Article Category: Editorial
Publicado en línea: 04 oct 2018
Páginas: 221 - 224
Recibido: 20 ago 2018
Aceptado: 29 ago 2018
DOI: https://doi.org/10.34763/devperiodmed.20182203.221224
© 2018 Annet M. Bosch, published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.
Classical galactosaemia (CG) is a disorder of galactose metabolism which results from a deficiency of galactose-1 phosphate uridyltransferase (GALT, EC 2.7.7.12) activity caused by mutations in the GALT gene (NM_000155.3). Patients have absent or barely detectable GALT enzyme activity and present in the first weeks of life with life threatening illness (feeding difficulties, liver failure, sepsis, cataract) after the ingestion of galactose from breast milk or infant formula. A lactose-free and galactose-restricted diet is life saving and the only available treatment at this time [1].
Newborn screening for CG by measuring GALT enzyme activity [2] was introduced in the 1960s with the expectation that early diagnosis and dietary treatment would prevent severe illness in the newborn period and that patients would have a normal outcome. However, since 1982 long-term complications have been reported in the literature. At this time it is clear that, in spite of an early diagnosis and immediate start of treatment, many CG patients suffer from long-term complications affecting their quality of life, such as impaired cognitive abilities, language and speech defects, neurological complications, and hypergonadotropic hypogonadism in females [3, 4, 5, 6, 7, 8, 9]. The most probable cause of these long-term complications is the persistent elevation of metabolites due to the endogenous production of galactose [10]. The fact that long-term complications are not prevented recurrently brings up the dilemma whether galactosaemia should be screened in newborns.
Newborn screening has historically been implemented with consideration of the ten principles of Wilson and Junger [11]. Some of these principles are nowadays easily dealt with in most countries: the condition should be an important health problem; facilities for diagnosis and treatment should be available; case finding should be a continuing process. However, for CG newborn screening some other principles are still subject to discussion.
Classical galactosaemia is mostly screened by GALT enzyme measurement, often combined with total galactose (TGAL) measurement. Screening will result in the identification of false positive (FP) cases, as has been demonstrated in several reports [12,13]. It is of utmost importance to minimize the number of FP referrals, as these have been demonstrated to cause anxiety, parentchild dysfunction and alterations in parental perception of the child’s health [14]. CG newborn screening in the Netherlands started in 2007 with a very high rate of FP referrals. Multiple adjustments since then in methods and cutoff values have now reduced the number of false positives [13]. A study in Sweden reported a decrease in the number of FP referrals to less than 0.01%, and a positive predictive value of 64% using a two-tier test strategy of GALT enzyme measurement followed by the measurement of total galactose [15]. An important limitation of combining GALT and TGAL measurements is that children on a low lactose or lactose-free diet (i.e. parenteral feeding or hypoallergenic formula) may not demonstrate elevated TGAL values and can be missed by newborn screening.
The only available treatment at this time is accepted and easily implemented: a life-long lactose-free and galactose restricted diet, which rapidly resolves the illness in the newborn period. It is advised to introduce this diet, which is in infants based on lactose free formula based on soy or a hydrolysate, as soon as the diagnosis is suspected, without awaiting results of diagnostic tests [16].
Depending on the day of screening, most patients will be symptomatic and may already be hospitalized at the time of diagnosis by newborn screening [13]. However, early diagnosis and an immediate start of treatment significantly reduce morbidity and mortality. In Germany Schweitzer-Krantz (2003) demonstrated that early detection with newborn screening performed at day 5 prevented mortality in the first weeks of life, with death reported in 19/49 patients diagnosed before the implementation of newborn screening and 1/99 diagnosed after the start of newborn screening [17]. In Sweden only 4 CG patients diagnosed before the start of screening in 1967 survived, while since then only one patient has died [15]. Unfortunately, early diagnosis and treatment do not prevent long-term complications [17,18].
Newborn screening often results in the detection of individuals with previously unreported phenotypes and genotypes, for whom the need for treatment and the potential outcomes are unclear. Indeed, in the Netherlands, after the start of CG newborn screening, 14% of the diagnosed patients had a previously unreported phenotype and genotype. These individuals did not demonstrate any symptoms at the time of diagnosis while still being exposed to galactose, and some demonstrated normal metabolite levels after the start of dietary treatment. The recent international guideline for CG recommends dietary treatment in all patients with GALT enzyme activity <10%, and states that there is insuffcient evidence whether patients with 10-15% of GALT enzyme activity need to be treated. In the Netherlands, currently all the patients with enzyme activity below 15% are treated. Future studies on the need for treatment and the outcome of these patients are warranted [13, 16].
A small number of studies evaluating cost benefits with different methods provide contradictory results [19, 20, 21].
Currently newborn screening is performed in 9 European countries: Austria, Estonia (on a research basis), Germany, Greece, Italy, the Netherlands, Spain, Switzerland and Ireland. Two recent papers discussed the appropriateness of galactosaemia newborn screening. Varela Lema et al. (2016) concluded from their systematic review that there was insufficient evidence to establish the appropriateness of CG newborn screening, but that health benefIts could be expected if early diagnosis and treatment is achieved [22]. A Cochrane review published in 2017 concluded that it is not possible to draw conclusions based on randomized controlled studies, but that there are uncontrolled studies which support the efficacy of newborn screening for CG and that a number of reviews and economic analyses of non-trial literature suggest that screening is appropriate [23].
The striking effects of early diagnosis on the morbidity and mortality of patients in the first weeks of life strongly confirm the appropriateness of CG newborn screening, even when taking into consideration the fact that early diagnosis does not prevent long-term complications and the lack of insight into the cost-benefit ratios. However, with the implementation of CG newborn screening, It is of utmost importance to minimize the number of FP referrals and to educate the professionals involved in the treatment that if TGAL is one of the screening parameters newborns on low lactose diets may not be detected by the screening.