Introduction to the Maastricht workshop: lessons from the past and new directions in galactosemia

Abstract

Hereditary galactosemia is an autosomal recessive genetic disorder of carbohydrate metabolism (OMIM 230400; Fridovich-Keil andWalter 2008; Elsas 2010; Berry and Walter 2011). The mutated gene encodes a protein, galactose1-phosphate uridyltransferase (GALT, EC 2.7.7.12), that catalyzes the conversion of galactose-1-phosphate and UDPglucose to UDP-galactose and glucose-1-phosphate (Fig. 1). In the newborn period, a life-threatening disease with multiorgan involvement emerges, particularly in those infants ingesting lactose in breast milk and proprietary baby formulas containing the ingredients of cow’s milk (Berry and Walter 2011). The first observation of this nutritional toxicity state involving the neonate and breast milk was by von Reuss in 1908 (von Reuss 1908). In the next decade, Goppert documented the presence of excess galactose in the urine of a similarly affected infant (Goppert 1917). The first well characterized infant with hypergalactosemia and galactosuria who responded to a lactose-restricted diet was described by Mason and Turner in 1935 (Mason and Turner 1935). This paper, describing an African-American infant with a variant form of galactosemia, served to reveal marked hypergalactosemia as an integral component of GALT deficiency. However, establishment of the abnormal biochemistry awaited the discovery of Schwarz in 1956 (Schwarz et al. 1956) that the substrate, galactose-1-phosphate, was elevated in erythrocytes from galactosemic patients exposed to galactose, and the demonstration later that year in the Kalkar laboratory that GALTenzyme activity was absent (Isselbacher et al. 1956). This rare Mendelian disorder with a world-wide frequency of 1/40,000 to 1/60,000 newborn infants entered the modern era of molecular biology when Reichardt and Berg cloned a GALT cDNA from a human liver library (Reichardt and Berg 1988), and its correct cDNA sequence enabled cloning and delineation of the structure of the GALT gene (Flach et al. 1990; Leslie et al. 1992). Soon thereafter, many causative gene mutations were identified producing a heterogeneous array of impaired pGALT function (Elsas and Lai 1998; Tyfield 2000; Calderon et al. 2007). It was clear in the decades following the landmark Mason and Turner paper that restriction of galactose intake in the affected newborn infant would usually permit survival and allow the following early infantile complications to remit, resolve or disappear: poor growth, poor feeding, emesis, jaundice, liver enlargement and dysfunction that includes hyperbilirubinemia, transaminasemia, hypofibrinoginemia with bleeding diathesis, cataracts, encephalopathy, including lethargy, irritability and hypotonia, hyperchloremic metabolic acidosis, albuminuria, generalized aminoaciduria and anemia. Yet, between 1970 and 1990, there was a growing awareness that there were “clouds over galactosemia” (Anonymous 1982; Holton and Leonard 1994), that patients were not faring as well as physicians had expected (Komrower and Lee 1970; Lee 1972; Fishler et al. 1972, 1980; Komrower 1982; Waisbren et al. 1983; Gitzelmann and Steinmann 1984), especially given the fact that lactose restriction largely eliminates death from E. coli sepsis (Levy et al. 1977). And, this was all the more poignant, as infants Communicated by: Estela Rubio