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GALT Deficiency 1.5 ANCC Contact Hours YAY Media AS / Alamy Stock Photo YAY GALT Defi ciency Galactosemia Abstract alactosemia is an autosomal recessive Galactosemia is an inborn error of galactose metabolism that results from a genetic condition caused by a defect in deficiency in one of three enzymes, uridine diphosphate galactose 4’epimerase, the Leloir pathway resulting in defi - galactokinase, or galactose-1-phosphate uridyltransferase (GALT). This article G ciency of one of three enzymes, uridine focuses on classical, clinical variant, and biochemical variant (Duarte) galac- diphosphate galactose 4’epimerase (GALE), tosemias caused by GALT enzyme deficiency. A brief overview of galactosemia galactokinase (GALK), or galactose-1- phosphate and newborn screening is presented, followed by detailed information about (Gal-1-P) uridyltransferase (GALT). Although each of the conditions. Confirmatory testing, acute and long-term manage- the mechanism for galactosemia is not fully ment, and outcome for these galactosemia types are discussed as well as the understood, changes in the GALT gene reduce importance of genetic counseling and testing for the infant and family to refine GALT enzyme that prevents conversion of Gal- reproductive risk. 1-P to glucose-1-phosphate. As such, Gal-1-P Key words Classic; Galactosemia; Galactose-1-phosphate uridyltransferase defi - ciency disease; Galactose-1-phosphate uridylyltransferase; GALT defi ciency. Sharon Anderson, DNP, NNP-BC, APNG 44 volume 43 | number 1 January/February 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. accumulates in cells and galactose is converted to galacti- tol or oxidized to galactonate. Accumulation of these Galactosemia is an inborn error of galactose substances in blood and tissue triggers symptoms ( Varela-Lema et al., 2016). The biochemical and clinical metabolism caused by a genetic change that variability between GALT defi ciency types depends on residual enzyme activity. results in defi ciency of one of three enzymes, Because classic GALE and GALK defi ciency galactose- uridine diphosphate galactose 4’epimerase mias are rare, this review provides nurses, practitioners, and midwives with information about three more fre- (GALE), galactokinase (GALK), or galactose- quently encountered GALT defi ciency galactosemias. 1-phosphate uridyltransferase (GALT). Newborn screening, diagnostic process, presenting symp- toms, initial and ongoing management, and associated outcomes are covered. Importance and rationale for ge- netic testing as part of the diagnostic process is discussed Homozygosity or compound heterozygosity for CG mu- and nursing implications are summarized. tations will cause severe disease. Overall incidence of CG varies based on race and ethnicity. It is highest among Newborn Screening for Galactosemia Caucasians ranging from approximately 1 in 16,000 to 1 Newborn screening for galactosemia may identify all in 44,000 infants in the United Kingdom and Ireland galactosemia types; however, the primary target is (Coss et al., 2013). Across the United States and world- GALT defi ciency galactosemia identifi ed by a combina- wide, prevalence ranges between 1 in 30,000 and 1 in tion of total galactose, GALT enzyme and for select pro- 60,000 infants (Fridovich-Keil & Walter, 2008). The grams, mutation screening. A signifi cantly reduced most prevalent CG mutation is Q188R, accounting for GALT enzyme and elevated total galactose level suggest 60% to 70% of alleles, followed by K285N that accounts classical (CG) and sometimes, classical variant galacto- for 25% to 40% of alleles among individuals from south- semia (VG), whereas more subtle changes suggest Du- ern Germany, Austria, and Croatia (Mayo Clinic, n.d.). arte galactosemia (DG) (Table 1). Some states offer a common galactosemia gene panel refl ex test to refi ne the Presenting Symptoms diagnosis. Since implementation of newborn screening, fewer infants Even with screening, an infant with galactosemia may with CG present with overwhelming illness and life- be missed. Blood transfusion or infants receiving a low threatening symptoms (Berry, 2012). However, deaths galactose-containing formula at screening may elicit a false- have been reported as early as 8 days of age (Berry, 2014) negative result. Careful review of the test result, patient and those who survive and continue to ingest galactose- history, and feeding at the time of testing ensures accurate containing formulas and foods will suffer severe brain interpretation. Most importantly, even when newborn damage (Otaduy et al., 2006). Subtle symptoms include screening results are normal, infants who present with lethargy, hypotonia, poor feeding, vomiting, diarrhea, and symptoms suggestive of galactosemia should be tested. prolonged jaundice. Cataracts may or may not be present. With ongoing galactose exposure, hepatocellular damage, Classical Galactosemia bleeding diathesis, cerebral edema, Escherichia coli The GALT gene has more than 300 mutations (ARUP (E. coli) sepsis, and hyperchloremic acidosis with amino- Laboratories, n.d.). It is located on chromosome 9p13. aciduria may develop. If left untreated, encephalopathy, shock, and death may occur (Berry, 2014; Broomfi eld, Table 1. Newborn Screening Total Galactose and Brain, & Gruenwald, 2011; Varela-Lema et al., 2016). GALT Enzyme Levels in GALT Defi ciency Galactosemia Diagnostic Testing Galactosemia Total GALT Enzyme Confi rmatory testing for CG includes GALT enzyme and/ Type Galactose (activity level) or mutation analysis (Welling et al., 2017). Galactose- Classical ↑↑↑ ↓↓↓ (<1%) 1-phosphate, RBC, free galactose, and urine galactitol Clinical variant ↑↑ ↓↓–↓↓↓ (1%–10%) may be part of the diagnostic evaluation and ongoing sur- veillance (Table 2). Although a biochemical diagnosis can Biochemical Normal to ↑↓ (15%–33%) variant (Duarte) be made based on enzyme activity and biochemical me- tabolites, if GALT enzyme is <50% and genetic testing has These values refl ect levels for newborns fed breast or cow's not been performed, it should be offered. The common milk-based formula who have not received blood transfusion. mutation panel has a detection frequency of almost 88% Soy-based formula feedings will result in lower total galactose levels than those receiving galactose feedings. The enzyme (Berry, 2014) but if mutations are not identifi ed, gene se- level, however, will not be affected by dietary galactose intake. quencing and deletion/duplication testing are available. Total galactose and GALT levels may be low in infants who have received a blood transfusion because it may refl ect the Initial Treatment galactosemia status of the donor, rather than the newborn. Whether symptomatic or asymptomatic, treatment for GALT = galactose-1-phosphate uridyltransferase CG is immediate and begins by removing exogenous January/February 2018 MCN 45 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Table 2. Diagnostic and Surveillance Testing for Classical and Clinical Variant Galactosemias Test Normal Galactosemia Galactose-1-phosphate ≥24.5 nmol/h/mg Hgb Classical: <1% activity uridyltransferase Clinical variant: 1%–10% activity Galactose-1-phosphate, <1 mg/dL >10 mg/dL (as high as 120 mg/dL) RBC On treatment: <5 mg/dL Plasma-free galactose 5–20 mmol/L >10 mg/dL (as high as 90–360 mg/dL) Urine galactitol Values vary based on age: Elevations vary (age-specifi c normals) Infants: <109 mmol/mol creatinine On treatment: <78 mmol/mol creatinine Adults: <13 mmol/mol creatinine sources of dietary galactose to prevent galactose expo- are replaced with galactose-free/low-galactose substitu- sure and accumulation. After discontinuing breast and tions. There are food lists, on-line and published cow's milk-based formula, symptomatic newborns may resources, and parent and peer support groups to help require intravenous hydration, phototherapy, and/or ex- parents, care providers, and eventually patients monitor change transfusion. Vitamin K and fresh frozen plasma galactose intake. are used to treat bleeding concerns resulting from hepatic When over-the-counter or prescription medications are injury. Other treatments may include bicarbonate for aci- required, galactose content must be checked. Generally, dosis and antibiotics for disease-associated E. coli sepsis liquid medications do not contain galactose but tablet (Berry, 2012). Once stabilized, feedings of galactose-free medications often do. When an alternate galactose-free formula can be provided (Table 3). drug is available, it should be substituted. If not, the ben- efi ts and limitations of a short-term course of galactose- Lifelong Management containing medication must be weighed. During early infancy, diet is formula-based and easy to man- With strict dietary control, Gal-1-P, RBC should re- age. To minimize exposure to small amounts of galactose in main <5 mg/dL and urine galactitol <78 mmol/mol cre- premixed formulas, powdered formula is recommended. atinine (Berry, 2014). After diagnosis, ongoing metabolic Breastfeeding mothers require guidance and support to genetic visits are recommended every 3 months for the wean breast milk production. Infants receiving services fi rst year, every 6 months for 1 year, and then annually. through the Special Supplemental Nutrition Program Visits include diet analysis, nutritional counseling with a for Women, Infants, and Children (WIC) may require metabolic dietitian, and assessment of metabolic control, documentation to change formula and over time, supply growth, and coordination of care based on disease- condition-appropriate
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