Classical galactosemia (GASM) is one of the most common innate errors in metabolism identified by neonatal screening in the United States. Galactosemia is the result of a profound deficiency of galactose-1-P uridyltransferase (GALT; Isselbacher et al., 1956), the average enzyme in the Leloir pathway of galactose metabolism. Affected neonates may appear normal at birth, but following exposure to breast milk or a milk formula, there is a rapid and devastating decline that may progress in days of vomiting, diarrhea and jaundice to hepatomegaly, lack of development, sepsis and neonatal death. Early detection by neonatal screening that may or may not be pre-symptomatic, associated with rapid dietary restriction of galactose, may prevent or resolve the acute and life-threatening symptoms of GASM. However, despite early diagnosis and intervention, since the early childhood many treated patients experience one or more long-term constellations that may include language disability, cognitive and behavioral deficits in at least half of all patients, tremor and / or other movement problems in almost 40% of patients, growth retardation and low mineral bone density in many patients, and primary ovarian failure in> 80% of girls and young women. The mechanisms and the primary or secondary nature of these complications remain unclear and the variability of the severity of long-term outcomes among patients remains largely unexplained.
Diet management
One factor proposed as a potential contributor to the variability of long-term outcomes in GASM is the degree to which exposure to food galactose is limited, especially in early childhood. In fact, dietary recommendations for children with GAMS have evolved over time largely due to better knowledge of the galactose content of certain non-dairy foods, together with endogenous galactose production in children and adults. Essentially all children diagnosed with GASM drink soy (low galactose content) or elementary formula in the first months of life after diagnosis. Once solid foods are introduced, however, some children continue with a diet that strictly excludes not only milk and all dairy products (with galactose), but also legumes, fruits and vegetables and other foods that are believed to contain unsafe amounts of galactose. Health care providers and parents advocating rigorous continuous dietary restriction, even from non-dairy sources of galactose beyond childhood, argue that any exposure to galactose endangers a child who grows with galactosemia.
Those who recommend a more liberal diet beyond childhood rely on the fact that the levels of galactose in legumes, fruits, vegetables, other non-dairy foods and even some hard cheeses, are negligible compared to the production of endogenous galactose and to children with GASM, like other children, would do well with a varied and balanced diet. There has even been concern that excessive vigorous dietary restriction of galactose may worsen clinical outcomes, such as osteoporosis that appears with age. Dietary recommendations for children and adults with GASM have been liberalized in recent years following a review of the 2014 Task Force literature, but the authors of this report clearly stated that their new recommendations were not based on data showing that a liberalized diet is safe, but rather in the absence of data demonstrating that a liberalized diet is not. This reality has left health care providers and many concerned parents, who had spent years examining food packaging labels, at their mercy.
Debates on early prevention
Neonatal screening for classical galactosemia has been discussed for years, but no consensus has been reached. The principles originally articulated by Wilson and Jungner for screening and subsequently expanded by Pollitt et al. they have been accepted as criteria for neonatal screening. Galactosemia has been ruled out by some neonatal screening programs based on two main topics: it can be diagnosed clinically and long-term complications develop despite early treatment. Although it was recognized that the actual availability of treatment was not an absolute prerequisite for the inclusion of a disease in neonatal screening programs, specific screening for galactosemia was not yet recommended. However, there were recommendations for all samples with increased phenylalanine (phenylketonuria), to be screened for galactosemia as a secondary test. One study compared 139 children with metabolic diseases identified by neonatal screening (17 galactosemics) with 124 children identified on the basis of clinical symptoms (9 galactosemics). The research concluded that, despite the similar hospitalization rate, 47% of the clinically identified children had mental retardation compared to only 14% of those identified by neonatal screening. Neonatal screening for galactosemia is now included in European countries such as Austria, Germany, Hungary, Ireland, Sweden, Switzerland, Turkey, Italy and Belgium. Ireland has a high incidence of (on average 1: 16.450), especially in the population of travelers (1: 430), and neonatal screening for classical galactosemia has been carried out since 1972.
Therapeutic options for screening
Mason and Turner described in 1935 how the removal of galactose from the diet eliminated neonatal toxicity and, subsequently, the dietary restriction of galactose became the first recommended therapy for galactosemia that still prevails today. Considering that the GASM is characterized by a lack of UDP-sugars, the potential therapeutic role of uridine has been evaluated in a 5-year longitudinal study of galactosemic patients. Despite no improvement in cognitive function, it remains to be clarified whether uridine was able to play its role. The inhibition of the enzyme aldose reductase has been suggested as a therapeutic option, as galactitol (alcohol derived from galactose) is an important pathogen in galactosemia. However, the fact that patients with GALK1 deficiency have accumulation of galactitol, but not the wide range of serious long-term complications of classical galactosemia, strongly suggests a limited efficacy of inhibitors of this enzyme. Another therapeutic strategy under study is the conversion of classical galactosemia into a deficiency of GALK1 (galactose kinase), a milder form of galactosemia in which patients do not accumulate Gal-1-P. Patients with GALK1 deficiency may have cataracts (attributed to the accumulation of galactitol) and neurological sequelae. Some enzyme inhibitors have been developed and are currently being studied. Finally, it has been hypothesized that the anthocyanins (pigments) of the sweet purple potato, previously shown to have a protective effect against the toxicity of galactose in mice with a diet rich in this sugar, can alleviate certain cellular damage of galactosemia.
- edited by Dr. Gianfrancesco Cormaci, PhD,specialist in Clinical Biochemistry.
Scientific references
Berry GT (2012) Mol Genet Metab 106:7–11.
Bosch AM et al. (2004a) Arch Dis Child 89:1034–1036.
Bosch AM et al. (2004b) Pediatrics 113:e423–e428.
Hughes J et al. J Pediatr. 2009; 154(5):721–726.
Isselbacher KJ et al. Science. 1956; 123(3198):635–636.
Jensen UG et al. (2001) Clin Chem 47:1364–1372.
Kaufman FR et al. (1995) Eur J Pediatr 154:S2–S5
Kim H et al. (2007) J Agric Food Chem 55:8133–8137.
Ohlsson A et al. J Inherit Metab Dis Rep Case Res Rep 2:113–17.
Ryan EL et al. J Inherit Metab Dis. 2013; 36(6):1049–1061.
Sanders RD et al. Fertil Steril. 2009; 92(1):344–351.
Schadewaldt P et al. Arch Physiol Biochem. 2014; 120(5):228–39.
Suzuki M et al. (2001) Human Genet 109:210–215.
Welling LJ et al. Inherit Metab Dis. 2017; 40(2):171–176.