Disorders of Galactose Metabolism Clinical Manifestations

Galactose is an important constituent of the complex polysaccharides which are part of cell glycoconjugates, key elements of immunologic determinants, hormones, cell membranes structures, endogenous animal lectins, and numerous other glycoproteins. In addition galactose is incorporated in galactolipids, important structure elements of the central nervous system. It is not difficult to assume that the abnormal galactose metabolism in galacto-semic patients could have profound and widespread effects on glycoconjugate structures and their biological function.

Classically, the term 'galactosemia' was associated with an inherited disorder of galactose utilization characterized by malnutrition, liver disease, cataracts, and mental retardation, resulting from the specific deficiency of galactose-1-phosphate uridyl-transferase. However, other enzymatic defects with variations of clinical presentation can also lead to galactosemia (Table 1). Thus it is preferably better to refer to these abnormalities of metabolism by the specific enzymatic deficiencies which are described below.

Transferase deficiency Failure to thrive is the most common initial clinical sign of galactose-1-phosphate uridyltransferase deficiency, and it is present in all cases. Vomiting or diarrhea is present in almost all patients, usually starting within a few days of milk ingestion. Jaundice, hepatomegaly, or both are present almost as frequently after the first week of life. The jaundice of intrinsic liver disease may be accentuated by severe hemolysis in some

Table 1 Disorders of galactose metabolism

Enzyme deficiency Primary clinical manifestations

Galactose-1-phosphate Failure to thrive uridyltransferase Emesis/diarrhea

Jaundice, hepatomegaly

Cataracts

Galactosuria

Gonadal dysfunction

Developmental delay, neurologic symptoms Cataracts

Galactokinase Similar manifestations as transferase deficiency, but with no liver, kidney, or gonadal dysfunction UDP-galactose Mostly asymptomatic

4'-epimerase Rarely same manifestations as transferase deficiency but with no gonadal dysfunction patients. Abnormal liver function tests and ascites may develop. The reason for liver toxicity remains obscure. The liver of affected patients has a characteristic acinar formation, and liver biopsy on occasion has been helpful in establishing the diagnosis. There is high frequency of neonatal death due to Escherichia coli sepsis, possibly caused by the inhibition of leucocyte bactericidal activity.

Galactose 1-phosphate and galactitol have been detected in the kidneys of patients with galactosemia. Renal toxicity may manifest as renal tubular dysfunction and a defect in urine acidification mechanisms. Galactosuria, hyperchloremic acidosis, albuminuria, and aminoaciduria may also occur. Hyperchloremic acidosis could be also secondary to the gastrointestinal disturbance and poor food intake. Galactosuria may be intermittent, depending on oral intake, and can disappear within 3-4 days with the use of intravenous glucose. The finding of urinary reducing substances which do not react in a glucose oxidase test should raise the suspicion of galactosemia. This finding, however, does not establish the diagnosis, since galactosuria can also occur in intestinal lactase deficiency and in severe liver disease due to other causes.

Ovarian atrophy appears to be an important manifestation of galactose toxicity, with clinical and biochemical evidence of ovarian dysfunction present in nearly all affected females. The basis of the toxicity has not been defined. The consequences of the gonadal dysfunction range from failure of pubertal development, through primary amenorrhea to secondary amenorrhea or premature menopause (75-76% of affected females). Although gonadal function has been described as early as infancy based on elevations of follicle stimulating hormones

(FSH) and abnormal stimulation testing, no predisposing factor for gonadal dysfunction can be found. Previous recommendations that dietary lactose restriction from birth may be beneficial have in fact not prevented gonadal dysfunction. In the galac-tosemic male, a complete understanding of gonadal dysfunction has not yet been described. The majority— but not all—of male galactosemic patients had normal pubertal development, and a few individuals have been found to have normal semen.

Cataracts have been observed within a few days of birth. These may be found only on slit-lamp examination and can be missed with an ophthalmoscope, since they consist of punctate lesions in the fetal lens nucleus. Several hypotheses have been postulated to account for their formation and are mentioned above. It seems conclusive that the initiator of the process in rats is galactitol and not galactose 1-phosphate. Galactose 1-phosphate accumulates only late in the process and is absent in patients with galactokinase deficiency who present with cataracts.

Development of mental retardation may be apparent after the first months of life. Signs of increased intracranial pressure and cerebral oedema have been observed as a presenting feature.

Many of the toxicity symptoms can rapidly resolve with institution of dietary lactose restriction. However, a substantial percentage of children have subnormal IQs and speech and language deficits, but rarely devastating neurological sequelae. Most galactosemic patients with lactose restriction are deficient of cognitive functioning in one or more areas. The deficits are variable and do not appear to be related to the age, diagnosis, or the severity of illness at presentation. The pathophysiology of these impairments in galactosemia remains unknown. Several hypotheses are suggested, including toxic oedema due to increased brain galactitol concentrations, changes in the second messenger pathway, and changes of the energy status of the brain.

Galactokinase deficiency Galactokinase deficiency is characterized by the occurrence of cataracts without liver, kidney, or ovarian dysfunction and no increased risk of infections. A number of infants are reported to have pseudotumor cerebri, with very rare neurological involvement, suggesting that retardation is not a feature. The absence of liver and kidney damage in galactokinase deficiency and the presence of damage to these organs in transferase deficiency make it likely that toxicity in the later condition is in some way associated with galactose 1-phosphate formation.

Epimerase deficiency Elevated red cell levels of galactose 1-phosphate with absence of UDP-galactose 4'-epimerase have been described in a patient with normal growth, development, and normal ability to metabolize ingested galactose. Several cases of biochemical deficiency have been described but symptomatic cases are extremely rare. A few had cataracts, sepsis, liver, kidney, and brain abnormalities, including a few with neurosensory deafness. There appears to be no ovarian dysfunction. The absence of ovarian dysfunction suggests that elevated UDP-galactose levels may protect the ovary from damage observed in transferase deficiency. Screening programs have been established in Japan, where the incidence is reported to be 1 in 23 000. In epimerase deficiency, when dietary galactose is low, galactose 1-phosphate concentrations in red blood cells may be reduced to normal, but UDP-galactose concentrations remain elevated. Despite the many phenotypic similarities between transferase and epimerase deficiency, the latter is characterized by elevated red cell levels of UDP-galactose even with modest galactose intake.

Diagnosis

The presence of reducing substance in urine which does not react with glucose oxidase reagents is consistent with galactosuria; however, occasionally some infants (particularly premature babies) also develop galactosuria. It is important to note that the presence of lactose, fructose, and pentose in the urine may give the same results. The presence of cataracts in infants without other systemic symptoms suggests the possibility of galactokinase deficiency. The presence of cataracts in older patients with the absence of gastrointestinal dysfunction or failure to thrive in galactosemic patients helps to differentiate between galactokinase deficiency and transferase deficiency.

The diagnosis of transferase deficiency is suggested by abnormally high amounts of red cell galactose 1-phosphate and confirmed by direct assay of red cell transferase activity. The red cell UDP-glucose consumption test may help to differentiate homozygous patients with a complete absence of transferase in red cells from heterozygous patients who have intermediate levels. Normal red cell values are of 6mmol UDP-glucose consumed per hour per millilitre of red blood cells. In galactokinase deficiency the diagnosis can be made by the presence of normal amounts of galactose-1-phosphate uridyl-transferase and the absence of galactokinase in the red blood cells.

Galactose-1-phosphate uridyltransferase deficiency can be diagnosed prenatally, by assay of galactose-1-phosphate uridyltransferase activity in cultured amniotic fluid cells or chorionic villi, and by galactitol measurement in amniotic fluid supernatant. The perinatal diagnosis is undertaken rarely, because the transferase deficiency is seen as a treatable condition.

Methods for mass screening of newborns for galactosemia are available, although galactosemia is rare. The incidence in Norway is 1 in 96 000, in Sweden 1 in 81000, in the USA 1 in 62 000, in Switzerland 1 in 58 000, in Germany 1 in 40 000, and the worldwide incidence is about 1 in 70 000. Newborn screening has not been introduced in Great Britain, the Netherlands, or in some states of the USA. Most newborn screening programs designed for the detection of anomalies of galactose metabolism use tests to measure either blood galactose or the activity of galactose-1-phosphate uridyl-transferase. Beutler and Baluda developed a fluorescence test in which the activity of uridyltrans-ferase in the dried blood spot is required for the reduction of NADP, yielding fluorescence under long-wave ultraviolet light; the intensity of the fluorescence corresponds to the activity of uridyltrans-ferase. The main advantage of this test is that it can be completed in short time, although false positive results do occur. The disadvantage of this test is that patients with galactokinase deficiency are not detected by this method. Guthrie and Paigen described a more efficient test using the principle of metabolite inhibition; galactose inhibited the growth of an E. coli mutant strain lacking uridyl-transferase. Later, Paigen used an E. coli mutant strain which lacks UDP-galactose 4'-cpimerase activity. Using the Paigen test it is possible to detect galactokinase and uridyltransferase deficiencies. Epi-merase deficiency can also be detected by the Paigen test if alkaline phosphatase is added to hydrolyze galactose phosphatase. In many screening laboratories the Beutler test is combined with the microbiological Paigen test.

Management

A galactose-free diet is the current treatment for galactosemia. It is important to know that galactose is present not only in milk but in other sources of food. A strict galactose-free diet in galactosemic patients with transferase deficiency is not harmful. The quality of the galactose-free diet and patient compliance are usually monitored by measuring free galactose in plasma and galactose 1-phosphate in erythrocytes.

Growth retardation, cognitive impairment, speech impediment, tremor, ataxia, and ovarian failure are frequent complications in spite of a strict galactose-free diet. Elevated galactose phosphate levels may occur in erythrocytes of even well-treated galactosemic patients. This elevation is attributed to endogenous production of the metabolite. A galactose-free diet is recommended from birth. It is recommended to restrict galactose in the diet of pregnant mothers diagnosed perinatally with trans-ferase deficiency; a galactose-free diet should be started as soon as the diagnosis is made in the infant regardless of any preexisting manifestation of toxi-city. The strict galactose-free diet will cause regression of symptoms and findings. It is important for the families to be aware of the high incidence of verbal dyspraxia even on a very strict diet. The speech intervention program and language stimulation are recommended as early as the first year of life. Many patients with normal IQ values who were treated from birth have learning disabilities, speech and language deficit, and psychological problems. Neurological sequelae have been described also in patients on strict galactose-free diets. These sequelae include cerebellar ataxia, tremor, choreoathetosis, and encephalopathy. Gonadal dysfunction in female galactosemic patients is an almost universal finding, even with a strict galactose-free diet. There is no current therapy for ovarian dysfunction except palliative replacement of oestrogen and progesterone. This is suggested in galactosemic females to develop secondary sexual characters and establish regular menses. There is no universal recommendation for the management of newborns screened positive nor for galactosemic heterozygotic patients.

In patients with epimerase deficiency, UDP-glucose cannot be converted to UDP-galactose. Thus a complete absence of galactose from the diet and the lack of formation of UDP-galactose via transferase would have serious consequences. There would be an inability to form complex polysaccha-rides and an inability to provide an adequate galactose component for brain cerebrosides. The treatment of epimerase deficiency relies on providing a small amount of dietary galactose.

See also: Early Origins of Disease: Fetal. Glucose: Chemistry and Dietary Sources; Metabolism and Maintenance of Blood Glucose Level; Glucose Tolerance. Glycemic Index. Inborn Errors of Metabolism: Classification and Biochemical Aspects. Liver Disorders.

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