Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X‐linked ichthyosis)

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age‐related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory‐related processes in humans. We investigated self‐reported memory performance (Multifactorial Memory Questionnaire), word‐picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X‐linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI‐associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory‐related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non‐carriers (n = 34,522). We found poorer word‐picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI‐associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally‐significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non‐carriers. In humans, constitutive STS deficiency appears associated with mood‐independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally. Animals in which the steroid sulphatase protein is absent or non‐functional show evidence for enhanced memory and longevity. Here we show that, in contrast, humans carrying deletions of the STS gene show poorer memory performance (and more adverse mood symptoms) than non‐carriers, but no differences from controls regarding associated neuroanatomy.