Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson’s coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I–V β = −1.06, P < 0.001; lobules VI–VII β = −0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion

Functional imaging of human crossmodal identification and object recognition

The perception of objects is a cognitive function of prime importance. In everyday life, object perception benefits from the coordinated interplay of vision, audition, and touch. The different sensory modalities provide both complementary and redundant information about objects, which may improve recognition speed and accuracy in many circumstances. We review crossmodal studies of object recognition in humans that mainly employed functional magnetic resonance imaging (fMRI). These studies show that visual, tactile, and auditory information about objects can activate cortical association areas that were once believed to be modality-specific. Processing converges either in multisensory zones or via direct crossmodal interaction of modality-specific cortices without relay through multisensory regions. We integrate these findings with existing theories about semantic processing and propose a general mechanism for crossmodal object recognition: The recruitment and location of multisensory convergence zones varies depending on the information content and the dominant modality

Abrupt environmental and climatic change during the deposition of the Early Permian Haushi limestone, Oman

During the late Sakmarian (Early Permian), the Haushi limestone was deposited in a shallow embayment of the Neotethys Ocean covering what is now north Oman and parts of southeast Saudi Arabia. The sea persisted through the late Sakmarian, but by the time of the deposition of the ?Artinskian Middle Gharif Member, limestone deposition had ceased and generally arid fluvial and minor lacustrine palaeonvironments in a low accommodation space setting had become established. Analysis of three subsurface cored boreholes and other surface sections of the Haushi limestone shows an upward change in microfacies from bryonoderm to molechfor associations reflecting the passage from heterozoan to photozoan communities. The biotic turnover indicates cooler climate and eutrophy in the lower parts of the unit and an upward trend towards warmer climate and more oligotrophic conditions in the upper part. Common autochthonous algal palynomorphs and high δ13Corg in the lower part suggest that high nutrient levels were due to greater fluvial runoff, while allochthonous pollen assemblages indicate that the climate of the hinterland became more arid through the deposition of the unit, causing upward increasing seawater trends in δ18Ocarb. Several extraneous factors are likely to have contributed to this palaeoenvironmental change, which was more abrupt than in other parts of post glacial Early Permian Gondwana. First, the Haushi sea, being an embayment partially isolated by Hawasina rift shoulder uplift, was more vulnerable to changes in rainfall and runoff than an open sea. Second, continued post glacial global warming and small northward movement of Gondwana may have contributed to temperature increase. Aridity may have been caused by the onset of monsoons and the influence of rift shoulders to the northeast and southeast