Ovarioleukodystrophy due to EIF2B5 mutations.

Ovarioleukodystrophy-the co-occurrence of leukodystrophy and premature ovarian failure-is a rare presentation now recognised to be part of the clinical spectrum of vanishing white matter disease. We describe a woman with epilepsy and neuroimaging changes consistent with leukoencephalopathy who presented with non-convulsive status epilepticus after starting hormone replacement therapy in the context of premature ovarian failure. Genetic testing confirmed her to be a compound heterozygote for EIF2B5 mutations; the gene encodes a subunit of eukaryotic translation initiation factor 2B. Mutations in EIF2B1-5 result in vanishing white matter disease. We highlight the importance of ovarian failure as a diagnostic pointer to eukaryotic translation initiation factor 2B (eIF2B)-related ovarioleukodystrophy and present a brief literature review of ovarioleukodystrophy.

Small vessel disease disrupts EEG postural brain networks in 'unexplained dizziness in the elderly'.

OBJECTIVE: To examine the hypothesis that small vessel disease disrupts postural networks in older adults with unexplained dizziness in the elderly (UDE). METHODS: Simultaneous electroencephalography and postural sway measurements were undertaken in upright, eyes closed standing, and sitting postures (as baseline) in 19 younger adults, 33 older controls and 36 older patients with UDE. Older adults underwent magnetic resonance imaging to determine whole brain white matter hyperintensity volumes, a measure of small vessel disease. Linear regression was used to estimate the effect of instability on electroencephalographic power and connectivity. RESULTS: Ageing increased theta and alpha desynchronisation on standing. In older controls, delta and gamma power increased, and theta and alpha power reduced with instability. Dizzy older patients had higher white matter hyperintensity volumes and more theta desynchronisation during periods of instability. White matter hyperintensity volume and delta power during periods of instability were correlated, positively in controls but negatively in dizzy older patients. Delta power correlated with subjective dizziness and instability. CONCLUSIONS: Neural resource demands of postural control increase with age, particularly in patients with UDE, driven by small vessel disease. SIGNIFICANCE: EEG correlates of postural control saturate in older adults with UDE, offering a neuro-physiological basis to this common syndrome.

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

An fMRI study of visuo-vestibular interactions following vestibular neuritis.

Vestibular neuritis (VN) is characterised by acute vertigo due to a sudden loss of unilateral vestibular function. A considerable proportion of VN patients proceed to develop chronic symptoms of dizziness, including visually induced dizziness, specifically during head turns. Here we investigated whether the development of such poor clinical outcomes following VN, is associated with abnormal visuo-vestibular cortical processing. Accordingly, we applied functional magnetic resonance imaging to assess brain responses of chronic VN patients and compared these to controls during both congruent (co-directional) and incongruent (opposite directions) visuo-vestibular stimulation (i.e. emulating situations that provoke symptoms in patients). We observed a focal significant difference in BOLD signal in the primary visual cortex V1 between patients and controls in the congruent condition (small volume corrected level of p < .05 FWE). Importantly, this reduced BOLD signal in V1 was negatively correlated with functional status measured with validated clinical questionnaires. Our findings suggest that central compensation and in turn clinical outcomes in VN are partly mediated by adaptive mechanisms associated with the early visual cortex.