Baby food and bedtime: Evidence for opposite phenotypes from different genetic and epigenetic alterations in Prader-Willi and Angelman syndromes

Abstract

Prader–Willi and Angelman syndromes are often referred to as a sister pair of neurodevelopmental disorders, resulting from different genetic and epigenetic alterations to the same chromosomal region, 15q11-q13. Some of the primary phenotypes of the two syndromes have been suggested to be opposite to one another, but this hypothesis has yet to be tested comprehensively, and it remains unclear how opposite effects could be produced by changes to different genes in one syndrome compared to the other. We evaluated the evidence for opposite effects on sleep and eating phenotypes in Prader–Willi syndrome and Angelman syndrome, and developed physiological–genetic models that represent hypothesized causes of these differences. Sleep latency shows opposite deviations from controls in Prader–Willi and Angelman syndromes, with shorter latency in Prader–Willi syndrome by meta-analysis and longer latency in Angelman syndrome from previous studies. These differences can be accounted for by the effects of variable gene dosages of UBE3A and MAGEL2, interacting with clock genes, and leading to acceleration (in Prader–Willi syndrome) or deceleration (in Angelman syndrome) of circadian rhythms. Prader–Willi and Angelman syndromes also show evidence of opposite alterations in hyperphagic food selectivity, with more paternally biased subtypes of Angelman syndrome apparently involving increased preference for complementary foods (“baby foods”); hedonic reward from eating may also be increased in Angelman syndrome and decreased in Prader–Willi syndrome. These differences can be explained in part under a model whereby hyperphagia and food selectivity are mediated by the effects of the genes SNORD-116, UBE3A and MAGEL2, with outcomes depending upon the genotypic cause of Angelman syndrome. The diametric variation observed in sleep and eating phenotypes in Prader–Willi and Angelman syndromes is consistent with predictions from the kinship theory of imprinting, reflecting extremes of higher resource demand in Angelman syndrome and lower demand in Prader–Willi syndrome, with a special emphasis on social–attentional demands and attachment associated with bedtime, and feeding demands associated with mother-provided complementary foods compared to offspring-foraged family-type foods.

An overview of health issues and development in a large clinical cohort of children with Angelman syndrome

“…One‐third of our cohort showed hyperphagia as was reported previously in children with AS (Barry, Leitner, Clarke, & Einfeld, ; Mertz, Christensen, et al, ; Salminen et al, ; Welham et al, ; Williams et al, ). In the Danish cohort children with UPD showed significantly more hyperphagia, leading the authors to the hypothesis of a role for paternal gene overexpression, as discussed with the higher weight association (Mertz, Christensen, et al, ).…”

“…Both biological and behavioral factors may influence sleep in AS. In mouse models a mechanistic connection was found between the lack of UBE3A expression, interaction with clock genes, and changes in sleep–wake cycle (Ehlen et al, ; Salminen, Crespi, & Mokkonen, ; Shi, Bichell, Ihrie, & Johnson, ). Behavioral treatment on the other hand can have a positive effect on sleep problems in AS (Allen, Kuhn, DeHaai, & Wallace, ).…”

Why and How Imprinted Genes Drive Fetal Programming

“…Optimal post-natal development for paternal genes engenders vigorous and frequent sucking and rapid early growth (when growth is food-limited rather than hormone-regulated, and involves growth in lean mass as well as fat), delayed weaning, enhanced solicitation of both complementary foods and later, other-provided "family" foods (in comparison to self-feeding), and delayed puberty that lengthens the overall period of dependence (11,14,21,22).…”

“…Maternal gene optima also involve postnatal growth that does not involve statural "catch-up" during early infancy, which is energetically costly via lactation. Such offspring are instead expected to put on relatively more fat (white adipose tissue) in infancy and childhood, as a low-metabolic rate store of food; they are also expected to reduce and delay acceptance of complementary foods (which are also costly to mothers), instead transitioning relatively early to self-foraging and self-feeding (6,22). Overall, these maternal-gene optima reflect the maternal energetic tradeoff between investment in current vs. future offspring, whereby the inclusive fitness of mothers is maximized by producing more offspring but investing less in each.…”

“…In humans, lactation is normally supplemented by feeding of 'baby foods' (so-called "complementary" foods) (13, 71) some months after birth. Individuals with Angelman syndrome, involving a paternal gene bias, show evidence of 'picky' eating with preference for such foods, which are costly to mothers to acquire and process (22). By contrast, individuals with Prader-Willi syndrome, involving a maternal-gene bias, show highly indiscriminate food choice and high rates of self-foraging, in association with hyperphagia.…”