Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits

Molecular genetics of autosomal dominant retinitis pigmentosa (ADRP): a comprehensive study of 43 Italian families

Retinitis pigmentosa is the most common form of retinal degeneration and is heterogeneous both clinically and genetically. The autosomal dominant forms ( ADRP) can be caused by mutations in 12 different genes. This report describes the first simultaneous mutation analysis of all the known ADRP genes in the same population, represented by 43 Italian families. This analysis allowed the identification of causative mutations in 12 of the families (28% of the total). Seven different mutations were identified, two of which are novel (458delC and 6901C --> T (P2301S), in the CRX and PRPF8 genes, respectively). Several novel polymorphisms leading to amino acid changes in the FSCN2, NRL, IMPDH1, and RP1 genes were also identified. Analysis of gene prevalences indicates that the relative involvement of the RHO and the RDS genes in the pathogenesis of ADRP is less in Italy than in US and UK populations. As causative mutations were not found in over 70% of the families analysed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of ADRP

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU. Methods: Subjects included patients with SMA aged 2 months–60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2–6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study. Results: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment. Interpretation: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam

Mesozoic rift magmatism in the North Sea region: Ar-40/Ar-39 geochronology of Scanian basalts and geochemical constraints

More than 100 volcanic necks composed of basanites and melanephelinites occur in Scania, southern Sweden, at the junction of two major tectonic lineaments, the Phanerozoic Sorgenfrei-Tornquist Zone (STZ) and the Proterozoic Protogine Zone. New Ar-40/Ar-39 isotope analyses of whole rock fragments of nine selected basalt necks suggest that the Mesozoic alkaline volcanism in the Scanian province commenced earlier than previously reported and comprised three separate volcanic episodes that span a total period of ca. 80 Myr: a first Jurassic (191-178 Ma), a second at the Jurassic/Cretaceous boundary (ca. 145 Ma), and a final middle Cretaceous episode (ca. 110 Ma). The new results allow for precise time correlations between eruption events in the Scanian and those in the North Sea volcanic provinces. The older, early Jurassic event in Scania is largely synchronous with that in the Egersund Basin and the Forties field whereas the event at ca. 145 Ma is correlated with activity in the Central Graben. These volcanic episodes also correlate in age with Kimmerian tectonic activity. Volcanic activity in the middle Cretaceous period has also been dated in the triple junction in the North Sea and offshore in the Netherland Sector. The correlation of basalt volcanism in Scania with the Egersund nephelinites strongly suggest that volcanism was triggered by repeated tectonic activity along the STZ. Geochemical data of alkaline mafic rocks in the Scanian and the North Sea volcanic provinces imply that different provinces have largely unique geochemical signatures in favour of a heterogeneous mantle in the North Sea volcanic region. However, basalts of different generations in one and the same province cannot be readily separated on the basis of geochemistry, suggesting that the same lithospheric mantle was the source of repeated volcanism over time in each province. The data suggest a low degree of melting of a volatile-bearing mantle lherzolite enriched in incompatible elements with the exception of the Forties basalts in the rift centre, produced by larger degree of melting and evolved by fractional crystallization