Galactosemia. Galactosemia results from congenital inability to metabolize galactose to glucose. The most common source of galactose is milk, which contains lactose. Lactose is converted to glucose and galactose in the gastrointestinal (GI) tract by the enzyme lactase. There are three forms of galactosemia, each with autosomal recessive inheritance, and each caused by an enzyme defect in the galactose-glucose metabolic pathway. This enzyme system is located primarily in RBCs. The classic and most common type of abnormality is found in 1 in 62,000 infants and is due to deficiency of the enzyme galactose-1-phosphate uridyltransferase (Gal-1-PUT); the defect is called transferase deficiency galactosemia (TD-galactosemia). Normally, galactose is metabolized to galactose-1-phosphate, and Gal-1-PUT mediates conversion to the next step in the sequence toward glucose-1-phosphate.

TD-galactosemia is not clinically evident at birth, but symptoms commence within a few days after the infant starts a milk diet. Failure to thrive occurs in 50%-95% of patients. Vomiting (about 50% of cases), diarrhea (about 30%), or both occur in nearly 90% of patients. Evidence of liver dysfunction develops in about 90% of patients, consisting of hepatomegaly (about 70%), jaundice (about 60%), or both. Physiologic jaundice may seem to persist, or jaundice may develop later. Splenomegaly may appear in 10%-30% of patients. Individual signs and symptoms are sufficiently variable that a complete full-blown classic picture does not appear in a substantial number of affected infants. Cataracts develop in several weeks in about 50%, and mental retardation is a sequel in about one third of the patients. The disease is treatable with a lactose-free diet, if the diet is begun early enough.

Laboratory abnormalities. Transferase deficiency galactosemia has multiple laboratory test abnormalities. Urinalysis typically reveals protein and galactose, although in one series only two thirds of patients demonstrated urine galactose. Urine galactose excretion depends on lactose ingestion and may be absent if the infant refuses milk or vomits persistently. Galactose in urine can be detected by a positive copper sulfate-reducing substance test (e.g., Clinitest) plus a negative test specific for glucose (such as glucose oxidase test strips). A nonglucose reducing substance must be identified by more specific tests, because lactose and various other sugars can produce the same reaction as galactose on the screening procedure. There is also abnormal amino acid urine excretion that can be detected by chromatography, although such information adds little to the diagnosis. Positive urine galactose test results do not mean that the infant has galactosemia, since occasionally normal newborns have transient galactosuria. However, urine screening is important, because detection of galactose enables a tentative diagnosis to be made and treatment started, pending results of confirmatory tests.

Other nonspecific abnormalities in classic transferase-deficient galactosemia include hepatomegaly and jaundice, although jaundice may not be present. Liver function test results are variable, although the aspartate aminotransferase (AST, formerly serum glutamate oxaloacetate) and possibly alkaline phosphatase levels are frequently elevated. Liver function test results must be interpreted with knowledge that the reference ranges are different in the neonate than in adults. Liver biopsy has been used in certain problematic patients (mostly before Gal-1-PUT assays were available). The histologic changes are suggestive but not conclusive and consist of early fatty metamorphosis, with a type of cirrhosis pattern often developing after about 3 months of age.

Diagnosis. Diagnosis of classic TD-galactosemia depends on assay of Gal-1-PUT in the RBCs of the infant. Several methods have been described, all of which are sufficiently difficult that the test is available only in university centers and a few large reference laboratories. The specimen presents certain problems. RBCs from anticoagulated whole blood are tested, so the specimen cannot be frozen. On the other hand, one report indicates that 25% of the enzyme activity is lost after 24 hours at either room temperature or refrigerator temperature. For this and other reasons, many physicians rely on screening tests for transferase enzyme deficiency and, after starting therapy, refer the patient to a specialized center for definitive diagnosis.

The galactose tolerance test was once the most widely used method for confirmation of galactosemia. However, there is considerable danger of hypoglycemia and hypokalemia during the test, and it has been replaced by chromatography and RBC enzyme assay.

Screening tests. Several screening tests are available. The most popular are a bacterial inhibition method (Paigen assay, roughly similar to the PKU Guthrie test) and the Beutler fluorometric method. The Paigen assay measures elevated blood galactose (or galactose-6-phosphate) levels, and the Beutler assay measures Gal-1-PUT activity. Both can be performed on filter paper blood spots. The Paigen test depends on elevated blood galactose levels, and therefore milk feeding is necessary. Specimens from patients not receiving milk or specimens drawn several hours after a milk feeding may yield false negative (normal) results. If the Paigen test is adapted to detect galactose-1-phosphate rather than galactose, length of time after feeding is not a problem, and even most cases in patients on a galactose-free diet are reportedly detected. The Paigen test (either type) detects galactokinase deficiency as well as transferase deficiency. The Beutler test does not depend on milk feeding. However, the test does not detect galactokinase deficiency and is more subject to effects of heat and humidity on the filter paper specimen. The Beutler test also can detect certain nonpathologic variants of transferase enzyme such as the Duarte variant.

Variants. There are at least four variants of the transferase enzyme. The Duarte variant is the most frequent. Patients with this disorder exhibit about 50% of normal Gal-1-PUT activity on RBC assay and are clinically asymptomatic. In classic (homozygous) transferase deficiency there is almost no Gal-1-PUT activity on assay.

Other forms of galactosemia. There are two other forms of galactosemia. One consists of deficiency in the enzyme galactokinase. Development of cataracts is the only symptom. The incidence of galactokinase deficiency has been variously reported as equal to that of transferase deficiency or less. The third type is deficiency of the enzyme erythrocyte epimerase, of which very few cases have been reported. These patients seem to be completely asymptomatic.

Disaccharide malabsorption. Certain enzymes are present in the lumen border of small intestinal mucosal cells that aid in absorption of various complex sugars by preliminary hydrolyzation. Deficiency of one or more of these enzymes may impair absorption of the affected sugar, depending on the degree of enzyme deficiency. The most common deficiency affects the disaccharide sugar lactose. Lactose is present in milk or milk products such as ice cream, yogurt, and many types of cheese. Northern Europeans as a group usually have normal intestinal lactase throughout life and only about 10%-15% develop lactose intolerance. Many other ethnic populations have a high incidence of lactase deficiency. The highest incidences are reported in Asians (such as Chinese and Japanese) and Native Americans (over 90% are said to develop lactose intolerance). Eastern European (Ashkenazic) Jews, African Americans, and persons of Mediterranean or South American ancestry have a lesser but still high rate of deficiency (60%-70% incidence). Besides primary (genetic) lactase deficiency, secondary deficiency may be induced, more or less temporarily, by certain diseases affecting the small intestine. These include primary small intestine mucosal disease (sprue), short bowel syndrome, severe acute gastroenteritis, prolonged protein-calorie malnutrition, and certain antibiotics (e.g., neomycin and kanamycin). Lactase deficiency may also occur due to prematurity. Between 26 and 34 weeks of gestation there is only about one third of full-term lactase activity present. This increases to about 70% between 35 and 38 weeks. Full activity levels are attained by birth at 40 weeks.

Persons who inherit the trait for lactase deficiency usually have normal lactase activity levels at (full-term) birth. However, at about age 3-5 years there is a fall in lactase activity. After this time there is some individual variation in degree of clinical tolerance to milk, even when intestinal lactase activity measurement is low.

Symptoms of lactose intolerance include some combination of abdominal cramps, diarrhea, bloating, and flatulence, usually occurring at or becoming worse after meals. One study involving children from age 4 years to the teen-age years who had intermittent abdominal pain found their symptoms could be explained by lactose malabsorption in a high proportion of those from ethnic groups with a high incidence of lactase deficiency. Lactase deficiency in full-term newborns or young children is thought to be rare. Milk allergy may produce similar symptoms but is uncommon, usually includes allergy symptoms such as asthma with any GI symptoms, and the parents usually have a history of allergy.

Screening tests for lactase deficiency include testing of stool for pH and sugar at a time when the patient is symptomatic. Normal stool pH is 7.0-8.0. A stool pH below 6.0 raises the question of lactase deficiency. The stool can be tested for sugar by either a reducing substance method or a glucose oxidase paper strip method. The presence of glucose in the stool suggests lactase deficiency. However, in one study, parenteral antibiotics administered to neonates caused an increase in fecal reducing substances beginning within 48 hours after starting the antibiotics. Negative test results for pH and sugar do not exclude the diagnosis, and positive test results do not conclusively establish the diagnosis. Acidic stool pH can be found in certain other conditions associated with diarrhea, especially steatorrhea.

Diagnostic tests for lactase deficiency include the lactose tolerance test, hydrogen breath test, and small intestine biopsy with tissue assay for lactase. The lactose tolerance test is performed in a similar manner to the oral glucose tolerance test. After overnight fasting, 50 gm of oral lactose (in children, 1-2 gm of lactose/kg of body weight) is given in some type of flavored liquid. Serum glucose levels are assayed before lactose administration and 15, 30, 60, and 90 minutes afterward (some investigators use different time intervals; some beginning at 30 minutes instead of 15 and some ending at 120 minutes instead of 90 minutes). Normal lactase activity results in a postdose glucose elevation more than 20 mg/100 ml (1.1 mmol/L) over baseline. This assumes that malabsorption from some other cause is excluded. Some investigators measure galactose instead of glucose; 150 mg of ethanol/kg of body weight is administered with the lactose dose to inhibit liver conversion of galactose to glucose. A single blood or urine sample is obtained 40 minutes after the test dose and is assayed for galactose. The advantage of this procedure is need for only one test specimen. However, this method has not been evaluated as thoroughly as the standard lactose tolerance procedure. The hydrogen breath test is currently considered the most accurate of the tolerance tests. Briefly, it consists of analysis of expiratory breath for hydrogen, followed by administration of oral lactose and retesting of breath samples at either 30- or 60-minute intervals for 2-4 hours. Lactase deficiency results in deposition of excess lactose into the colon, where bacterial fermentation produces excess hydrogen, which is excreted through the lungs. The hydrogen breath test can be performed only by specialized medical centers. Small intestine biopsy with quantitation of tissue levels of intestinal lactase is performed during an endoscopy procedure. Tissue biopsy has the added advantage that some of the secondary causes of lactase deficiency (e.g., sprue) can be detected. However, intestinal lactase measurement is available only at specialized medical centers.

Lactosuria. Some patients with lactase deficiency absorb lactose from the GI tract after oral intake of lactose and excrete the lactose in the urine. However, other lactase-deficient persons do not exhibit lactosuria. Premature infants are said to be predisposed to temporary lactosuria (presumably due to their relatively lactase-deficient state). Lactosuria is apparently not uncommon in the last trimester of pregnancy and for several days following delivery.

Sucrase enzyme deficiency. The disaccharide sugar sucrose is commonly used as a carbohydrate supplement. Sucrose is hydrolyzed by the enzyme sucrase in small intestine mucosa cells. Congenital sucrase deficiency has been reported but is not common. Most cases became clinically manifest within the first year of life, with symptoms predominantly of failure to thrive, diarrhea, or both. Stool pH is usually acidic. Reducing substance sugar test methods are not accurate for stool testing, since sucrose is not a biochemical reducing substance. Fructose may also be malabsorbed by some persons. Diagnosis is most often made by the hydrogen breath test. Definitive diagnosis usually requires small intestine biopsy with tissue assay for sucrase (or fructose) activity.

Glycogen storage disease. Glycogen storage disease includes a spectrum of syndromes resulting from defective synthesis or use of glycogen. Clinical manifestations depend on the organ or tissue primarily affected and the specific enzyme involved. The disease in one or another of its clinical syndromes may affect the liver, heart, or skeletal muscle. The most common is von Gierke’s disease, whose clinical manifestations primarily involve the liver. Classic cases usually have elevated levels of triglyceride, cholesterol, and uric acid. Some have hypoglycemia. Patients typically have a diabetic type of oral glucose tolerance curve.

Diagnosis. Diagnosis of the various forms of glycogen storage disease requires biopsy of liver or muscle (depending on the particular disease variant) for glycogen and enzyme analysis. In some cases, enzyme assay can be performed on other tissues. These are specialized tests, and it is best to contact a pediatric research center rather than expose the patient to inappropriate or incomplete diagnostic procedures.