Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis

Abstract

X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors.

Brain gene expression in a novel mouse model of postpartum mood disorder

“…In both humans and rodents, STS expression and activity increases in brain and peripheral tissues towards the end of pregnancy and into the postpartum period; hence, enzyme deficiency or dysfunction could potentially be associated with postpartum psychopathology [Davies, 2018;Davies, 2012]. Consistent with this, we have recently shown that women who are heterozygous for genetic mutations encompassing STS are at increased risk of postpartum mood disorders [Cavenagh et al, 2019]. We have also demonstrated that female mice, in which STS activity is acutely, and systemically, inhibited with 667-Coumate shortly after giving birth, show altered maternal behaviour (specifically anxiety-related and startle phenotypes) relative to vehicle-treated mice; these drug-induced behavioural abnormalities can be partially reversed by concurrent administration of the atypical antipsychotic drug ziprasidone .…”

“…STS is expressed in numerous mammalian tissues, with highest expression in the placenta [www.ncbi.nlm.nih.gov/unigene/]; in the developing and adult human brain, relatively high STS expression and activity is seen in the cortex, thalamus, cerebellum, basal ganglia, hipocampus and hypothalamus [Stergiakouli et al, 2011;Perumal and Robins, 1973]. STS deficiency is associated with increased developmental and mood disorder risk and a number of behavioural differences including: inattention, increased impulsivity and altered mood and social function [Cavenagh et al, 2019;Chatterjee et al, 2016;; these behavioural differences may be mediated, in part, by underlying changes in serotonergic or cholinergic function Rhodes et al, 1997].…”

X‐linked ichthyosis: Molecular findings in four pedigrees with inconspicuous clinical manifestations

“…Additionally, most female carriers of XLI are reported to have no detectable clinical symptoms, and scales are rarely seen in the skin. It has been reported that neuropsychiatric disorders predominantly occur in male patients with XLI, and there are few reports regarding the development of neuropsychiatric symptoms in female carriers of XLI . The pregnant woman in Pedigree 4 was a carrier of XLI and had clinical manifestations of risibility, impaired verbal communication, and mental retardation; however, the associations of these clinical symptoms with the deletion of the STS gene remained unknown.…”

Reversal learning performance in the XY* mouse model of Klinefelter and Turner Syndromes

“…Nevertheless, dysregulation of Sts in 40, XXY mice may still occur (e.g., due to skewed X-inactivation – X vs. X Y* – and/or escape from inactivation). Interest in STS as a contributor to phenotypic features of KS remains high because of previous studies in mice (Davies et al, 2009, 2014), and because of the association of STS with cognitive function and deficits in humans (Cavenagh et al, 2019; Chatterjee et al, 2016; Kent et al, 2008; Stergiakouli et al, 2011).…”