Galactosemia

Inborn error of metabolism with the inability to metabolize galactose appropriately. This results in toxic effects on brain, liver, kidney, and eyes. Early diagnosis and galactose-free diet are key.

Galactose-1-Phosphate Uridyltransferase Deficiency; GALT Deficiency.

The incidence in the general population is estimated between 1:30,000 and 1:70,000, with the highest incidence in Ireland. It occurs in all races, but the incidence is lower among Asian people. Both genders are equally affected.

Transmission is autosomal recessive. The responsible gene encoding galactose-1-phosphate uridyltransferase (GALT) has been mapped to 9p13.

Lactose is a disaccharide consisting of galactose and glucose that is metabolized to glucose-6-phosphate via uridine diphosphate (UDP)-glucose in the Leloir pathway. Three different enzyme defects within the Leloir pathway can lead to galactosemia. Classic galactosemia, the most common form, is caused by GALT deficiency. The inability to metabolize galactose-1-phosphate to UDP-galactose results in accumulation of the former in brain, kidney, and liver, where it exerts a toxic effect. Galactosemia also can be caused by a deficiency in galactokinase, the enzyme responsible for the initial phosphorylation of galactose to galactose-1-phosphate. Erythrocytic galactokinase activity (used for diagnostic purposes) is significantly diminished in homozygous patients, whereas intermediate activities are measured in heterozygous children. Increased galactose levels are found in blood and urine samples after ingestion of lactose. In general, the prognosis is better than observed for the classic form. Finally, UDP-galactose-4-epimerase is necessary for the conversion of UDP-galactose to UDP-glucose. The deficiency of this enzyme comes in two different clinical forms. The benign form usually is detected during newborn screening tests with increased levels of erythrocytic galactose-1-phosphate concentrations, whereas galactokinase and uridyltransferase activities are normal. In this benign form, the defect affects only blood cells, so no treatment is required. In the generalized form, however, the clinical course is indistinguishable from classic galactosemia. In patients with black ethnic background, the most frequent mutation (S135L, which was previously called “Negro” or “African American” variant) accounts for approximately 45% of the mutant alleles. Homozygosity for the S135L allele and for two other mutant alleles (Duarte and Los Angeles variants) results in approximately 50% of normal GALT activity and a mild clinical course. A certain amount of free galactose may be reduced to galactitol through aldose reductase; however, this is a dead-end pathway and the poorly diffusable galactitol accumulates in the cells. It is partly responsible for the toxic effects seen in galactosemia.

Most often galactosemia is detected by standard newborn screening tests for inborn errors of metabolism. The test requires that the child be fed with human or cow's milk or a lactose-containing formula. A galactose breath test with orally administered stable isotope-labeled galactose can be used to determine whole-body galactose oxidation to CO2. The absence of a marked CO2 peak after 2 to 5 hours is found in patients with a severe clinical course or in affected neonates exposed to galactose.

Upon being fed with milk, newborns develop a variable combination of the following symptoms: lethargy, irritability, hypotonia, vomiting, hypoglycemia, seizures, failure to thrive, jaundice, hepatomegaly, liver dysfunction (including coagulopathy with bleeding), ascites, and splenomegaly. Cataracts are typical and already present in the neonatal period. It is essential to diagnose galactosemia early, otherwise hardly reversible or even irreversible and severe damage to brain (mental retardation), liver (macronodular cirrhosis, portal hypertension, hypersplenism), and eyes (cataract) may be established. Transfer of galactose from maternal into fetal circulation can lead to toxic changes in utero. Although not common on a normal diet, hypoglycemic episodes can occur after ingestion of galactose and are caused by either elevated levels of galactose-1-phosphate, which can inhibit the conversion of glycogen to glucose, or increased insulin release. A higher risk of Escherichia coli sepsis in galactosemia patients has been reported. In fact, galactosemia should be ruled out in neonates with sepsis from this pathogen. Renal tubular dysfunction and albuminuria with later transition into generalized amino aciduria has been described. Hypergonadotropic hypogonadism is a common finding. The condition should be suspected in males presenting with small testes. Females with primary ovarian failure and primary (or secondary) amenorrhea but normal development and even uncomplicated pregnancy have been described. Short stature, ataxia, tremor, EEG abnormalities, and difficulties with learning and speech (verbal dyspraxia) are other features of galactosemia. Treatment consists of elimination of galactose from the diet as soon as the diagnosis is made. No specific drug therapy exists. Although a galactose-free diet protects the body from the severe toxic effects of galactose-1-phosphate, it cannot prevent all the long-term complications (e.g., hypogonadism, cerebellar signs). These long-term complications have been suggested to be caused by “self-intoxication” of the body with galactose, because UDP-galactose can be synthesized from glucose through the enzymes UDP-glucose-pyrophosphorylase and UDP-galactose-4-epimerase, which both are part of the Leloir pathway. Other researchers believe that cerebral complications are the result of in utero exposition to high levels of galactose-1-phosphate.

Obtain a complete blood count (renal anemia, thrombocytopenia), check electrolytes (hypokalemia) and glucose levels, and assess renal and hepatic function (coagulation). Sedative or anxiolytic premedication may be helpful in the presence of mental retardation.

Blood glucose should be monitored perioperatively, depending on the degree of renal dysfunction and the nature of the procedure. An arterial line for a close followup of acid-base changes is recommended.

Depending on the degree of renal and hepatic dysfunction, drugs with predominantly renal and hepatic elimination, respectively, should be titrated carefully. In the presence of known seizures, avoid potentially epileptogenic drugs such as methohexital, ketamine, enflurane, atracurium, cis-atracurium, and meperidine (the last three only if given in large quantities because of their metabolites, laudanosine and normeperidine, respectively). The potential association of seizure activity during induction of anesthesia with high concentration of sevoflurane should be considered. Lactulose and voriconazole contain lactose and should not be used in these patients.

Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance): Severe autosomal recessive inborn error affecting the metabolism of glucides caused by a deficiency of hepatic fructose 1-aldolase becomes clinically apparent only when fructose is ingested. Characterized by vomiting, hypoglycemia, severe metabolic acidosis, coma, growth retardation (even cachexia), hepatomegaly, jaundice, coagulopathy, and renal Fanconi syndrome. The responsible gene has been mapped to 9q22.3.