Galactosemia is an autosomal recessive genetic condition caused by a defect in the Leloir pathway resulting in deficiency 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 accumulates in cells and galactose is converted to galactitol 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 deficiency types depends on residual enzyme activity.

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Because classic GALE and GALK deficiency galactosemias are rare, this review provides nurses, practitioners, and midwives with information about three more frequently encountered GALT deficiency galactosemias. Newborn screening, diagnostic process, presenting symptoms, initial and ongoing management, and associated outcomes are covered. Importance and rationale for genetic 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 deficiency galactosemia identified by a combination of total galactose, GALT enzyme and for select programs, mutation screening. A significantly reduced GALT enzyme and elevated total galactose level suggest classical (CG) and sometimes, classical variant galactosemia (VG), whereas more subtle changes suggest Duarte galactosemia (DG) (Table 1). Some states offer a common galactosemia gene panel reflex test to refine the diagnosis.

Table 1. Newborn Screening Total Galactose and GALT Enzyme Levels in GALT Deficiency Galactosemia

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. Homozygosity or compound heterozygosity for CG mutations 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 worldwide, 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 southern 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 aminoaciduria may develop. If left untreated, encephalopathy, shock, and death may occur (Berry, 2014; Broomfield, Brain, & Gruenwald, 2011; Varela-Lema et al., 2016).

Diagnostic Testing

Confirmatory 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 surveillance (Table 2). Although a biochemical diagnosis can be made based on enzyme activity and biochemical metabolites, 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 identified, gene sequencing and deletion/duplication testing are available.

Table 2. Diagnostic and Surveillance Testing for Classical and Clinical Variant Galactosemias

Initial Treatment

Whether symptomatic or asymptomatic, treatment for CG is immediate and begins by removing exogenous sources of dietary galactose to prevent galactose exposure and accumulation. After discontinuing breast and cow's milk-based formula, symptomatic newborns may require intravenous hydration, phototherapy, and/or exchange transfusion. Vitamin K and fresh frozen plasma are used to treat bleeding concerns resulting from hepatic injury. Other treatments may include bicarbonate for acidosis and antibiotics for disease-associated E. coli sepsis (Berry, 2012). Once stabilized, feedings of galactose-free formula can be provided (Table 3).

Table 3. Acceptable Formulas for Use in GALT Deficiency Galactosemia

Lifelong Management

During early infancy, diet is formula-based and easy to manage. 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 galactose restriction guided by a metabolic dietitian. Milk, milk products, and casein- and whey-containing foods are replaced with galactose-free/low-galactose substitutions. 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 benefits and limitations of a short-term course of galactose-containing medication must be weighed.

With strict dietary control, Gal-1-P, RBC should remain <5 mg/dL and urine galactitol <78 mmol/mol creatinine (Berry, 2014). After diagnosis, ongoing metabolic genetic visits are recommended every 3 months for the first 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 exposure and even, strict galactose restriction. Intellectual impairment, verbal dyspraxia, and neurological impairment 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 children with CG (70-90) especially among those with the Q188R mutation (Broomfield et al., 2011). It has been hypothesized intellectual abilities decline over time, but this has not been supported in the literature. Developmental 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 deficits. Speech difficulties are common and include delayed vocabulary, articulation problems and, less frequently, verbal dyspraxia. Speech and language screening performed alone or in combination with cognitive screening should take place at 7 to 12 months and ages 2, 3, and 5 years (Welling et al., 2017). When indicated, speech therapy is intensive and, unfortunately, a large percentage of individuals are refractory (Berry, 2014).

Neurological problems. Speech and coordination disorders frequently cooccur. Despite strict dietary galactose restriction, over time, 10% to 20% develop extrapyramidal symptoms including severe, progressive ataxia, fine-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 occupational therapies may be warranted.

Cataracts. Accumulation of galactitol is thought to be the cause for cataracts (Broomfield et al., 2011). Cataracts were originally reported in up to 30% of patients with CG but more recent evidence suggests the rate is closer to 14% (Broomfield 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 recommended 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, phosphorus, and 25-hydroxyvitamin D levels are recommended 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 recommended 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 childhood and early adolescence and those with higher residual enzyme levels have improved adult height (Berry, 2014). Although some women may fall short of calculated midparental height (Panis, Gerver, & Rubio-Gozalbo, 2007), most will reach normal height-for-age. Careful monitoring of growth is recommended through puberty. Endocrinology should be consulted to address atypical growth concerns.

Hypergonadotropic hypogonadism. Primary ovarian insufficiency (POI) and premature menopause are symptoms 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 endocrinologist and estrogen and progestin support provided as needed (Broomfield et al., 2011; Mayatepek et al., 2010). The risk for POI does not directly correlate with strict dietary galactose restriction, which suggests ovarian toxicity may occur early in life. Although approximately 80% of women develop ovarian dysfunction, spontaneous pregnancy can occur (Broomfield et al.). Birth control should be offered to women not wishing to conceive 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 toxicity 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 better 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 galactose restriction, surveillance, and anticipatory guidance.

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, hepatic enzyme levels as high as 10% make hypergalactosemia 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 problems, and POI (Berry). Treatment recommendations are similar to CG and based on the severity of enzyme deficiency. Overall, the prognosis for VG is good.

Biochemical Variant (Duarte) Galactosemia

A milder variant of galactosemia, DG, results when an individual 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 CG and VG, GALT enzyme levels are higher, ranging between 15% and 33% (Berry, 2014). Although Gal-1-P, RBC, and urine galactitol galactose metabolites are elevated during infancy, most normalize by age 2. There is controversy about the short- and long-term significance 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 galactose metabolites (n = 17) the first year of life, whereas the other received no restriction (n = 11). No significant 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, cerebral 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.

The risk for potential long-term ovarian dysfunction was studied by Sanders et al. (2009). Anti-mullerian and follicle-stimulating hormones were obtained in girls with DG and compared with controls. Values were indistinguishable between the groups. This suggests females with DG are not at risk for POI and as such, endocrine evaluation is not recommended (Welling et al., 2017).

Treatment

The lack of consensus regarding treatment makes it difficult to recommend any one approach. Clinical management may range from strict dietary galactose restriction with ongoing biochemical and developmental surveillance to no dietary restriction or testing with annual follow-up for the first 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 recently 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 parents to have another child with galactosemia is at least 25%. Inheritance patterns and options for parental genetic testing to refine recurrence risks for future pregnancies should be discussed (Table 4). Identifying GALT mutations for the patient and carrier screening for parents and other family members should be offered. Preimplantation genetic diagnosis and prenatal diagnosis by chorionic villus sampling or amniocentesis should be discussed with interested parents, especially those at risk to have a child with CG. In the absence of prenatal diagnosis, conservative treatment includes soy formula feedings until newborn screening and diagnostic testing can be performed. Mothers committed to breastfeeding should be provided with instructions regarding how to safely express and store breast milk until test results are available.

Table 4. Risk to Have a Child with Galactosemia Based on Parent Carrier Status: Exemplars

Nursing Implications

Care for a newborn with a suspected or confirmed diagnosis of GALT deficiency galactosemia can be complex. Nurses at all practice levels must have a basic understanding of newborn screening and galactosemia to provide information and support to families. Based on the specific diagnosis, nursing considerations vary. An overview of diagnosis-specific nursing implications is provided in Table 5.

Table 5. Nursing Implications and Considerations

Conclusion

Newborn screening for galactosemia is complex and, despite decades of experience with screening, treatments and research, patient outcomes vary depending on galactosemia type and there remains variability regarding patient management and monitoring. This emphasizes the importance of ongoing study to establish evidence-based practice guidelines and role nurses play during care of these patients and families across the lifespan. Despite evidence that questions the benefits of strict dietary restriction, lifelong galactose restriction and long-term follow-up remain standard of care for CG and VG, whereas restriction for DG remains controversial. Genetic counseling to review genetic testing options to provide prognosis, guide treatment, and refine recurrence risk for future pregnancies should be offered.

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References