Background Pathogenic CASK variants are associated with neurodevelopmental disorders of variable severity including X-linked intellectual disability (XLID) and microcephaly with pontocerebellar hypoplasia (MICPCH). Although the number of diagnosed cases is rising, current understanding of the CASK-related neurodevelopmental spectrum is limited. Here, we systematically review the published characteristics of individuals with CASK-related disorder, and compare these to a more recently-diagnosed group. We provide quantitative information about the ranges of adaptive abilities, motor function, visual function and social-emotional-behavioural characteristics, and explore within-group associations. Methods One hundred and fifty-one individuals with CASK variants were identified in published literature. Thirty-one children and young people with CASK variants were recruited to the UK-based Brain and Behaviour in Neurodevelopmental disorders of Genetic Origin (BINGO) project. BINGO-participating caregivers completed a bespoke medical history questionnaire and battery of standardised neurodevelopmental measures. Results Comparing the recently diagnosed BINGO CASK-related disorder group to previously reported individuals, we found consistent prevalence of tone abnormalities, sensorineural hearing loss and epilepsy, but lower prevalence of severe/profound ID, MICPCH, optic atrophy and nystagmus. Areas of frequent difficulty not highlighted in previous reports include sleep difficulties and cerebral visual impairment (CVI). Neurodevelopmental characteristics were highly variable within the BINGO CASK-related disorder group, and group-wide patterns were similar to those observed in other rare genetic conditions. Within the BINGO CASK-related group, epilepsy is significantly associated with ID severity, after controlling for age. Sub-groups with MICPCH or microcephaly only have equivalent ranges of adaptive function, but MICPCH may be associated with more severe motor difficulties. Conclusion The spectrum of neurodevelopmental characteristics associated with CASK-related disorder appears to be broadening with increased access to genome-wide diagnostic testing. Further studies are needed to elucidate the relationships between CASK variants, structural brain development, epilepsy, and neurodevelopmental characteristics.

Background Impaired phonological short-term memory is a core feature of the logopenic variant of primary progressive aphasia (lvPPA), but it is not clear whether a core phonological processing deficit is also present. Methods We asked three questions: (i) beyond short-term memory impairment, do lvPPA patients have an impairment within phonology itself?; (ii) is their performance in working memory and naming reflective of this phonological impairment?; and (iii) is their repetition performance related to structural and functional differences in key language-dominant regions? We compared non-word and word repetition and short-term memory performance in patients with typical Alzheimer’s disease (tAD), lvPPA per consensus criteria, and others who previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (lvPPA+). Results Bayesian analyses revealed no group differences in phonological tasks of word and non-word repetition. We found very strong evidence for an effect of self-reported hearing loss on word and non-word repetition, but not multi-syllabic word/phrase repetition. A comparison of phonological versus working memory and naming tasks produced either no evidence or evidence for no correlation. Beyond the expected grey matter reductions in patients relative to controls, there was anecdotal evidence for an association between non-word repetition and functional connectivity between dorsal premotor and posterior superior temporal gyrus regions in patients. Conclusions Our results indicated that, in the absence of self-reported hearing loss, patients did not exhibit impairments in tasks tapping “pure” phonological processing. Our results suggest that instead of having a core phonological impairment, lvPPA patients have a working memory/buffering impairment.

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Whiteside et al. find that brain imaging can reveal temporal lobe atrophy related to semantic dementia around 3–5 years before symptom onset. Whereas clini