were previously described in other populations, were also found. The mutation X380R, which breaks the stop codon of the GALT gene, causes elongation of the GALT enzyme's protein chain. A deletion of four nucleotides in the 5' promoter region, in a position 116 - 119 nucleotides upstream from the initiate codon (5'UTR-119delGTCA), was revealed in Duarte (D2) alleles, in addition to N314D, IVS4nt-27g-->c, IVS5nt+62g-->a, and IVS5nt-24g-->a. An unusual molecular genotype was observed on 2 types of classical galactosemia alleles, with six variations from the normal nucleotide sequence presented in cis (mutation V151A or E340K plus five Duarte (D2) characteristic variations). In summary, galactosemia is a heterogeneous disorder at the molecular level, and mutation N314D, appears to be an ancient genetic variant of the GALT gene.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
BONE MINERAL DENSITY
Bone mineral density in patients with classic galactosaemia. Rubio-Gozalbo ME, Hamming S, van Kroonenburgh MJ, Bakker JA, Vermeer C, Forget PP. Department of Pediatrics, Academic Hospital Maastricht, Netherlands.	Arch Dis Child 2002 Jul;87(1):57-60 Abstract quote BACKGROUND: Diminished bone mineral density (BMD) is a well known complication in women with classic galactosaemia caused by premature ovarian failure. Diminished BMD in prepubertal patients of either sex has, however, only been reported once. Aim: To assess BMD in children with classic galactosaemia. METHODS: Eleven treated patients (five males, six females, aged 2-18 years) had BMD determined by dual energy x ray absorptiometry. Two measurements were performed, an areal measurement of the total body and a volumetric measurement of the femoral neck. Results were expressed as Z scores. Dietary calcium intake, blood calcium, phosphate, vitamin D, parathormone, and markers of bone formation (bone alkaline phosphatase, osteocalcin) and bone resorption (NTX) were determined. RESULTS: All patients had a significantly diminished BMD. Mean Z score of the volumetric BMD was -1.76 (range -0.7 to -3.3), and of the areal BMD -0.99 (range -0.5 to -1.4). Dietary calcium intake and calcium, phosphate, parathormone, bone alkaline phosphatase, vitamin D metabolites, and osteocalcin (free and carboxylated) were normal in all patients. NTX levels in blood were significantly lower (p < 0.001) than in control subjects. CONCLUSION: BMD in this group of children of both sexes with classic galactosaemia under dietary treatment was decreased. Lower NTX levels in galactosaemics point to an apparent decreased bone resorption.
PROTON MAGNETIC RESONANCE SPECTROSCOPY
Proton magnetic resonance spectroscopy of brain metabolites in galactosemia. Wang ZI, Berry GT, Dreha SF, Zhao H, Segal S, Zimmerman RA. Department of Radiology, The Children's Hospital of Philadelphia, PA 19104, USA.	Ann Neurol 2001 Aug;50(2):266-9 Abstract quote Brain edema may occur in infants with galactosemia and has been associated with accumulation of galactitol. Proton magnetic resonance spectra were obtained from 12 patients (four newly diagnosed neonates and eight patients on galactose-restricted diets, age range 1.7-47 years) and control subjects to measure brain galactitol levels in vivo and correlate them with urinary galactitol excretion. The results demonstrate that a markedly elevated brain galactitol level may be present only in newborn infants with galactosemia who exhibit massive urinary galactitol excretion.
LABORATORY MARKERS
SCREENING
Analysis of common mutations in the galactose-1-phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia. Dobrowolski SF, Banas RA, Suzow JG, Berkley M, Naylor EW. Neo Gen Screening, Inc., Bridgeville, Pennsylvania.	J Mol Diagn 2003 Feb;5(1):42-7 Abstract quote Classical galactosemia is a genetic disease caused by mutations in the galactose-1-phosphate uridyl transferase (GALT) gene. Prospective newborn screening for galactosemia is routine and utilizes the universally collected newborn dried blood specimen on filter paper. Screening for galactosemia is achieved through analysis of total galactose (galactose and galactose-1-phosphate) and/or determining the activity of the GALT enzyme. While this approach is effective, en vironmental factors and the high frequency of the Duarte D2 mutation (N314D) does lead to false positive results. Using DNA derived from the original newborn dried blood specimen and Light Cycler technology a panel of five assays able to detect the four most frequently encountered classical galactosemia alleles (Q188R, S135L, K285N, and L195P) and the N314D Duarte variant mutation are described. The five assays are performed simultaneously using common conditions. Including DNA preparation, set-up, amplification, and analysis the genotype data for all five loci is obtained in less than 2 hours. The assays are easily interpreted and amenable to high-throughput newborn screening. Mutational analysis is useful to reduce false positive results, differentiate D/G mixed heterozygotes from classical galactosemia, and to clearly identify a very high percentage of those affected by classical galactosemia.
Pitfalls in diagnosing galactosemia: false negative newborn screening following red blood cell transfusion. Sokol RJ, McCabe ER, Kotzer AM, Langendoerfer SI. Section of Pediatric Gastroenterology and Nutrition, University of Colorado School of Medicine, Denver 80262.	J Pediatr Gastroenterol Nutr 1989 Feb;8(2):266-8 Abstract quote Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose-1-phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions. We describe an infant with galactosemia who received packed red cell transfusions in the first few days of life and was misdiagnosed after an initial positive screening test result. Although the patient was thought to have cytomegaloviral hepatitis, a percutaneous liver biopsy helped direct the evaluation toward identifying the galactosemia carrier state in both parents. This case report illustrates the need for careful consideration of the patient's history of transfusion of blood products when evaluating newborn screening results.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
GEOGRAPHY
Galactosaemia in black South African children. Ojwang PJ, Manickum T, Deppe WM. Department of Chemical Pathology, Faculty of Medicine, University of Natal, Durban, South Africa.	East Afr Med J 1999 May;76(5):247-50 Abstract quote OBJECTIVE: To evaluate the clinical and biochemical features of all black children confirmed to have galactosaemia from the KwaZulu Natal Province of South Africa. DESIGN: Prospective laboratory study. SUBJECTS: These included all black children with the presenting clinical features suggestive of the diagnosis of galactosaemia. SETTING: Department of Chemical Pathology, King Edward VIII Hospital, Durban, South Africa. METHOD: In each case, urine was screened for the presence of a reducing substance using urinary dipstick followed by thin layer chromatography to establish the presence of galactosaemia. The diagnosis of galacotosaemia was then confirmed by analysis of galactose-1 phosphate uridyl transferase (GALT) activity in the erythrocytes using the established Beutler enzyme assay procedure. Age and sex-matched samples were used as controls for GALT activity. The presenting clinical features of each patient on admission were also recorded. INTERVENTIONS: Patients confirmed to have galactosaemia were immediately placed on a galactose free diet. RESULTS: The age distribution of affected individuals varied from six weeks to 27 months with 60% of the children being males. The most common presenting clinical features were jaundice in 77% of the patients, failure to thrive 62%, and cataracts 54%. Four patients had complete absence of GALT activity. Two infants who displayed acute toxicity symptoms and positive urine galactose, exhibited normal GALT activity. CONCLUSION: GALT deficiency is the most common form of galactosaemia in black children in the KwaZulu Natal region. Cases of galactokinase or epimerase enzyme deficiency appear to be present. Further investigation is required to establish the occurrence and prevalence of the latter in affected individuals in this region.
EPIDEMIOLOGIC ASSOCIATIONS
Large-scale molecular screening for galactosemia alleles in a pan-ethnic population. Suzuki M, West C, Beutler E. Department of Molecular and Experimental Medicine (MEM215), The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.	Hum Genet 2001 Aug;109(2):210-5 Abstract quote DNA samples from 4,796 subjects from diverse ethnic groups were screened for five frequently encountered galactose-1-phosphate uridyl transferase (GALT) mutations: S135L (cDNA nt 404C-->T, as numbered from the initiator ATG codon, with A=1); Q188R (cDNA nt 563A-->G); K285 N (cDNA nt 855G-->T); the Duarte variant, N314D (cDNA nt 940A-->G); and the Los Angeles variant, which contains L218L (cDNA nt 652C-->T) and N314D. Among Whites, the gene frequency of the Q188R mutation was 0.29%, and that of the K285 N mutation was 0.062%. Only one S135L mutation was encountered among 505 African-Americans (gene frequency 0.10%). The pan-ethnic gene frequencies of the Duarte and the Los Angeles variants were 5.1% and 2.7%, respectively. Both of these frequencies were significantly less among African-Americans and Asians than among Whites and Hispanics. Native Americans revealed a higher incidence of the both variants. Based upon the gene frequency of the Q188R mutation in the White population, the birth incidence of classic galactosemia is estimated at one patient per 47,000 in the White population. This prevalence would be increased by inbreeding. It agrees well with the results from newborn screening programs and is only minimally higher than that reported in most studies, suggesting that most, if not all, infants with the galactosemia genotype are born and survive sufficiently long to be screened.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
CLASSIC	Typical presentation includes: Enlarged liver K idney failure Cataract Brain damage
DUARTE	Occurs when the gene for classic galactosemia and the Duarte variant gene are inherited from either parent Galactose-1-phosphate uridyltransferase enzyme activity is approximately 25%-50% of that found in children born with no galactosemia gene Usually lack the usual complications of classic disease
VARIANTS
CATARACTS
Pregnancy-exaggerated galactosemia and congenital cataracts. Ramakrishnan S, Sulochana KN, Punitham R, Kar B, Ravishankar K, Vasanthi SB, Lakshminarayanan P. Biochemistry Research Department, Medical Research Foundation, Chennai, India.	Indian J Pediatr 1998 Nov-Dec;65(6):919-24 Abstract quote One child in a family and two children in another family had galactosemia and congenital cataract. Two of them had total soft cataracts while in one, cataract was less soft. In addition, they had mild lactosuria. The mothers of the affected children had significant lactosuria and mild galactosuria without cataracts. Fathers did not have galactosuria or lactosuria. Clinically unaffected siblings in one family had mild galactosuria and lactosuria. Pregnancy-exaggerated galactosemia was suspected in these two mothers who gave birth to children with congenital cataract. As an extension of this work, 5001 pregnant women were screened for galactose in urine just before the delivery of babies. Mild galactosuria was present in 54 (1.08%). Three children had congenital cataract and one had changes in posterior pole and cornea. Restriction of lactose by reducing intake of milk and milk products during pregnancy by mothers with galactosuria is recommended to avoid the birth of children with congenital cataract.