44 volume 43 | number 1 January/February 2018 YAY Media AS / Alamy Stock Photo 1.5 ANCC Contact Hours Galactosemia GALT Deficiency Abstract Galactosemia is an inborn error of galactose metabolism that results from a deficiency in one of three enzymes, uridine diphosphate galactose 4’epimerase, galactokinase, or galactose-1-phosphate uridyltransferase (GALT). This article focuses on classical, clinical variant, and biochemical variant (Duarte) galac- tosemias caused by GALT enzyme deficiency. A brief overview of galactosemia and newborn screening is presented, followed by detailed information about each of the conditions. Confirmatory testing, acute and long-term manage- ment, and outcome for these galactosemia types are discussed as well as the importance of genetic counseling and testing for the infant and family to refine reproductive risk. Key words Classic; Galactosemia; Galactose-1-phosphate uridyltransferase defi- ciency disease; Galactose-1-phosphate uridylyltransferase; GALT deficiency. G alactosemia is an autosomal recessive genetic condition caused by a defect in the Leloir pathway resulting in defi- ciency of one of three enzymes, uridine diphosphate galactose 4’epimerase (GALE), galactokinase (GALK), or galactose-1-phosphate (Gal-1-P) uridyltransferase (GALT). Although the mechanism for galactosemia is not fully understood, changes in the GALT gene reduce GALT enzyme that prevents conversion of Gal- 1-P to glucose-1-phosphate. As such, Gal-1-P Sharon Anderson, DNP, NNP-BC, APNG Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
GALT Deficiency - Galactosemia
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MCN0118_GALT_00158_Dharam.inddYA Y
M ed
ia AS
Abstract
Galactosemia is an inborn error of galactose metabolism that results from a deficiency in one of three enzymes, uridine diphosphate galactose 4’epimerase, galactokinase, or galactose-1-phosphate uridyltransferase (GALT). This article focuses on classical, clinical variant, and biochemical variant (Duarte) galac- tosemias caused by GALT enzyme deficiency. A brief overview of galactosemia and newborn screening is presented, followed by detailed information about each of the conditions. Confirmatory testing, acute and long-term manage- ment, and outcome for these galactosemia types are discussed as well as the importance of genetic counseling and testing for the infant and family to refine reproductive risk.
Key words Classic; Galactosemia; Galactose-1-phosphate uridyltransferase defi - ciency disease; Galactose-1-phosphate uridylyltransferase; GALT defi ciency.
G alactosemia is an autosomal recessive genetic condition caused by a defect in the Leloir pathway resulting in defi - ciency of one of three enzymes, uridine
diphosphate galactose 4’epimerase (GALE), galactokinase (GALK), or galactose-1- phosphate (Gal-1-P) uridyltransferase (GALT). Although the mechanism for galactosemia is not fully understood, changes in the GALT gene reduce GALT enzyme that prevents conversion of Gal- 1-P to glucose-1-phosphate. As such, Gal-1-P
Sharon Anderson, DNP, NNP-BC, APNG
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
January/February 2018 MCN 45
Homozygosity or compound heterozygosity for CG mu- tations will cause severe disease. Overall incidence of CG varies based on race and ethnicity. It is highest among Caucasians ranging from approximately 1 in 16,000 to 1 in 44,000 infants in the United Kingdom and Ireland (Coss et al., 2013). Across the United States and world- wide, prevalence ranges between 1 in 30,000 and 1 in 60,000 infants (Fridovich-Keil & Walter, 2008). The most prevalent CG mutation is Q188R, accounting for 60% to 70% of alleles, followed by K285N that accounts for 25% to 40% of alleles among individuals from south- ern Germany, Austria, and Croatia (Mayo Clinic, n.d.).
Presenting Symptoms Since implementation of newborn screening, fewer infants with CG present with overwhelming illness and life- threatening symptoms (Berry, 2012). However, deaths have been reported as early as 8 days of age (Berry, 2014) and those who survive and continue to ingest galactose- containing formulas and foods will suffer severe brain damage (Otaduy et al., 2006). Subtle symptoms include lethargy, hypotonia, poor feeding, vomiting, diarrhea, and prolonged jaundice. Cataracts may or may not be present. With ongoing galactose exposure, hepatocellular damage, bleeding diathesis, cerebral edema, Escherichia coli (E. coli) sepsis, and hyperchloremic acidosis with amino- aciduria may develop. If left untreated, encephalopathy, shock, and death may occur (Berry, 2014; Broomfi eld, Brain, & Gruenwald, 2011; Varela-Lema et al., 2016).
Diagnostic Testing Confi rmatory testing for CG includes GALT enzyme and/ or mutation analysis (Welling et al., 2017). Galactose- 1-phosphate, RBC, free galactose, and urine galactitol may be part of the diagnostic evaluation and ongoing sur- veillance (Table 2). Although a biochemical diagnosis can be made based on enzyme activity and biochemical me- tabolites, if GALT enzyme is <50% and genetic testing has not been performed, it should be offered. The common mutation panel has a detection frequency of almost 88% (Berry, 2014) but if mutations are not identifi ed, gene se- quencing and deletion/duplication testing are available.
Initial Treatment Whether symptomatic or asymptomatic, treatment for CG is immediate and begins by removing exogenous
accumulates in cells and galactose is converted to galacti- tol or oxidized to galactonate. Accumulation of these substances in blood and tissue triggers symptoms ( Varela-Lema et al., 2016). The biochemical and clinical variability between GALT defi ciency types depends on residual enzyme activity.
Because classic GALE and GALK defi ciency galactose- mias are rare, this review provides nurses, practitioners, and midwives with information about three more fre- quently encountered GALT defi ciency galactosemias. 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 and nursing implications are summarized.
Newborn Screening for Galactosemia Newborn screening for galactosemia may identify all galactosemia types; however, the primary target is GALT defi ciency galactosemia identifi ed by a combina- tion of total galactose, GALT enzyme and for select pro- grams, mutation screening. A signifi cantly reduced GALT enzyme and elevated total galactose level suggest classical (CG) and sometimes, classical variant galacto- semia (VG), whereas more subtle changes suggest Du- arte galactosemia (DG) (Table 1). Some states offer a common galactosemia gene panel refl ex test to refi ne the diagnosis.
Even with screening, an infant with galactosemia may be missed. Blood transfusion or infants receiving a low galactose-containing formula at screening may elicit a false- negative result. Careful review of the test result, patient history, and feeding at the time of testing ensures accurate interpretation. Most importantly, even when newborn screening results are normal, infants who present with symptoms suggestive of galactosemia should be tested.
Classical Galactosemia The GALT gene has more than 300 mutations (ARUP Laboratories, n.d.). It is located on chromosome 9p13.
Galactosemia is an inborn error of galactose
metabolism caused by a genetic change that
results in defi ciency of one of three enzymes,
uridine diphosphate galactose 4’epimerase
(GALE), galactokinase (GALK), or galactose-
1-phosphate uridyltransferase (GALT).
Table 1. Newborn Screening Total Galactose and GALT Enzyme Levels in GALT Defi ciency Galactosemia
Galactosemia
Type
Total
Galactose
Normal to ↑ ↓ (15%–33%)
These values refl ect levels for newborns fed breast or cow's milk-based formula who have not received blood transfusion. Soy-based formula feedings will result in lower total galactose levels than those receiving galactose feedings. The enzyme level, however, will not be affected by dietary galactose intake. Total galactose and GALT levels may be low in infants who have received a blood transfusion because it may refl ect the galactosemia status of the donor, rather than the newborn. GALT = galactose-1-phosphate uridyltransferase
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
46 volume 43 | number 1 January/February 2018
are replaced with galactose-free/low-galactose substitu- tions. There are food lists, on-line and published resources, and parent and peer support groups to help parents, care providers, and eventually patients monitor galactose intake.
When over-the-counter or prescription medications are required, galactose content must be checked. Generally, liquid medications do not contain galactose but tablet medications often do. When an alternate galactose-free drug is available, it should be substituted. If not, the ben- efi ts and limitations of a short-term course of galactose- containing medication must be weighed.
With strict dietary control, Gal-1-P, RBC should re- main <5 mg/dL and urine galactitol <78 mmol/mol cre- atinine (Berry, 2014). After diagnosis, ongoing metabolic genetic visits are recommended every 3 months for the fi rst year, every 6 months for 1 year, and then annually. Visits include diet analysis, nutritional counseling with a metabolic dietitian, and assessment of metabolic control, growth, and coordination of care based on disease- associated risks and complications.
Complications Although the exact mechanism remains unclear, there are long-term complications associated with pre- and postnatal exogenous and endogenous galactose expo- sure and even, strict galactose restriction. Intellectual impairment, verbal dyspraxia, and neurological impair- ment may be linked to cerebral white matter changes. Other complications include cataracts, osteopenia, growth delay, and hypergonadotropic hypogonadism in females.
Intellectual impairment. Mean IQ is reduced in chil- dren with CG (70–90) especially among those with the Q188R mutation (Broomfi eld et al., 2011). It has been hypothesized intellectual abilities decline over time, but this has not been supported in the literature. Develop- mental assessments are recommended at age 1 and then every 1 to 3 years (Berry, 2014). Early intervention and individualized education plans are important in meeting developmental, intellectual, and learning needs.
Speech and language defi cits. Speech diffi culties are common and include delayed vocabulary, articulation problems and, less frequently, verbal dyspraxia. Speech and language screening performed alone or in combina- tion with cognitive screening should take place at 7 to 12
sources of dietary galactose to prevent galactose expo- sure and accumulation. After discontinuing breast and cow's milk-based formula, symptomatic newborns may require intravenous hydration, phototherapy, and/or ex- change transfusion. Vitamin K and fresh frozen plasma are used to treat bleeding concerns resulting from hepatic injury. Other treatments may include bicarbonate for aci- dosis and antibiotics for disease-associated E. coli sepsis (Berry, 2012). Once stabilized, feedings of galactose-free formula can be provided (Table 3).
Lifelong Management During early infancy, diet is formula-based and easy to man- age. To minimize exposure to small amounts of galactose in premixed formulas, powdered formula is recommended. Breastfeeding mothers require guidance and support to wean breast milk production. Infants receiving services through the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) may require documentation to change formula and over time, supply condition-appropriate nutritious foods in lieu of milk and cheese.
As the diet advances, treatment rests with dietary ga- lactose restriction guided by a metabolic dietitian. Milk, milk products, and casein- and whey-containing foods
Table 2. Diagnostic and Surveillance Testing for Classical and Clinical Variant Galactosemias Test Normal Galactosemia
Galactose-1-phosphate uridyltransferase
Clinical variant: 1%–10% activity
Galactose-1-phosphate,
RBC <1 mg/dL >10 mg/dL (as high as 120 mg/dL)
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:
Infants: <109 mmol/mol creatinine
Adults: <13 mmol/mol creatinine
Elevations vary (age-specifi c normals)
On treatment: <78 mmol/mol creatinine
Table 3. Acceptable Formulas for Use in GALT Defi ciency Galactosemia Soy-Based Formulas*
Similac® Soy Isomil®
GALT = galactose-1-phosphate uridyltransferase
*Generic soy formulas are comparable. Because they may vary, it is recommended providers check with the manufacturer.
Notes. 1) Enfamil™ Lactose Free formula contains cow's milk as the protein source and is not galactose-free. 2) It is recom- mended infants with classical and clinical variant galactose- mia receive powdered (not concentrate or premixed) formula.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
January/February 2018 MCN 47
Endocrinology should be consulted to address atypical growth concerns.
Hypergonadotropic hypogonadism. Primary ovarian insuffi ciency (POI) and premature menopause are symp- toms of hypergonadotropic hypogonadism experienced by women with CG. Although believed to be a result of chronic Gal-1-P and galactitol exposure, the mechanism remains unknown. Estradiol, follicle stimulating, and luteinizing hormone levels should be assessed at age 1 and 2 years and puberty. Typically, females present with pubertal delay and primary or secondary amenorrhea progressing to POI. As they approach puberty, girls should be carefully monitored by a pediatric endocri- nologist and estrogen and progestin support provided as needed (Broomfi eld et al., 2011; Mayatepek et al., 2010). The risk for POI does not directly correlate with strict dietary galactose restriction, which suggests ovarian tox- icity may occur early in life. Although approximately 80% of women develop ovarian dysfunction, spontane- ous pregnancy can occur (Broomfi eld et al.). Birth control should be offered to women not wishing to con- ceive and reproductive options should be discussed with women with POI.
Patient Outcome The rationale for screening newborns for galactosemia is to identify at-risk newborns and minimize galactose toxic- ity and associated morbidity and mortality. There is no question, galactose restriction for newborns with CG is life-saving. Several researchers, however, have examined presymptomatic treatment and failed to demonstrate bet- ter long-term outcome for those treated earlier rather than later. Antenatal maternal dietary galactose restriction does not improve patient outcome and in some cases, resulted in poorer outcomes (Hughes et al., 2009). Although not yet well studied, several researchers hypothesize strict dietary galactose restriction may contribute to long-term systemic problems and a more liberal intake of galactose may improve outcomes (Coman et al., 2010; Hughes et al.). The long-term effect of this remains unknown and therefore, treatment for CG remains lifelong dietary galac- tose restriction, surveillance, and anticipatory guidance.
months and ages 2, 3, and 5 years (Welling et al., 2017). When indicated, speech therapy is intensive and, unfortu- nately, a large percentage of individuals are refractory (Berry, 2014).
Neurological problems. Speech and coordination dis- orders frequently cooccur. Despite strict dietary galactose restriction, over time, 10% to 20% develop extrapyrami- dal symptoms including severe, progressive ataxia, fi ne- motor tremors, dysmetria, and dystonia (Rubio-Agusti et al., 2013; Waisbren et al., 2012; Welling et al., 2017). Clinical screening should begin at 2 to 3 years (Welling et al.) and neurology consultation and physical and oc- cupational therapies may be warranted.
Cataracts. Accumulation of galactitol is thought to be the cause for cataracts (Broomfi eld et al., 2011). Cata- racts were originally reported in up to 30% of patients with CG but more recent evidence suggests the rate is closer to 14% (Broomfi eld et al.). Most cataracts resolve with dietary galactose restriction and newborns should receive ophthalmology follow-up until resolved (Welling et al., 2017). After baseline, slit lamp examination is rec- ommended at ages 1, 5, and during adolescence (Berry, 2014) and for all patients who do not comply with dietary galactose restriction (Welling et al.).
Osteopenia and osteoporosis. Strict restriction of milk and milk products places individuals at increased risk for osteopenia and premature osteoporosis. Calcium, phos- phorus, and 25-hydroxyvitamin D levels are recommend- ed annually. Optimized dietary calcium intake and vitamin D3 and calcium supplementation, laboratory testing, and regular exercise are recommended (Welling et al., 2017). Bone mineral density scanning is recom- mended annually beginning at school age (Berry, 2014; Mayatepek, Hoffmann, & Meissner, 2010) and every 5 years after puberty is complete (Welling et al.).
Growth delay. Growth is generally delayed in child- hood and early adolescence and those with higher residu- al enzyme levels have improved adult height (Berry, 2014). Although some women may fall short of calculat- ed midparental height (Panis, Gerver, & Rubio-Gozalbo, 2007), most will reach normal height-for-age. Careful monitoring of growth is recommended through puberty.
Treatment for classical and clinical variant galactosemia rests with lifelong
dietary galactose restriction, whereas
more controversial.
Af ric
a St
ud io
48 volume 43 | number 1 January/February 2018
CG and VG, GALT enzyme levels are higher, ranging be- tween 15% and 33% (Berry, 2014). Although Gal-1-P, RBC, and urine galactitol galactose metabolites are elevat- ed during infancy, most normalize by age 2. There is con- troversy about the short- and long-term signifi cance and treatment of this milder galactosemia type. Most patients are lost-to-follow-up and thus, there are sparse long-term data to support any one approach to care. As a result, there are varying opinions regarding whether DG is a “real disease” (Berry) and what, if any, treatment is required.
Treatment Controversy Several studies have compared infants and children with DG treated with strict galactose restriction to those who were not with mixed results. One frequently cited study by Ficicioglu et al. (2008) compared a cohort of children with DG ages 1 to 6 years (n = 28). One group received strict dietary restriction with periodic assessment of ga- lactose metabolites (n = 17) the fi rst year of life, whereas the other received no restriction (n = 11). No signifi cant differences in clinical or long-term outcomes between the two groups were revealed. Similarly, Powell et al. (2009) examined a patient cohort of 59 children with DG and found no increased rates of intellectual disability, cere- bral palsy, autism spectrum disorder, hearing or vision impairment. There were, however, higher rates of special education (primarily speech and language disorders) among children with DG.
Clinical Variant Galactosemia Clinical VG caused by homozygosity of S135L occurs primarily among African Americans and native Africans in South Africa. Newborns with VG present with barely detectable or absent (0%–10%) GALT activity. Different from CG, individuals with VG have higher enzyme levels in the brain and intestines.
A portion of infants with VG will have Gal-1-P, RBC levels similar to newborns with CG and thus, manifest early clinical symptoms such as growth failure, liver disease, and cataracts (Berry, 2014). For the majority, he- patic enzyme levels as high as 10% make hypergalactose- mia less severe than with CG. As such, timely treatment minimizes risk for E. coli sepsis and chronic, long-term complications such as intellectual disability, speech prob- lems, and POI (Berry). Treatment recommendations are similar to CG and based on the severity of enzyme defi - ciency. Overall, the prognosis for VG is good.
Biochemical Variant (Duarte) Galactosemia A milder variant of galactosemia, DG, results when an in- dividual is compound heterozygous for a classical (e.g., Q188R) and Duarte (N314D) change in the GALT gene. Duarte galactosemia affects approximately 1 in every 4,000 newborns and is far more common than either CG and VG combined (Ficicioglu et al., 2008). In contrast to
Table 4. Risk to Have a Child with Galactosemia Based on Parent Carrier Status: Exemplars Classical/Classical Variant Galactosemia Carrier (NG) Parents
Parent 1 Unless one of the parents has classical or classical variant galactosemia, each parent is an obligate carrier for galactosemia. As such, the recurrence risk to have a child with clas- sical galactosemia (GG) with each pregnancy is 1 in 4 (25%). There is a 50% risk with each pregnancy to have a child who is a carrier for galactosemia (NG) and 25% chance to have a child with two normal alleles (NN).P
ar en
Carrier (ND) Parents
Parent 1 This diagram shows the risk for two parents, one a carrier for the classical galactosemia gene (Parent 1) and the other, the Duarte variant (Parent 2). In this case, the recurrence risk to have a child with Duarte galactosemia (DG) with each pregnancy is 1 in 4 (25%). There is a 25% risk with each pregnancy to have a child who is a carrier for classical ga- lactosemia (NG), 25% risk to have a child who is a carrier for the Duarte variant (ND), and 25% chance to have a child with two normal alleles (NN).P
ar en
(DG) Parents
Parent 1 In the unlikely event, one parent (Parent 1) has Duarte galactosemia (DG), the recurrence risk to have a child with classical galactosemia (GG) will depend on the carrier status of the other parent. In this diagram, if Parent 2 is a carrier for classical galactosemia, there is a 25% risk with each pregnancy to have a child with Duarte galactosemia (DG) but there is also a 25% risk to have a child with classical galactosemia (GG).
P ar
en t
N = normal allele; D = Duarte allele; G = classical galactosemia allele; GG = classical/variant galactosemia; DG = Duarte galacto- semia, NG = carrier for classical/variant galactosemia; ND = carrier for Duarte gene
Note. Newborns homozygous for the Duarte gene (DD) may also be identifi ed through newborn screening. Typically, these infants have approximately 50% GALT enzyme activity and do not require treatment or follow-up.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
January/February 2018 MCN 49
follow-up for the fi rst 1 to 2 years of life. To balance these divergent approaches, some have opted to alternate breast with soy-based formula feedings for mothers who want to breastfeed. Although there is no one standard approach to DG at this time, a group of international experts re- cently published treatment guidelines recommending these patients not be treated (Welling et al., 2017).
Genetic Counseling Regardless of the type and severity, genetic counseling should be provided to families of a newborn diagnosed with galactosemia. Because it is an autosomal recessive condition, at a minimum, both parents are obligate carriers for galactosemia and the recurrence risk for
The risk for potential long-term ovarian dysfunction was studied by Sanders et al. (2009). Anti-müllerian and follicle-stimulating hormones were obtained in girls with DG and compared with controls. Values were indistin- guishable between the groups. This suggests females with DG are not at risk for POI and as such, endocrine evalu-…
M ed
ia AS
Abstract
Galactosemia is an inborn error of galactose metabolism that results from a deficiency in one of three enzymes, uridine diphosphate galactose 4’epimerase, galactokinase, or galactose-1-phosphate uridyltransferase (GALT). This article focuses on classical, clinical variant, and biochemical variant (Duarte) galac- tosemias caused by GALT enzyme deficiency. A brief overview of galactosemia and newborn screening is presented, followed by detailed information about each of the conditions. Confirmatory testing, acute and long-term manage- ment, and outcome for these galactosemia types are discussed as well as the importance of genetic counseling and testing for the infant and family to refine reproductive risk.
Key words Classic; Galactosemia; Galactose-1-phosphate uridyltransferase defi - ciency disease; Galactose-1-phosphate uridylyltransferase; GALT defi ciency.
G alactosemia is an autosomal recessive genetic condition caused by a defect in the Leloir pathway resulting in defi - ciency of one of three enzymes, uridine
diphosphate galactose 4’epimerase (GALE), galactokinase (GALK), or galactose-1- phosphate (Gal-1-P) uridyltransferase (GALT). Although the mechanism for galactosemia is not fully understood, changes in the GALT gene reduce GALT enzyme that prevents conversion of Gal- 1-P to glucose-1-phosphate. As such, Gal-1-P
Sharon Anderson, DNP, NNP-BC, APNG
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
January/February 2018 MCN 45
Homozygosity or compound heterozygosity for CG mu- tations will cause severe disease. Overall incidence of CG varies based on race and ethnicity. It is highest among Caucasians ranging from approximately 1 in 16,000 to 1 in 44,000 infants in the United Kingdom and Ireland (Coss et al., 2013). Across the United States and world- wide, prevalence ranges between 1 in 30,000 and 1 in 60,000 infants (Fridovich-Keil & Walter, 2008). The most prevalent CG mutation is Q188R, accounting for 60% to 70% of alleles, followed by K285N that accounts for 25% to 40% of alleles among individuals from south- ern Germany, Austria, and Croatia (Mayo Clinic, n.d.).
Presenting Symptoms Since implementation of newborn screening, fewer infants with CG present with overwhelming illness and life- threatening symptoms (Berry, 2012). However, deaths have been reported as early as 8 days of age (Berry, 2014) and those who survive and continue to ingest galactose- containing formulas and foods will suffer severe brain damage (Otaduy et al., 2006). Subtle symptoms include lethargy, hypotonia, poor feeding, vomiting, diarrhea, and prolonged jaundice. Cataracts may or may not be present. With ongoing galactose exposure, hepatocellular damage, bleeding diathesis, cerebral edema, Escherichia coli (E. coli) sepsis, and hyperchloremic acidosis with amino- aciduria may develop. If left untreated, encephalopathy, shock, and death may occur (Berry, 2014; Broomfi eld, Brain, & Gruenwald, 2011; Varela-Lema et al., 2016).
Diagnostic Testing Confi rmatory testing for CG includes GALT enzyme and/ or mutation analysis (Welling et al., 2017). Galactose- 1-phosphate, RBC, free galactose, and urine galactitol may be part of the diagnostic evaluation and ongoing sur- veillance (Table 2). Although a biochemical diagnosis can be made based on enzyme activity and biochemical me- tabolites, if GALT enzyme is <50% and genetic testing has not been performed, it should be offered. The common mutation panel has a detection frequency of almost 88% (Berry, 2014) but if mutations are not identifi ed, gene se- quencing and deletion/duplication testing are available.
Initial Treatment Whether symptomatic or asymptomatic, treatment for CG is immediate and begins by removing exogenous
accumulates in cells and galactose is converted to galacti- tol or oxidized to galactonate. Accumulation of these substances in blood and tissue triggers symptoms ( Varela-Lema et al., 2016). The biochemical and clinical variability between GALT defi ciency types depends on residual enzyme activity.
Because classic GALE and GALK defi ciency galactose- mias are rare, this review provides nurses, practitioners, and midwives with information about three more fre- quently encountered GALT defi ciency galactosemias. 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 and nursing implications are summarized.
Newborn Screening for Galactosemia Newborn screening for galactosemia may identify all galactosemia types; however, the primary target is GALT defi ciency galactosemia identifi ed by a combina- tion of total galactose, GALT enzyme and for select pro- grams, mutation screening. A signifi cantly reduced GALT enzyme and elevated total galactose level suggest classical (CG) and sometimes, classical variant galacto- semia (VG), whereas more subtle changes suggest Du- arte galactosemia (DG) (Table 1). Some states offer a common galactosemia gene panel refl ex test to refi ne the diagnosis.
Even with screening, an infant with galactosemia may be missed. Blood transfusion or infants receiving a low galactose-containing formula at screening may elicit a false- negative result. Careful review of the test result, patient history, and feeding at the time of testing ensures accurate interpretation. Most importantly, even when newborn screening results are normal, infants who present with symptoms suggestive of galactosemia should be tested.
Classical Galactosemia The GALT gene has more than 300 mutations (ARUP Laboratories, n.d.). It is located on chromosome 9p13.
Galactosemia is an inborn error of galactose
metabolism caused by a genetic change that
results in defi ciency of one of three enzymes,
uridine diphosphate galactose 4’epimerase
(GALE), galactokinase (GALK), or galactose-
1-phosphate uridyltransferase (GALT).
Table 1. Newborn Screening Total Galactose and GALT Enzyme Levels in GALT Defi ciency Galactosemia
Galactosemia
Type
Total
Galactose
Normal to ↑ ↓ (15%–33%)
These values refl ect levels for newborns fed breast or cow's milk-based formula who have not received blood transfusion. Soy-based formula feedings will result in lower total galactose levels than those receiving galactose feedings. The enzyme level, however, will not be affected by dietary galactose intake. Total galactose and GALT levels may be low in infants who have received a blood transfusion because it may refl ect the galactosemia status of the donor, rather than the newborn. GALT = galactose-1-phosphate uridyltransferase
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
46 volume 43 | number 1 January/February 2018
are replaced with galactose-free/low-galactose substitu- tions. There are food lists, on-line and published resources, and parent and peer support groups to help parents, care providers, and eventually patients monitor galactose intake.
When over-the-counter or prescription medications are required, galactose content must be checked. Generally, liquid medications do not contain galactose but tablet medications often do. When an alternate galactose-free drug is available, it should be substituted. If not, the ben- efi ts and limitations of a short-term course of galactose- containing medication must be weighed.
With strict dietary control, Gal-1-P, RBC should re- main <5 mg/dL and urine galactitol <78 mmol/mol cre- atinine (Berry, 2014). After diagnosis, ongoing metabolic genetic visits are recommended every 3 months for the fi rst year, every 6 months for 1 year, and then annually. Visits include diet analysis, nutritional counseling with a metabolic dietitian, and assessment of metabolic control, growth, and coordination of care based on disease- associated risks and complications.
Complications Although the exact mechanism remains unclear, there are long-term complications associated with pre- and postnatal exogenous and endogenous galactose expo- sure and even, strict galactose restriction. Intellectual impairment, verbal dyspraxia, and neurological impair- ment may be linked to cerebral white matter changes. Other complications include cataracts, osteopenia, growth delay, and hypergonadotropic hypogonadism in females.
Intellectual impairment. Mean IQ is reduced in chil- dren with CG (70–90) especially among those with the Q188R mutation (Broomfi eld et al., 2011). It has been hypothesized intellectual abilities decline over time, but this has not been supported in the literature. Develop- mental assessments are recommended at age 1 and then every 1 to 3 years (Berry, 2014). Early intervention and individualized education plans are important in meeting developmental, intellectual, and learning needs.
Speech and language defi cits. Speech diffi culties are common and include delayed vocabulary, articulation problems and, less frequently, verbal dyspraxia. Speech and language screening performed alone or in combina- tion with cognitive screening should take place at 7 to 12
sources of dietary galactose to prevent galactose expo- sure and accumulation. After discontinuing breast and cow's milk-based formula, symptomatic newborns may require intravenous hydration, phototherapy, and/or ex- change transfusion. Vitamin K and fresh frozen plasma are used to treat bleeding concerns resulting from hepatic injury. Other treatments may include bicarbonate for aci- dosis and antibiotics for disease-associated E. coli sepsis (Berry, 2012). Once stabilized, feedings of galactose-free formula can be provided (Table 3).
Lifelong Management During early infancy, diet is formula-based and easy to man- age. To minimize exposure to small amounts of galactose in premixed formulas, powdered formula is recommended. Breastfeeding mothers require guidance and support to wean breast milk production. Infants receiving services through the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) may require documentation to change formula and over time, supply condition-appropriate nutritious foods in lieu of milk and cheese.
As the diet advances, treatment rests with dietary ga- lactose restriction guided by a metabolic dietitian. Milk, milk products, and casein- and whey-containing foods
Table 2. Diagnostic and Surveillance Testing for Classical and Clinical Variant Galactosemias Test Normal Galactosemia
Galactose-1-phosphate uridyltransferase
Clinical variant: 1%–10% activity
Galactose-1-phosphate,
RBC <1 mg/dL >10 mg/dL (as high as 120 mg/dL)
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:
Infants: <109 mmol/mol creatinine
Adults: <13 mmol/mol creatinine
Elevations vary (age-specifi c normals)
On treatment: <78 mmol/mol creatinine
Table 3. Acceptable Formulas for Use in GALT Defi ciency Galactosemia Soy-Based Formulas*
Similac® Soy Isomil®
GALT = galactose-1-phosphate uridyltransferase
*Generic soy formulas are comparable. Because they may vary, it is recommended providers check with the manufacturer.
Notes. 1) Enfamil™ Lactose Free formula contains cow's milk as the protein source and is not galactose-free. 2) It is recom- mended infants with classical and clinical variant galactose- mia receive powdered (not concentrate or premixed) formula.
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January/February 2018 MCN 47
Endocrinology should be consulted to address atypical growth concerns.
Hypergonadotropic hypogonadism. Primary ovarian insuffi ciency (POI) and premature menopause are symp- toms of hypergonadotropic hypogonadism experienced by women with CG. Although believed to be a result of chronic Gal-1-P and galactitol exposure, the mechanism remains unknown. Estradiol, follicle stimulating, and luteinizing hormone levels should be assessed at age 1 and 2 years and puberty. Typically, females present with pubertal delay and primary or secondary amenorrhea progressing to POI. As they approach puberty, girls should be carefully monitored by a pediatric endocri- nologist and estrogen and progestin support provided as needed (Broomfi eld et al., 2011; Mayatepek et al., 2010). The risk for POI does not directly correlate with strict dietary galactose restriction, which suggests ovarian tox- icity may occur early in life. Although approximately 80% of women develop ovarian dysfunction, spontane- ous pregnancy can occur (Broomfi eld et al.). Birth control should be offered to women not wishing to con- ceive and reproductive options should be discussed with women with POI.
Patient Outcome The rationale for screening newborns for galactosemia is to identify at-risk newborns and minimize galactose toxic- ity and associated morbidity and mortality. There is no question, galactose restriction for newborns with CG is life-saving. Several researchers, however, have examined presymptomatic treatment and failed to demonstrate bet- ter long-term outcome for those treated earlier rather than later. Antenatal maternal dietary galactose restriction does not improve patient outcome and in some cases, resulted in poorer outcomes (Hughes et al., 2009). Although not yet well studied, several researchers hypothesize strict dietary galactose restriction may contribute to long-term systemic problems and a more liberal intake of galactose may improve outcomes (Coman et al., 2010; Hughes et al.). The long-term effect of this remains unknown and therefore, treatment for CG remains lifelong dietary galac- tose restriction, surveillance, and anticipatory guidance.
months and ages 2, 3, and 5 years (Welling et al., 2017). When indicated, speech therapy is intensive and, unfortu- nately, a large percentage of individuals are refractory (Berry, 2014).
Neurological problems. Speech and coordination dis- orders frequently cooccur. Despite strict dietary galactose restriction, over time, 10% to 20% develop extrapyrami- dal symptoms including severe, progressive ataxia, fi ne- motor tremors, dysmetria, and dystonia (Rubio-Agusti et al., 2013; Waisbren et al., 2012; Welling et al., 2017). Clinical screening should begin at 2 to 3 years (Welling et al.) and neurology consultation and physical and oc- cupational therapies may be warranted.
Cataracts. Accumulation of galactitol is thought to be the cause for cataracts (Broomfi eld et al., 2011). Cata- racts were originally reported in up to 30% of patients with CG but more recent evidence suggests the rate is closer to 14% (Broomfi eld et al.). Most cataracts resolve with dietary galactose restriction and newborns should receive ophthalmology follow-up until resolved (Welling et al., 2017). After baseline, slit lamp examination is rec- ommended at ages 1, 5, and during adolescence (Berry, 2014) and for all patients who do not comply with dietary galactose restriction (Welling et al.).
Osteopenia and osteoporosis. Strict restriction of milk and milk products places individuals at increased risk for osteopenia and premature osteoporosis. Calcium, phos- phorus, and 25-hydroxyvitamin D levels are recommend- ed annually. Optimized dietary calcium intake and vitamin D3 and calcium supplementation, laboratory testing, and regular exercise are recommended (Welling et al., 2017). Bone mineral density scanning is recom- mended annually beginning at school age (Berry, 2014; Mayatepek, Hoffmann, & Meissner, 2010) and every 5 years after puberty is complete (Welling et al.).
Growth delay. Growth is generally delayed in child- hood and early adolescence and those with higher residu- al enzyme levels have improved adult height (Berry, 2014). Although some women may fall short of calculat- ed midparental height (Panis, Gerver, & Rubio-Gozalbo, 2007), most will reach normal height-for-age. Careful monitoring of growth is recommended through puberty.
Treatment for classical and clinical variant galactosemia rests with lifelong
dietary galactose restriction, whereas
more controversial.
Af ric
a St
ud io
48 volume 43 | number 1 January/February 2018
CG and VG, GALT enzyme levels are higher, ranging be- tween 15% and 33% (Berry, 2014). Although Gal-1-P, RBC, and urine galactitol galactose metabolites are elevat- ed during infancy, most normalize by age 2. There is con- troversy about the short- and long-term signifi cance and treatment of this milder galactosemia type. Most patients are lost-to-follow-up and thus, there are sparse long-term data to support any one approach to care. As a result, there are varying opinions regarding whether DG is a “real disease” (Berry) and what, if any, treatment is required.
Treatment Controversy Several studies have compared infants and children with DG treated with strict galactose restriction to those who were not with mixed results. One frequently cited study by Ficicioglu et al. (2008) compared a cohort of children with DG ages 1 to 6 years (n = 28). One group received strict dietary restriction with periodic assessment of ga- lactose metabolites (n = 17) the fi rst year of life, whereas the other received no restriction (n = 11). No signifi cant differences in clinical or long-term outcomes between the two groups were revealed. Similarly, Powell et al. (2009) examined a patient cohort of 59 children with DG and found no increased rates of intellectual disability, cere- bral palsy, autism spectrum disorder, hearing or vision impairment. There were, however, higher rates of special education (primarily speech and language disorders) among children with DG.
Clinical Variant Galactosemia Clinical VG caused by homozygosity of S135L occurs primarily among African Americans and native Africans in South Africa. Newborns with VG present with barely detectable or absent (0%–10%) GALT activity. Different from CG, individuals with VG have higher enzyme levels in the brain and intestines.
A portion of infants with VG will have Gal-1-P, RBC levels similar to newborns with CG and thus, manifest early clinical symptoms such as growth failure, liver disease, and cataracts (Berry, 2014). For the majority, he- patic enzyme levels as high as 10% make hypergalactose- mia less severe than with CG. As such, timely treatment minimizes risk for E. coli sepsis and chronic, long-term complications such as intellectual disability, speech prob- lems, and POI (Berry). Treatment recommendations are similar to CG and based on the severity of enzyme defi - ciency. Overall, the prognosis for VG is good.
Biochemical Variant (Duarte) Galactosemia A milder variant of galactosemia, DG, results when an in- dividual is compound heterozygous for a classical (e.g., Q188R) and Duarte (N314D) change in the GALT gene. Duarte galactosemia affects approximately 1 in every 4,000 newborns and is far more common than either CG and VG combined (Ficicioglu et al., 2008). In contrast to
Table 4. Risk to Have a Child with Galactosemia Based on Parent Carrier Status: Exemplars Classical/Classical Variant Galactosemia Carrier (NG) Parents
Parent 1 Unless one of the parents has classical or classical variant galactosemia, each parent is an obligate carrier for galactosemia. As such, the recurrence risk to have a child with clas- sical galactosemia (GG) with each pregnancy is 1 in 4 (25%). There is a 50% risk with each pregnancy to have a child who is a carrier for galactosemia (NG) and 25% chance to have a child with two normal alleles (NN).P
ar en
Carrier (ND) Parents
Parent 1 This diagram shows the risk for two parents, one a carrier for the classical galactosemia gene (Parent 1) and the other, the Duarte variant (Parent 2). In this case, the recurrence risk to have a child with Duarte galactosemia (DG) with each pregnancy is 1 in 4 (25%). There is a 25% risk with each pregnancy to have a child who is a carrier for classical ga- lactosemia (NG), 25% risk to have a child who is a carrier for the Duarte variant (ND), and 25% chance to have a child with two normal alleles (NN).P
ar en
(DG) Parents
Parent 1 In the unlikely event, one parent (Parent 1) has Duarte galactosemia (DG), the recurrence risk to have a child with classical galactosemia (GG) will depend on the carrier status of the other parent. In this diagram, if Parent 2 is a carrier for classical galactosemia, there is a 25% risk with each pregnancy to have a child with Duarte galactosemia (DG) but there is also a 25% risk to have a child with classical galactosemia (GG).
P ar
en t
N = normal allele; D = Duarte allele; G = classical galactosemia allele; GG = classical/variant galactosemia; DG = Duarte galacto- semia, NG = carrier for classical/variant galactosemia; ND = carrier for Duarte gene
Note. Newborns homozygous for the Duarte gene (DD) may also be identifi ed through newborn screening. Typically, these infants have approximately 50% GALT enzyme activity and do not require treatment or follow-up.
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January/February 2018 MCN 49
follow-up for the fi rst 1 to 2 years of life. To balance these divergent approaches, some have opted to alternate breast with soy-based formula feedings for mothers who want to breastfeed. Although there is no one standard approach to DG at this time, a group of international experts re- cently published treatment guidelines recommending these patients not be treated (Welling et al., 2017).
Genetic Counseling Regardless of the type and severity, genetic counseling should be provided to families of a newborn diagnosed with galactosemia. Because it is an autosomal recessive condition, at a minimum, both parents are obligate carriers for galactosemia and the recurrence risk for
The risk for potential long-term ovarian dysfunction was studied by Sanders et al. (2009). Anti-müllerian and follicle-stimulating hormones were obtained in girls with DG and compared with controls. Values were indistin- guishable between the groups. This suggests females with DG are not at risk for POI and as such, endocrine evalu-…
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