Galactosemia is an autosomal recessive disorder that results from a deficiency of any 1 of the 4 enzymes catalyzing the conversion of galactose to glucose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), uridine diphosphate galactose-4-epimerase (GALE), and galactose mutarotase (GALM). Galactose-1-phosphate (Gal-1-P) accumulates in the erythrocytes of patients with galactosemia due to GALT, GALE, or neonates with GALM deficiency. The quantitative measurement of Gal-1-P is useful for monitoring compliance with dietary therapy for either GALT or GALE deficiency. Gal-1-P is thought to be the causative factor for development of liver disease in these patients and, because of this, patients should maintain low levels and be monitored on a regular basis. The concentration of Gal-1-P in erythrocytes is the most sensitive index of dietary control.
GALT deficiency is the most common cause of galactosemia and is often referred to as classic galactosemia. The complete or near-complete deficiency of GALT enzyme is life-threatening if left untreated. Complications in the neonatal period include failure to thrive, liver failure, sepsis, and death.
Galactosemia due to GALT deficiency is treated by a galactose-restricted diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, individuals with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Female patients with galactosemia are at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of classic galactosemia in the United States is approximately 1 in 30,000, although literature reports range from 1 in 10,000 to 1 in 60,000 live births.
Epimerase deficiency galactosemia can be categorized into 3 types: generalized, peripheral, and intermediate. Generalized epimerase deficiency galactosemia results in profoundly decreased enzyme activity in all tissues, whereas peripheral epimerase deficiency galactosemia results in decreased enzyme activity in red and white blood cells, but normal enzyme activity in all other tissues. This is compared with intermediate epimerase deficiency galactosemia, which results in decreased enzyme activity in red and white blood cells and less than 50% of normal enzyme levels in other tissues.
Clinically, infants with generalized epimerase deficiency galactosemia develop symptoms such as liver and renal dysfunction and mild cataracts when on a normal milk diet, while infants with peripheral or intermediate epimerase deficiency galactosemia do not develop any symptoms. Generalized epimerase deficiency galactosemia is treated by a galactose- and lactose-restricted diet, which can improve or prevent the symptoms of renal and liver dysfunction and mild cataracts. Despite adequate treatment from an early age, individuals with generalized epimerase deficiency galactosemia remain at increased risk for developmental delay and intellectual disability. Unlike patients with classic galactosemia resulting from a GALT deficiency, female patients with generalized epimerase deficiency galactosemia experience normal puberty and are not at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of epimerase deficiency galactosemia in the United States ranges from approximately 1 in 6700 African American infants to 1 in 70,000 infants of European ancestry.
GALM deficiency is a rare form of galactosemia that is due to a deficiency of galactose mutarotase, which may manifest clinically with bilateral cataracts. Infants with GALM deficiency have increased blood galactose concentrations with levels of galactose 1-phosphate ranging from 0.3 to 10.8 mg/dL. Neonates with GALM deficiency have elevated galactose-1-phosphate, but Gal1P decreases rapidly in early infancy. To date, only pediatric patients have been described in the literature, and so the long-term, adult consequences of GALM deficiency remain unknown.
The incidence of GALM deficiency has been reported as 1 in 10,000 in African populations and close to 1 in 80,000 in the Japanese population, with an overall estimation of about 1:228,411 in all populations.