Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Givinostat Comparing cognitive and clinical measures across

    2018-10-30

    Comparing cognitive and clinical measures across all case groups and controls (Table 2) showed group effects for all measures, except physical anhedonia, and WAIS Perceptual Organization, Verbal Comprehension, and Working Memory indexes. Examining symptoms among case groups showed significant effects for psychopathology (p<.008), with SLC39A13 carriers having the most severe symptoms and being significantly more symptomatic than TGM5 and non-carriers. SLC39A13 had the highest mania and negative symptoms and it was noteworthy that it was the only group to show a preponderance of negative versus positive symptoms, although not statistically significant in these small samples. Scores for social and physical anhedonia and social adjustment did not differ significantly across these groups. Multiple separate ANCOVA analyses comparing each Givinostat carrier group to the non-carriers, adjusting for sex, age, and age of onset showed SLC39A13 had higher scores for general psychopathology (F[1,27]=10∙45, p=.003) and activation (F[1,27]=8.79, p=.006) meeting the studies Bonferroni corrected significance level of <.01, with other consistent but only marginally significant results for autism (F[1,27]=6.17, p=.02), PANSS negative scale scores (F[1,27]=5.28, p=.03) and negative factor scores (F[1,27]=5.52, p=.026). Findings for more social anhedonia (F[1,29]=3.99, p=.055) and worse social function (F[1,29]=3.94, p=.057) were also consistent with the negative symptoms but did not reach study criteria for significance. The ARMS/KIDINS220 carriers demonstrated the highest autistic factor scores of any group (F[1,26]=5.51, P=.027). By contrast, ratings for TGM5 carriers were similar in all measures to the non-carrier group of cases and these two groups had the lowest positive symptoms scores. PANSS symptoms configured into factors are shown in Fig. 1. The profiles are of interest although the differences did not achieve significance. The groups showed similar positive symptoms (F=1.5 (4,35), p=.22), with marginal group effects for negative (F=2.2 (4,35), p=.09), activation (F=2.4 (4,35), p=.07), and dysphoric mood factors (F=2.3 (4,35), p=.08). The severe symptoms of the SLC39A13 carriers drove these effects (higher negative symptoms than TGM5, ARMS/KIDINS220, and non-carriers; higher activation scores than TGM5; and higher dysphonic mood scores than TGM5 and non-carrier cases). The trend-level group difference in the autistic factor (F=3.1 (4,35), p=.027) was driven by higher autistic scores for the ARMS/KIDINS220 variant carriers. Cognitive data is presented in Fig. 2a for IQ scores and 2b for the WAIS indices. The WAIS Processing Speed Index (PSI), a measure of one\'s ability to process simple visual information quickly and to efficiently perform tasks based on that information, significantly differed based on gene groups (p<.008). Other comparisons, while not significant, suggest diverse profiles of cognitive functioning. TGM5 carriers were the slowest and this index was their weakest compared to all other indexes. ARMS/KIDINS220 demonstrated the second slowest processing speed but they scored similarly on all of the cognitive measures. PTPRG carriers had the fastest PSI, but they (and SLC39A13 carriers) showed weakness on the Working Memory index, which is a measure of short-term memory skills, concentration, and the ability to mentally manipulate information. As PSI Givinostat was notably better than the other WAIS indices for SLC39A13, impairment in this domain is unlikely to have driven their pathology.
    Discussion Despite the relatively small numbers of cases with genetic alterations in these particular signaling genes, this study demonstrated different multilevel phenotypes for groups of cases with schizophrenia-related psychoses based on which of the sequenced genes harbored rare missense coding polymorphisms or novel mutations in PTPRG, SLC39A13, TGM5, and ARMS/KIDINS220. The allele frequencies of all rare missense coding polymorphisms was <2% in accordance to the respective ethnicity. Moreover, it is noteworthy that some of these rare polymorphisms have not been annotated yet in the respective ethnicity group in the 1000 Genomes project (Table 3). These results suggest that a meaningful proportion of the genetic complexity of the psychoses may be resolved by focussing on the CNS signaling genes that had been identified as harboring de novo missense coding variants in sporadic cases. Previous large-scale studies performing whole exome sequencing in schizophrenia cases (familial and non-related individuals) showed that rare polymorphisms and mutations are enriched in genes involved in synaptic plasticity and neuronal development (Purcell et al., 2014; Fromer et al., 2014) and our analysis of the multilevel phenotypes for several such genes show this body of work may be relevant for the development of precision treatment. In concordance with other large-scale analyses, these findings support the contention that schizophrenia is not a single disease, but is a group of distinct disorders for which major influential genes harboring rare disruptive variants may be discerned (Arnedo et al., 2015) and for which specific treatments may be developed.