Clinical manifestations

Presentation and course

Acute clinical manifestations.

	• Untreated infants with severely deficient galactose-1-phosphate uridyltransferase (GALT) activity typically present with the following variable findings:
		- Poor growth within the first few weeks of life - Jaundice - Bleeding from coagulopathy - Liver dysfunction or hepatomegaly - Cataracts (sometimes as early as the first few days of life) - Lethargy - Hypotonia - Brain edema (bulging anterior fontanel) - Sepsis (E coli) - Death

Long-term or chronic clinical manifestations

	• Learning problems and speech and language deficits are common; language acquisition may be delayed (125; 83; 59; Webb et al 2003; 90; 89; 112; 117; 91; 73; 72; 118). Cognitive impairment is present in the majority of patients (30; 105; 51).
	• Almost all females with classic disease manifest hypergonadotropic hypogonadism or primary ovarian insufficiency presenting as primary or secondary amenorrhea (57; 37; 102; 99; 36; 44); some women have become pregnant, including African Americans who probably had variant disease (08; 45; 43).
	• Short stature or poor growth occurs in a minority of patients (88).
	• Neurologic abnormalities (eg, tremor, ataxia, dystonia) occur in a minority of patients (28; 48; 55; 133; 18; 63; 96; Hughes et al 2009; 26; 98).
	• Decreased bone mineral density (58; 100; 04).
	• Anxiety, depression, and reduced quality of life (46; 116; 50; 126).

As over 300 mutations or polymorphisms in the GALT gene have been identified, different forms of the deficiency exist (32; 119; 22; ARUP GALT Database). Infants with complete or near-complete deficiency of the enzyme (classic galactosemia) have normal weight at birth but, as they start ingesting lactose-containing breast milk or formula, lose more weight than their healthy peers and fail to regain birth weight (107; 17; 38; Berry et al 2016). Almost all infants on a lactose-containing diet manifest poor weight gain. Symptoms appear in the second half of the first week and include refusal to feed, vomiting, jaundice, and lethargy. Parents often complain to physicians about various feeding difficulties with their newborn, most notably, vomiting. Hepatomegaly, edema, and ascites may follow. Ascites may be detected in early infancy. In some patients, ascites is detected as early as the first few days of life. Death from sepsis, usually due to E coli, may occur in the majority of infants with classic disease who have not been detected by newborn screening. Symptoms are milder and the course is less precipitous when milk is temporarily withdrawn and replaced by intravenous nutrition. Nuclear cataracts appear within days or weeks and become irreversible within weeks of their appearance. Congenital cataracts and vitreous hemorrhages may also be present (70; 115). In an infant or child with cataracts, galactosemia must be excluded. An ophthalmologist needs to be consulted because some cataracts, especially congenital cataracts, are visible only by using a slitlamp. Vitreous hemorrhage is a known complication of galactosemia, although its prevalence is unknown (70; 115).

In many countries, newborns with galactosemia are discovered through newborn screening by quantifying blood galactose, the GALT enzyme, or both; this screening is performed using dried blood spots, usually collected in the second day of life in the United States (09; 93; 94). At the time of discovery, the first symptoms may already have appeared, and the infant may already have been admitted to a hospital, usually for jaundice. Where newborns are not screened for galactosemia or when the results of screening are not yet available, diagnosis rests on clinical awareness. It is crucial that milk feeding be stopped as soon as galactosemia is considered and resumed only when a galactose disorder has been excluded. The presence of a reducing substance in a routine urine specimen may be the first diagnostic lead. Galactosuria is present provided the last milk feed does not date back more than a few hours, and vomiting has not been excessive. However, owing to the early development of a proximal renal tubular syndrome, the acutely ill galactosemic infant may also excrete some glucose, together with an excess of amino acids. However, glucosuria may be recognized, and the galactosuria missed. On withholding milk, galactosuria ceases, but amino acids in excess continue to be excreted for a few days. However, galactitol and galactonate continue to be excreted in large amounts. Albuminuria may also be an early finding that disappears with dietary lactose restriction.

Duarte partial transferase deficiency associated with 25% residual GALT activity is usually asymptomatic in infancy (Fridovich-Keil et al 2014). It is more frequent than classic galactosemia and is most often discovered by newborn screening because of moderately elevated blood galactose (free or total) or low GALT activity. In partial deficiency with only 10% residual hepatic GALT activity, there may be liver disease and developmental delay/cognitive impairment in patients left untreated during early infancy. These patients are best exemplified by the original inhabitants of South Africa and the African American who was the subject of the original Mason and Turner report in 1935 (108; 110; 03; 109; 97; 107). Many if not the majority of these patients have been shown to be homozygous for the S135L GALT gene mutation (67; 68; 79; 17; 49). Patients with the clinical variant form of galactosemia due to homozygosity for the S135L GALT gene mutation can be missed when newborn screening depends on an elevated total galactose level (29; 09).

Prognosis and complications

Most patients with classic galactosemia who are detected via newborn screening between 4 to 7 days and placed on a lactose restricted diet will not develop the severe multiorgan disease process and E coli sepsis. However, if not, they are likely to die of E coli sepsis or go on to develop cirrhosis and/or severe white matter lesions (86). Even patients treated on day 1 of life may manifest CNS disease associated with language delay, speech defects, cognitive impairment, learning problems, and, less commonly, tremors, ataxia, and dystonia, plus, at least in females, hypergonadotropic hypogonadism or primary ovarian insufficiency. Therefore, all patients with classic disease require multiple evaluations at different points in time and the appropriate treatment for complications that can vary in severity for each individual independent of erythrocyte galactose-1-phosphate and urine galactitol levels collected over many years on diet therapy. The variation in developmental, cognitive, and neurologic complications may be striking for 1 individual compared to another, but this is less so for primary ovarian insufficiency in females, as almost all show biochemical evidence of hypergonadotropic hypogonadism.

Clinical vignette

On day 6 of life, a male infant was lethargic, feeding poorly, and had temperature instability. Results of sepsis workup were negative. On day 8, urine-reducing substances were 4+, and results of newborn screening on a sample obtained on day 2 were positive for galactosemia with a total blood galactose plus galactose-1-phosphate level higher than 9 mg/dL (normal, less than 7.2). Galactose-restricted feeding was initiated with Isomil (Ross, Columbus, Ohio). Because his condition continued to deteriorate, he was transferred to the neonatal intensive care unit on day 10. On physical examination, the infant was quiet but arousable. Skin perfusion was poor. Spontaneous deep hyperventilation was occasionally noted. Jaundice and hepatomegaly were present. Major laboratory abnormalities consisted of hyperchloremic metabolic acidosis, mild hypertransaminasemia, hypofibrinogenemia, prolonged prothrombin and partial thromboplastin times, hyperbilirubinemia, and thrombocytopenia. The erythrocyte galactose-1-phosphate level was 33.9 mg/dL (normal, less than 1 mg/dL). The plasma galactitol concentration was 407 μmol/L (normal, less than 1 μmol/L), and urinary galactitol excretion was 4754 μmol/mmol creatinine (normal, 2 to 78 μmol/mmol creatinine for infants younger than 1 year old). Erythrocyte GALT activity was absent, and the patient was homozygous for Q188R, the most common severe GALT mutation. Brain magnetic resonance imaging and 1H-MRS studies were performed with a Siemens Magnetom Vision 1.5 T whole-body MRI scanner. MRI scans of the brain were obtained on day 10. Brain MRI revealed cytotoxic edema in white matter. On the midline sagittal T1-weighted image, there was diffuse low signal in the supratentorial white matter. On the T2-weighted images, signal intensities were increased in the white matter in a patchy distribution. The most prominent abnormalities were in the periventricular white matter, in the middle cerebellar peduncles, and around the dentate nuclei. The apparent diffusion coefficient in the white matter of the patient was consistently lower than that of a healthy control subject of the same age. Using in vivo proton magnetic resonance spectroscopy, approximately 8 mmol galactitol per kilogram of brain tissue was detected.

Biological basis

Etiology and pathogenesis

Individuals with a profound deficiency of GALT can phosphorylate ingested galactose but fail to metabolize galactose-1-phosphate (54). As a consequence, galactose-1-phosphate and galactose accumulate, and the alternate pathway metabolites, galactitol and galactonate, are formed. Cataract formation can be explained by galactitol accumulation. The pathogenesis of the hepatic, renal, and cerebral disturbances is less clear but is probably related to the accumulation of galactose-1-phosphate; galactitol may play a role as well, especially in brain edema (10). However, the mechanisms of the disease are far from clear (Hughes et al 2009; 24; 27; 131; 80).

Hypergalactosemia per se is associated with the following 3 enzyme deficiencies:

	• Galactokinase (GALK) converts galactose to galactose-1-phosphate and is not a common deficiency.
	• Uridine diphosphate (UDP) galactose-4-epimerase (GALE) epimerizes UDP galactose to UDPglucose and is also uncommon.
	• GALT is primarily responsible for classic hereditary galactosemia and is the most common deficiency. This enzyme catalyzes conversion of galactose-1-phosphate and UDP glucose to UDPgalactose and glucose-1-phosphate. Individuals with GALT deficiency manifest abnormal galactose tolerance. This review focuses primarily on hereditary galactosemia due to severe GALT deficiency.

Galactose-1-phosphate uridyltransferase (GALT) deficiency. Reichardt and Berg cloned the first cDNA encoding human GALT in 1988 (95). Over 300 mutations or polymorphisms of the GALT gene have now been reported (69; 32; 119; 22; ARUP GALT Database). Classic galactosemia is caused by a severe deficiency in GALT. The deficiency is an autosomal recessive genetic condition. The gene for GALT is located on chromosome 9p13. It has 11 exons and contains approximately 4.3 kb of genomic DNA. (Please see the ARUP website). Almost 90% of mutant alleles in classic galactosemia are due to the following 4 severe mutations.

Amino acid alteration	Genomic DNA/nucleotide mutation	Region	Comments
Q188R	c. 563 A-> G	Exon 6	Severe- 60% to 70% of mutant alleles
K285N	c. 855 G->T	Exon 9	Severe: 8% of European alleles
S135L	c.404 C->T	Exon 5	Clinical variant: 50% of mutant alleles in African Americans
N314D + c.-116-119 del GTCA (D2 with 5´ 4-bp deletion in cis)	c. 940 A->G	Exon 10	Biochemical variant: allele frequency of 0.133 in populations of European ancestry
L195P	c.584 T->C	Exon 7	Severe
Δ5.2 kb del	5.2 kb del	Almost all exons	Severe: 1 in 127 individuals of Ashkenazi Jewish descent in Israel are carriers (41)

Galactokinase (GALK) deficiency. The human GALK1 gene is located on chromosome 17q24. The enzyme catalyzes the first step in galactose metabolism, and its deficiency, although rare, results in cataracts in infancy.

Uridine diphosphate galactose-4´-epimerase (GALE) deficiency. GALE deficiency galactosemia is also known as epimerase deficiency galactosemia. The human GALE gene is located on chromosome 1p36.

Epidemiology

The incidence of galactosemia due to GALT deficiency is approximately 1 case per 40,000 to 60,000 persons in the United States. Internationally, the incidence varies widely (ie, 1 case in 70,000 people in the United Kingdom but 1 case in 16,476 people in Ireland). The disorder is thought to be much less common in Asians. Galactosemia occurs in all races; however, galactosemia variants are based on the exact gene defect. Clinical variants are most notable among African Americans (09). Affected individuals may have approximately 10% of enzyme activity in liver and intestinal epithelium but no activity in erythrocytes. The ability of an individual with the variant gene defect to tolerate ingestion of some milk may hinder diagnosis in locales without newborn screening. A likely benign variety is recognized as the Duarte-2 galactosemia compound heterozygous variant (23; Fridovich-Keil et al 2014). Neonates with this variant may or may not have positive (ie, abnormal) newborn screening test results, and most can tolerate normal diets. During infancy, but less so in childhood, these individuals may have elevated galactose metabolite levels (33). Whether dietary galactose restriction is necessary or beneficial for patients with Duarte variant galactosemia is unknown and is a matter of intense debate (92; 02; Fridovich-Keil et al 2014; 78). Many metabolic disease specialists take a conservative approach and recommend galactose restriction in the first year of life when milk intake is highest, but this restriction is based primarily on theoretical concerns of galactose toxicity in infants with the Duarte variant. Galactosemia equally affects males and females. Galactosemia is most often diagnosed in infancy by newborn screening because all states include galactosemia as part of their newborn screen, but methods are not uniform (09; 94). Variant forms of galactosemia can present later.

Differential diagnosis

The differential diagnosis for galactosemia includes:

• Severe UDP galactose-4´-epimerase (GALE) deficiency • Galactokinase (GALK) deficiency • Fructose 1-phosphate aldolase deficiency (hereditary fructose intolerance) • Neonatal hemochromatosis • Fanconi-Bickel syndrome • Tyrosinemia type 1 • Respiratory chain disorders (usually associated with hyperlacticacidemia) • Citrullinemia type 2 • Alpha1-antitrypsin deficiency • Sepsis

Galactokinase deficiency.

Clinical presentation. Cataracts are the only consistent manifestation of the untreated disorder, though pseudotumor cerebri has been described (Gitzelmann 1967; 20; 38). Liver, kidney, and brain damage, as seen in transferase deficiency, are not features of untreated galactokinase deficiency, and hypergalactosemia and increased galactose and galactitol excretion are the only chemical signs.

Metabolic derangement. Persons with GALK deficiency lack the ability to phosphorylate galactose. Consequently, nearly all of the ingested galactose is excreted, either as such or as its reduced metabolite, galactitol, formed by aldose reductase. As in GALT deficiency, cataracts result from the accumulation of galactitol in the lens, causing osmotic swelling of lens fibers and denaturation of proteins.

Genetics. The mode of inheritance is autosomal recessive. In most parts of Europe, in the United States, and in Japan, birth incidence is in the order of 1 in 150,000 to 1 million. It is higher in the Balkan countries, the former Yugoslavia, Romania, and Bulgaria, where it favors the Romani population, in whom the birth incidence was calculated as 1 in 2500.

The gene GK1, which encodes galactokinase, is located on chromosome 17q24. Many GK1 mutations have now been described. The GK1 P28T mutation was identified as the founder mutation responsible for galactokinase deficiency in the Romani from eastern European regions and in immigrants from Bosnia in Berlin (52). Different mutations have been documented (84).

Diagnostic tests. Provided they have been fed breastmilk or a lactose-containing formula prior to the test, newborns with the defect are discovered by newborn screening methods for detecting elevated blood galactose. If they have been fed glucose-containing fluid, the screening test could be false-negative. Every person with nuclear cataracts ought to be examined for GALK deficiency. Final diagnosis is made by assaying GALK activity in red blood cell lysates (75).

Treatment and prognosis. Treatment may be limited to the elimination of milk and dairy products from the diet. Minor sources of galactose, such as fruit, vegetables, and legumes, can probably be disregarded. When diagnosis is made rapidly and treatment begun promptly (during the first 2 to 3 weeks of life), cataracts can clear. When treatment is late and the cataracts are too dense, they will not clear completely (or at all) and must be removed surgically.

As in carriers with GALT deficiency, the speculation that heterozygosity for GALK deficiency predisposes to the formation of presenile cataracts remains unproven. It has been suggested that heterozygotes restrict their milk intake, though scientific proof of the merits of this measure is lacking.

Uridine diphosphate-galactose-4'-epimerase deficiency.

Clinical presentation. This disorder exists in at least 2 forms (128; 38), both of which are discovered through newborn screening using suitable tests sensitive to both galactose and galactose-1-phosphate in dried blood spots. However, there are patients with intermediate levels of residual GALE activity, and it is unclear whether these subjects have disease-causing mutations (85). In 5 patients from 3 families with the severe form of the disorder, the enzyme defect was subtotal (128). The newborns presented with vomiting, jaundice, and hepatomegaly reminiscent of untreated classical galactosemia. All had galactosuria and hyperaminoaciduria, 1 had cataracts, and 1 had sepsis. In some, there was evidence for sensorineural deafness or dysmorphic features, but it is unclear whether this is related to solely to GALE deficiency because there was a high degree of consanguinity in the families of Pakistani/Asian ancestry with homozygosity for the V94M GALE gene mutation. An additional patient from India was reported (104).

Infants with the mild form appear healthy. The enzyme defect is incomplete. Lactose-fed newborns with the mild form detected in newborn screening are healthy and have neither hypergalactosemia nor galactosuria or hyperaminoaciduria.

Metabolic derangement. The GALE enzyme deficiency provokes an accumulation of UDPgalactose after milk feeding. This build-up also results in the accumulation of galactose-1-phosphate.

Genetics. Epimerase deficiency is inherited as an autosomal recessive trait. The epimerase gene resides on chromosome 1. Several mutations have been identified and characterized, including the V94M mutation that was present in a homozygous form in all of the patients tested with a severe phenotype (132). It is also well established that this enzyme catalyzes the conversion of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. A compound heterozygous patient (L183P/N34S) of mixed Pakistani/Caucasian ancestry with a mild form and mental retardation, which may or may not be related to the underlying GALE deficiency, has been reported. As in GALT deficiency, abnormal glycosylation of proteins that appears to be dependent, at least in part, on lactose consumption has been reported in severe GALE deficiency and is thought to be a secondary biochemical complication, not primarily related to the genetic defect.

Diagnostic tests. The deficiency should be suspected when red cell galactose-1-phosphate is measurable while GALT is normal. Diagnosis is confirmed by the assay of epimerase in erythrocytes. Diagnosis of the severe form is based on the clinical symptoms, chemical signs, and more marked deficiency of epimerase in red cells. The utility of studying the enzyme deficiency in whole white cell pellets, isolated lymphocytes, and EBV-transformed lymphoblasts in potentially clinically relevant variant cases is under scrutiny.

Treatment and prognosis. The child with the severe form of epimerase deficiency is unable to synthesize galactose from glucose and is, therefore, galactose-dependent. Dietary galactose in excess of actual biosynthetic needs will cause accumulation of UDPgalactose and galactose-1-phosphate, the latter being 1 presumptive toxic metabolite. When the amount of ingested galactose does not meet biosynthetic needs, synthesis of galactosylated compounds, such as galactoproteins and galactolipids, is impaired. As there is no easily available chemical parameter on which to base the daily galactose allowance (such as blood phenylalanine in phenylketonuria), treatment is extremely difficult. Children known to suffer from the disorder have impaired psychomotor development.

Infants with the mild form of epimerase deficiency described thus far have not required treatment, but it is advisable that 1 or 2 urine specimens be examined for reducing substances and aminoaciduria within a couple of weeks after diagnosis, while the infant is still being fed milk.

Fanconi-Bickel syndrome. This is a recessively inherited disorder of glucose and galactose transport due to GLUT2 deficiency and is extremely rare (103). Several cases have been discovered during newborn screening for galactose in blood.

Portosystemic venous shunting and hepatic arteriovenous malformation. Portosystemic bypass of splanchnic blood via ductus venosus Arantii or intrahepatic shunts cause alimentary hypergalactosemia, which may be discovered during metabolic newborn screening (40; 06; 60).

Diagnostic workup

Consultation with a clinical biochemical geneticist or metabolic disease specialist is advisable for diagnostic laboratory evaluation, monitoring, and clinical care of patients with galactosemia. All states perform newborn screening. A positive (abnormal) result on the newborn screen must be followed by a quantitative erythrocyte galactose-1-phosphate uridyltransferase (GALT) analysis by a laboratory that routinely performs biochemical genetic testing and consultation (74; 75). In the pre-molecular diagnostic era, a GALT isoelectric-focusing electrophoresis test helped distinguish variant forms such as the Duarte defect (31; 76). GALT genotyping usually provides a specific molecular diagnosis. The most common GALT allele in Caucasians is the Q188R mutation (approximately 65% of mutant alleles). The patients with a Q188R/Q188R genotype may have no residual GALT enzyme activity in erythrocytes (74). The S135L mutation is common in African Americans (67). The K285N mutation is common in Eastern Europe (77). A urine-reducing substances test may be helpful. This test's results are almost always abnormal (positive) in infants with galactosemia who are ingesting lactose. This is a tube test rather than a dipstick test and must be differentiated from the routine urine dipstick test for glucose. Patients with galactosemia may exhibit white matter abnormalities on MRI of the brain (59); uncommonly, cerebellar atrophy may also be present. Pseudotumor cerebri, as well as lethal cerebral edema, has been detected in the newborn period (53; 05; 81). In sick neonates, white matter edema may be associated with brain galactitol accumulation (11). Infants with galactosemia can become jaundiced. Hyperbilirubinemia is often unconjugated but can become conjugated later. Urine examination reveals evidence of albuminuria and, later, a generalized aminoaciduria. Eliminating lactose-containing formula from the diet quickly resolves the albuminuria. Fatty infiltration and inflammatory changes initially may occur in the liver. Portal hypertension and pseudoacinar formation occur in later stages. Cirrhosis occurs in the final stage and is indistinguishable from other causes.

Management

The mainstay of medical care in the postnatal period is to immediately discontinue breastfeeding and ingestion of a lactose-containing formula. This ameliorates the acute toxicity in the neonatal period but does not prevent all long-term complications. Clotting abnormalities may be cryptic and require fresh frozen plasma treatments. The sepsis workup and use of antibiotics must be employed as indicated. An enigmatic linkage of E coli sepsis with galactosemia is noted. Galactosemia should be high on the differential diagnosis of term infants with sepsis caused by infection with this pathogen.

Chronic management requires time-dependent testing and consultations (127). Infants should be screened for speech and language deficits between 7 to 12 months of age; additional screening should then be performed at 2, 3, and 5 years of age (91; 71). Affected infants and children should then be referred to appropriate language and speech centers (117; 73); optimal individualized treatment is necessary to help address learning problems. Adolescent females should be referred to an adolescent medicine specialist or endocrinologist and women to a reproductive gynecologist for appropriate treatment for primary ovarian insufficiency (113). Fertility preservation requires careful consideration as ethical concerns exist (121). Males do not appear to manifest severe primary gonadal disease (Rubio-Gonzalbo 2010; 47). No standardized treatment for short stature has been established, and the etiology is unknown in most instances. A fraction of patients have bone mineral density results below 2 standard deviations; it is important that calcium and vitamin D intake be monitored (126; 122). Gastrointestinal tract dysfunction may be more common during the lifetime of the patient (111). The etiology of the long-term complications is unknown (10). Complications may be related to endogenous production of galactose as galactose-1-phosphate and galactitol levels remain elevated despite strict adherence to a lactose-restricted diet (13; 12; 106). Not surprisingly, as patients maintain steady-state levels of galactose metabolites in blood and urine, even patients with absent GALT activity are capable of oxidizing galactose to CO₂ (14; 17; 15).

Because dietary therapy is necessary, patients need to be followed by a dietitian who has experience with metabolic disorders. A lactose-restricted diet must be provided for infants with galactosemia. Older patients may tolerate lactose better than infants. The restriction of milk intake throughout life is controversial. However, most metabolic specialists support a life-long diet therapy. Totally eliminating galactose is difficult because it is present in a wide variety of foods (infant foods, fruits, vegetables), especially in the macromolecular form (01). Dietary restrictions during the pregnancy of the carrier woman, as well as prospectively during postnatal life, may have no effect on long-term complications of an affected fetus (64; 34; 65; 124). Drug therapy currently is not a component of the standard of care for this condition. During the initial hospitalization for a child with symptomatic, severe classic galactosemia, the major concerns are sepsis, bleeding, liver dysfunction, and brain swelling. These conditions are to be treated as they would in patients who do not have galactosemia. Immediate and total removal of lactose from the diet is the only specific treatment for a patient with galactosemia that differs from treatments for patients with sepsis or liver dysfunction from other causes. Dietary therapy requires both parental and patient education. Children should be involved in their dietary management as soon as appropriate. Leptin levels may be altered in galactosemia (61). Rare reports of patients with severe galactosemia off of diet therapy since childhood have raised questions about whether lactose restriction needs to be maintained after infancy (Lee et al 2003; 21; 87). Liberalizing galactose intake in older patients has been reported to improve the glycan structures in circulating IgG molecules (25; 62; 114). There is a need to develop a more uniform and evidence-based medical approach to dietary therapy and disease management after infancy (19; 66; 56). To that end, an international clinical guideline for the management of classic galactosemia was published online in 2016 (130).

It does not appear to be reasonable to restrict fruits and vegetables, only cow’s milk and dairy products (120).

Outcomes

In all states, galactosemia is or should be detected with a positive (abnormal) newborn screening test result. Aside from the high mortality rate in newborn infants with sepsis caused by Escherichia coli, life expectancy has never been studied in patients with galactosemia. Most patients appear to reach adulthood following institution of a galactose-restricted diet. If untreated, classic galactosemia is a life-threatening disorder. Fortunately, most states and developed countries screen for galactosemia in the newborn period, and affected infants are treated before they become very ill. Infants with galactosemia who are severely ill (eg, those with sepsis, coagulopathy, or liver dysfunction) before treatment for galactosemia is initiated may develop permanent liver, brain, or eye damage (although cataracts are often completely reversible). Most patients with severe galactosemia who do not receive treatment probably do not survive the newborn period. Even with appropriate dietary therapy, most patients with classic disease have long-term complications, including delayed language acquisition, speech defect, learning problems, decreased bone mineral density, and hypergonadotropic hypogonadism. Less common is short stature, poor growth, tremors, ataxia, and dystonia (126). It is important to recognize that patients with clinical variant galactosemia with higher residual GALT enzyme activities may not develop these long-term complications (09; 101).

Special considerations

Pregnancy

Galactose restriction in the pregnant woman with a fetus with classic galactosemia does not appear to produce beneficial effects in the offspring. There have been over 20 pregnancies reported in women with galactosemia (124; 08; 45).

Anesthesia

There is no increased risk of an adverse event.