RESUMEN
IQSEC2 is an X-linked gene highly expressed at the excitatory synapses where it plays a crucial role in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and synaptic plasticity. To date, several males and females with severe to profound intellectual disability have been reported harbouring frameshift and nonsense variants in this gene, whereas a milder phenotype has been recognized in females carrying missense pathogenic variants. Here, we report two novel IQSEC2 variants in four females with psychiatric features and otherwise variable cognitive impairment. A female (case 1) with severe verbal language learning disorder and a psychotic episode (precipitated by exposure to anti-contraceptive pill) harboured a de novo pathogenic frameshift variant (c.1170dupG,p.Gln391Alafs*5), whereas the female proband of family 2, displaying severe psychomotor regression and complex psychiatric features carried a missense variant of uncertain significance (c.770G[A,p.Ser257Asn) that was maternally inherited. Skewed X-inactivation was noted in the carrier mother. The maternal aunt, affected by schizophrenia, was found to bear the same IQSEC2 variant. We discuss the variable clinical presentation of IQSEC2 spectrum disorders and the challenging genotype-phenotype correlation, including the possible role of environmental factors as triggers for decompensation. Our report highlights how psychiatric features may be the main clinical presentation in subtle IQSEC2 phenotype, suggesting that the prevalence of IQSEC2 mutations in patients with psychiatric disorders may be underestimated.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/genética , Discapacidad Intelectual/genética , Mutación/genética , Femenino , Genes Ligados a X , Estudios de Asociación Genética , Humanos , Secuenciación del Exoma , Inactivación del Cromosoma XRESUMEN
BACKGROUND: Older adults exhibit declines in auditory and motor functioning, which are compensated for through the recruitment of cognitive resources. Cognitive or physical training alone has been shown to improve cognitive functioning and transfer to motor tasks, but results are mixed when these are combined in studies of healthy older adults, and few studies have included those with age-related hearing loss (ARHL), who are at a higher risk of falls. RESEARCH QUESTION: To examine format effects in mixed training, we used a repeated measures intervention design to compare the efficacy of Simultaneous and Sequential multimodal training formats. METHODS: 42 older adults (Mageâ¯=â¯68.05, SDageâ¯=â¯4.65, femalesâ¯=â¯26) with (ARHL) and without hearing loss (OAH) completed an intervention study consisting of 12 sessions of multimodal training (computerized cognitive dual-task and recumbent aerobic cycling). Participants were randomly assigned to either the Simultaneous (concurrent cognitive and aerobic) or Sequential training group (cognitive followed by aerobic) and completed assessments of single- and dual-task mobility concurrent with an auditory working memory task. Training gains were assessed with repeated measures ANOVAs using magnitude of improvement from pre- to post-training on primary outcome measures as the dependent variable. RESULTS: Gains in auditory working memory were greater in the Sequential group than Simultaneous particularly among OAH. ARHL participants were unaffected by format. While all participants improved on a measure of chair rises, there was no benefit to standing balance. The results demonstrate an advantage to Sequential training, suggesting a benefit to focusing on each task in isolation. SIGNIFICANCE: The gains noted in the ARHL indicate the potential benefit of incorporating cognitive remediation into traditional audiological rehabilitation. Moreover, it is important to consider the cost of dividing attention when combining training.