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Galactosemia: Management and complications

Galactosemia: Management and complications
Literature review current through: Jan 2024.
This topic last updated: Aug 31, 2022.

INTRODUCTION — Galactose is a sugar found primarily in human and bovine milk and milk products as part of the disaccharide lactose. Lactose is hydrolyzed to glucose and galactose by the intestinal enzyme lactase. The galactose then is converted to glucose for use as an energy source (figure 1). Free galactose also is present in some fruits and vegetables, such as tomatoes, Brussels sprouts, bananas, and apples. Altered metabolism of galactose caused by deficient enzyme activity or impaired liver function results in elevated blood galactose concentration and the condition known as galactosemia.

The Galactosemia Network has published recommendations for the management of galactosemia based on evidence and clinical experience [1].

These recommendations, summarized below, should be tailored to the individual patient.

The management and outcome of galactosemia will be discussed here. The clinical features and diagnosis are discussed separately. (See "Galactosemia: Clinical features and diagnosis".)

CLASSIC GALACTOSEMIA

Management overview — The main goal of long-term treatment of classic galactosemia is to minimize dietary galactose intake. Galactose should be excluded from the diet as soon as galactosemia is suspected.

Other initial care should be provided as needed to treat jaundice, sepsis, and abnormalities of the liver, kidneys, and central nervous system. Supportive therapy typically includes intravenous hydration, antibiotics, and treatment of coagulopathy, although problems usually resolve quickly after dietary treatment is begun.

Nutritional therapy

Galactose restriction — Immediate diet intervention is necessary for infants with suspected galactosemia. Minimization of dietary galactose is accomplished by excluding milk and dairy products from the diet. A dietician experienced in dietary therapy of inborn errors of metabolism should provide consultation in dietary management.

In infants, human milk or formula based on bovine milk is discontinued, and a soy-based formula is given. Soy-based infant formulas appropriate for galactosemia include Alsoy, Isomil, Nursoy, and ProSobee. Lactose-free infant formulas should not be used, because they have not been proven to be safe for patients with galactosemia.

Once foods are introduced, ingredients containing lactose and galactose should be minimized. In addition to milk, butter, cream, and cheese, other forms of milk that contain lactose (eg, nonfat dry milk, whey, or casein) should be avoided. On the other hand, lactate, lactic acid, and lactalbumin do not contain lactose and are safe to eat. Fruits, legumes, and some hard cheeses are insignificant sources of galactose compared with endogenous production and, in most cases, do not need to be significantly restricted [2-4].

Calcium supplements — Adequate calcium is provided by soy formula in infancy as long as appropriate volumes are taken. However, as the amount of food increases and formula volume declines after approximately one year of age, calcium supplements should be given. A nutritionist familiar with galactosemia should evaluate the patient's diet for calcium content, and supplementation should be provided as needed to ensure that the dietary intake of the individual with galactosemia is meeting the recommended dietary allowance (RDA) for calcium. (See "Dietary history and recommended dietary intake in children", section on 'Dietary reference intakes'.)

Other nutrients — Other requirements for calories, protein, vitamins, and micronutrients are similar to those of normal individuals. (See "Introducing solid foods and vitamin and mineral supplementation during infancy", section on 'Infant nutritional requirements'.)

Monitoring — Patients with galactosemia should be followed throughout their lives. The Galactosemia Network recommends outpatient follow-up every three months until 1 year, every four months until 2 years, every six months until 14 years, and then annually [1]. These recommendations should be tailored to the individual patient. Female children may need to be seen more frequently to assess pubertal development.

In addition to laboratory monitoring, additional evaluations are performed to monitor the problems that may develop in children with galactosemia. Neurodevelopmental impairment, cataracts, growth delay, and premature ovarian failure should be detected promptly so that appropriate interventions can be undertaken. (See 'Complications and prognosis' below.)

Biochemical status — Red blood cell (RBC) galactose-1-phosphate concentration is monitored intermittently to detect serious deviations from the restricted diet. Frequent measurement is not necessary, because levels reflect galactose intake only in the previous 24 hours, have high intraindividual variability, and do not correlate with long-term outcome [5-7]. In addition, because of endogenous galactose production, levels are elevated in some patients who comply with the lactose-free diet, as discussed below. We typically test RBC galactose-1-phosphate every three months in children younger than one year of age and then every six months from one to three years of age. After age three years, we obtain either RBC galactose-1-phosphate or urinary galactitol levels every six months until age 14 years, then annually.

Urinary galactitol (the alcohol metabolite of galactose) concentration may better reflect more subtle, long-term increases in galactose intake than RBC galactose-1-phosphate [5,8]. Evidence from a rat model of classic galactosemia implicates galactitol as the primary compound responsible for neurologic features and cataracts [9]. However, there is limited evidence for this in humans, and the intraindividual biologic variability is high [6,7]. Thus, the role for laboratory monitoring of either galactitol or RBC galactose-1-phosphate in patients is unclear and requires further investigation.

Endogenous galactose synthesis — Blood and urine concentrations of galactose and its metabolites remain elevated in classic galactosemia, even with dietary restriction, because of endogenous galactose production. In one study, the endogenous galactose production rate (0.53 to 1.05 mg/kg per hour) was variable in galactosemic adults (homozygous for the Q188R allele) and in a range similar to that of normal adults [10]. The rate of endogenous galactose production correlates inversely with age [11]. Because the rate of endogenous production exceeds the amount of galactose in a nondairy diet, elevated galactose levels likely reflect endogenous production rather than noncompliance with dietary restrictions. The variable production rate also may contribute to the variability in phenotype, even in patients with similar genotypes.

Developmental status — Neurodevelopment should be assessed regularly. It should include yearly evaluation of speech and cognitive function after age two years. Referrals are made for speech therapy as needed and for evaluation of neurologic signs if they develop.

Cataract detection — An ophthalmologic evaluation to detect cataracts should be performed at the time the diagnosis is made. Eye examinations are scheduled every six months until age three years and then annually. More frequent evaluations are needed if cataracts are detected. (See "Cataract in children".)

Growth — Postnatal growth velocity for height and weight are lower in individuals with classic galactosemia than in the general population [12]. Endogenous growth hormone production in female children with classic galactosemia is in the low-normal range [13]. It is unclear whether final height is impaired and whether exogenous growth hormone or estrogen therapy plays a role. The diet should be assessed at least annually by a dietician with expertise in metabolic disorders. A record of the patient's diet kept by the parent(s)/caregiver(s) for the preceding three days is reviewed at each clinician visit. Dietary records are reviewed more frequently if growth is delayed or if dietary intake changes significantly.

Ovarian function — Primary ovarian insufficiency occurs in most females with classic galactosemia [14]. Approximately two-thirds of females achieve spontaneous menarche, but only approximately half of them are regularly cycling after three years, and fewer than 15 percent are regularly cycling after 10 years. The only known factor associated with spontaneous menarche is the presence of anti-Müllerian hormone [15]. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol concentrations are measured in females at 10 years of age. If gonadotrophin concentrations are increased and estradiol level is low, the patient should be referred to a pediatric endocrinologist for consideration of estradiol therapy.

Complications and prognosis — Newborn screening has resulted in early diagnosis and treatment of galactosemia. Withholding human milk or bovine milk-based formula feedings and providing a soy-based formula usually result in resolution of the clinical features. The principal cause of early mortality in classic galactosemia is sepsis, most often caused by Escherichia coli.

Most patients are healthy and intellectually normal during childhood. However, they frequently develop neuropsychological and ovarian problems during their teenage years. The natural history of galactosemia has been documented in a survey of 350 patients over a broad range of ages [16].

Neurodevelopment — Most individuals with classic galactosemia have intellectual deficits, although some have average or above-average intelligence [16-22]. Many affected children have speech and language problems [16,22-26].

In a survey of 177 patients with galactosemia who were at least six years old and had no other cause for poor outcome, 45 percent had developmental delay [16]. The mean intelligence quotient (IQ) scores of the group declined slightly (four to seven points) with increasing age. In cross-sectional studies, cognitive function appears to decline with age [16,18]. However, a longitudinal study of cognitive function in 23 patients demonstrated stability of cognitive function over time [27].

Problems with speech are frequent [16,23,24]. In the survey cited above, they were observed in 56 percent of 243 patients who were at least three years old [16]. The majority had delayed acquisition of vocabulary and difficulty with articulation (also known as verbal dyspraxia). The speech problem improved with time in only 24 percent.

Affected adolescents and adults often have focal neurologic findings, such as tremor, ataxia, and dysmetria (impaired ability to control actions) [16,17]. In the survey cited above, abnormalities of coordination, gait, and balance, as well as fine motor tremors, were seen in 18 percent of patients who were more than 3.5 years old, and two teenagers had severe ataxia [16].

Dietary compliance and RBC galactose-1-phosphate levels do not appear to affect IQ [16,19,28]. Whether cognitive function correlates with genotype is uncertain because data are conflicting. (See "Galactosemia: Clinical features and diagnosis", section on 'Genotype-phenotype correlation'.)

Ovarian failure — Premature ovarian failure occurs in most females with classic galactosemia, affecting 81 percent of 47 females older than 14 years of age in the survey [16]. In another report, most females with galactosemia had increased basal FSH and LH levels consistent with hypergonadotropic hypogonadism [29]. Residual enzymatic activity and anti-Müllerian hormone levels may predict ovarian function [30].

In females who menstruated, menarche occurred at an average age of 14 years. Most then developed oligomenorrhea or secondary amenorrhea within a few years, and few had normal menstrual function [16]. Approximately 24 percent had primary amenorrhea.

The mechanism of ovarian failure is unknown, but it appears to be an acquired condition. Galactose and galactose metabolites, such as galactose-1-phosphate and galactitol, may be toxic to the ovaries [31]. The toxicity of galactose is supported by a study in which the number of oocytes was reduced in rats with prenatal exposure to elevated galactose levels [32].

The risk of premature ovarian failure may be influenced by the patient's genotype. In one study of 53 females, ovarian failure was more likely if the genotype was homozygous for the most prevalent mutation Q188R (odds ratio [OR] 8.3) [33].

Most affected females are infertile because of their ovarian failure. However, spontaneous pregnancy has been reported [34]. Pubertal development and fertility in males with classic galactosemia are normal [29].

Cataracts — Cataracts occur in approximately 30 percent of patients with galactosemia. Typically, they are detected after two weeks of age, but they may be present at birth. The earliest change is in the nucleus, which shifts its refractive index. This results in an "oil droplet" distortion of the light on retinal exam. The cortex is clear initially but becomes milky as the epithelial cells die.

In a survey of long-term outcomes in 350 patients, dietary treatment began later in infants with cataracts than in those without cataracts (77 versus 20 days), although one child had been treated since birth [16]. Approximately one-half resolved with dietary treatment, although 2 percent required surgery. Retrospective review of another cohort of 100 patients found no correlation between development of cataracts and dietary compliance but corroborated the lack of significant effects of cataracts on vision in most patients with galactosemia [35]. (See "Cataract in children".)

DUARTE VARIANT — Children with Duarte galactosemia (ie, who have one Duarte allele and one classic allele [D/G]) may be able to tolerate dietary galactose because galactose-1-phosphate uridyl transferase (GALT) activity is impaired but not absent (typically approximately 25 percent of normal) [36,37]. It is the experience of the author that developmental issues in children with untreated Duarte galactosemia are not significantly different from the general population. Based upon observational studies [37,38] and clinical experience, we do not treat patients with Duarte galactosemia with a galactose-restricted diet. Infants may breastfeed or ingest cow's milk-based infant formula, and foods are not restricted. Other centers, however, choose to continue galactose restriction for one year, citing the relatively small size of the study cohorts and findings from an observational study that suggested that children with Duarte galactosemia may be at risk for neurodevelopmental problems despite residual GALT activity [39]. Further studies are required to definitively answer this question [40].

In a nonrandomized pilot study, the clinical, biochemical, and cognitive outcomes were similar among 28 children (aged 1.1 to 6 years) with Duarte galactosemia, whether or not they followed a galactose-restricted diet during the first year of life [38]. In a second study, outcomes were also similar among 206 children age 6 to 12 years with Duarte galactosemia regardless of galactose intake in infancy, and no significant differences in outcomes were found between children with Duarte galactosemia and their unaffected siblings [37].

In that population-based study, 59 children with Duarte galactosemia who were treated with dietary galactose restriction for the first year of life received special education services at approximately twice the rate of children without galactosemia (8.5 versus 4.5 percent of children aged 3 to 10 years and 15.2 versus 5.9 percent for eight-year-old children) [39]. The reason most often cited was speech and language problems. However, intelligence quotient (IQ) scores or other detailed measures of cognitive abilities were not provided.

Individuals with two Duarte alleles (D/D) typically have enzyme activity levels ≥50 percent of normal [36]. There is no evidence to suggest that dietary restriction of galactose is needed in D/D individuals.

GALACTOKINASE DEFICIENCY — Galactose intake is restricted throughout life in patients with galactokinase (GALK) deficiency to prevent cataract formation. Similar to patients with classic galactosemia, these patients also require calcium supplementation, consultation with a dietician, and regular monitoring of biochemical status, growth, and eye examination. These evaluations should occur according to the same schedule as for patients with classic galactosemia. (See 'Nutritional therapy' above and 'Monitoring' above.)

Patients with GALK are not at risk of neurodevelopmental problems or ovarian failure and do not need to be monitored for these problems. (See "Galactosemia: Clinical features and diagnosis", section on 'Galactokinase (GALK) deficiency'.)

URIDINE DIPHOSPHATE GALACTOSE 4-EPIMERASE DEFICIENCY — Epimerase deficiency confined to red blood cells (RBCs) requires no treatment. The role of dietary treatment in patients with generalized epimerase deficiency is unclear [41].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Galactosemia".)

SUMMARY AND RECOMMENDATIONS

Causes of galactosemia – Galactosemia can result from deficiencies of three different enzymes (figure 1), each with a distinct phenotype. (See "Galactosemia: Clinical features and diagnosis".)

Nutritional therapy:

Galactose restriction – The main goal of long-term treatment of classic galactosemia is to minimize dietary galactose. Galactose is excluded from the diet as soon as galactosemia is suspected. A dietician experienced in dietary therapy of inborn errors of metabolism should provide consultation in dietary management. (See 'Galactose restriction' above.)

Calcium supplementation – Calcium supplementation is suggested for children after one year of age. (See 'Calcium supplements' above.)

Monitoring – Long-term monitoring of biochemical, ophthalmologic, neurodevelopmental, and endocrinologic status is necessary for patients with classic galactosemia. (See 'Monitoring' above.)

Complications and prognosis – Prompt initiation of galactose restriction usually results in resolution of early clinical features. Most patients who adhere to the diet are healthy, but neurodevelopmental issues, neuropsychological problems, and, in females, ovarian problems may develop despite adherence to dietary galactose restrictions. (See 'Complications and prognosis' above.)

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