Rigor of non‐dairy galactose restriction in early childhood, measured by retrospective survey, does not associate with severity of five long‐term outcomes quantified in 231 children and adults with classic galactosemia

Abstract

One of many vexing decisions faced by parents of an infant with classic galactosemia (CG) is how carefully to restrict non-dairy galactose from their growing child’s diet. Until recently, many experts recommended vigorous lifelong dietary restriction of milk and all high-galactose dairy products as well as some non-dairy sources of galactose such as legumes and specific fruits and vegetables. Recently, experts have begun to relax their recommendations. The new recommendations, that restrict only high galactose dairy products, were made in the face of uncertainty, however, because no sufficiently powered study had been reported testing for possible association between rigor of non-dairy galactose restriction and severity of long-term outcomes in CG. Here we describe the largest study of diet and outcomes in CG reported to date, conducted using information gathered from 231 patients with CG and 71 unaffected sibling controls. We compared rigor of dietary galactose restriction, measured using a 4-point scale by a retrospective parent-response survey, with outcomes including growth, adaptive behaviors, receipt of speech therapy, receipt of special educational services, and for girls and women, a plasma marker of ovarian function (AMH). Our results confirmed the expected differences between patients and controls, but among patients showed no significant association between rigor of non-dairy galactose restriction in early childhood and any of the outcomes quantified. Indeed, some weak associations were seen suggesting that rigorous restriction of non-dairy galactose may be deleterious rather than beneficial. Despite limitations, these findings support the ongoing trend toward diet liberalization with regard to non-dairy sources of galactose for children and adults with classic galactosemia.

Biochemical changes and clinical outcomes in 34 patients with classic galactosemia

“…The socioeconomic status of patients could have a significant effect on clinical outcomes (Shulman et al 1991;MacDonald et al 2010;Stockler et al 2012) and this was not formally assessed in our study. However, a recent study of 231 patients with classic galactosemia (Frederick et al 2017) showed no association between family income or parent education level and rigor of child dietary galactose restriction as well as between rigor of non-dairy galactose restriction and long-term outcomes, including growth. The majority of galactosemia females ≥15 yo in group 2 exhibited varying degrees of ovarian function impairment from menstrual irregularities to premature ovarian insufficiency/infertility, and demonstrated abnormal levels of reproductive hormones including AMH (Fig.…”

“…A sample size of 32 (patients 3F and 6M excluded) with an allocation ratio of 1.9 between group 1 and group 2 was adequate to produce 80% power to detect a mean difference in the proportion of galactosemia patients with a negative long-term outcome of 0.55 (conservative estimation based on (Schweitzer et al 1993;Jumbo-Lucioni et al 2012;Frederick et al 2017) withanalphaof0.01inatwo-sidedanalysis.…”

Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions

“…Elevated Gal-1-P is a known competitive substrate for inositol monophosphatase 1 (IMPase1) and various glycosyltransferases and also inhibits UDP-hexose pyrophosphorylases [ 6 , 12 ]. In addition, over-restriction of galactose in the long-term may contribute to the disease phenotype by further depleting UDP-galactose in susceptible individuals, potentially disrupting glycosylation dependent pathways [ 13 , 14 ]. Down-regulation of the key P13K/Akt signalling pathway has also been recently reported in the GALT deficient mouse model [ 15 ].…”

Presentation, progression, and predictors of ovarian insufficiency in classic galactosemia

“…Primary ovarian insufficiency (POI) is one of the most common long-term complications associated with classic galactosemia (CG), impacting a large majority of girls and women with CG despite early detection (Fridovich-Keil et al 2011; Berry 2014) and careful lifelong dietary restriction of galactose (Frederick et al 2017). Details of the presentation and progression of POI in CG have remained unclear, however, as has clarification of a useful prognostic marker for this outcome (Welling et al 2017).…”