Alec Aeby

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: A case-control study

BACKGROUND Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING European Unions Seventh Framework Programme; European Research Council.

Levetiracetam efficacy in epileptic syndromes with continuous spikes and waves during slow sleep : Experience in 12 cases

Summary:  Purpose: To assess the add‐on efficacy of levetiracetam on the EEG, behavior, and cognition of children with continuous spikes and waves during slow sleep (CSWS).

Mutation of a potassium channel–related gene in progressive myoclonic epilepsy

We investigated a large consanguineous Moroccan family with progressive myoclonic epilepsy (PME) consistent with autosomal recessive inheritance, to describe the phenotype and identify the causal gene.

Structural asymmetries in motor and language networks in a population of healthy preterm neonates at term equivalent age: A diffusion tensor imaging and probabilistic tractography study

In this MRI study, we aimed to provide new in vivo structural markers of asymmetry in motor and language networks in a population of healthy preterm neonates scanned at term equivalent age. Using diffusion tensor imaging and probabilistic tractography, we showed that, besides volume and microstructural asymmetries in the parieto-temporal part of the superior longitudinal fasciculus (SLF) and a trend towards microstructural asymmetry in the corticospinal tract (CST), volume asymmetry in the motor part of the superior thalamic radiations (STR) and a trend towards volume asymmetry in the CST are already present in the neonatal period. No asymmetry was found in the sensory part of the STR, the anterior thalamic radiations (ATR), and posterior thalamic radiations (PTR) neither in the fronto-parietal part of the SLF. These results suggest that structural asymmetries in the motor and language networks are present in healthy preterm neonates at term equivalent age, well before the development of speech and hand preference.

Maturation of Thalamic Radiations between 34 and 41 Weeks' Gestation: A Combined Voxel- Based Study and Probabilistic Tractography with Diffusion Tensor Imaging

BACKGROUND AND PURPOSE: This study aimed to investigate brain maturation along gestational age with diffusion tensor imaging in healthy preterm and term neonates. Therefore, a voxel-based study of fractional anisotropy (FA) and mean diffusivity (Dav) was performed to reveal the brain regions experiencing microstructural changes with age. With tractography, the authors intended to identify which fiber tracts were included in these significant voxels. MATERIALS AND METHODS: There were 22 healthy preterm and 6 healthy term infants who underwent MR imaging between 34 and 41 weeks of gestation. A statistical parametric approach was used to evidence the effect of age on regional distribution of FA and Dav values. The fiber tracts suspected to be included in the significant clusters of voxels were identified with neuroanatomy and tractography atlases, reconstructed with probabilistic tractography, and superimposed on the parametric maps. RESULTS: Parametric analysis showed that FA increases with age in the subcortical projections from the frontal (motor and premotor areas) and parietal cortices, the centrum semiovale, the anterior and posterior arms of the internal capsules, the optic radiations, the corpus callosum, and the thalami (P < .05, corrected). Superimposition of the parametric maps on tractography showed that the corticospinal tract (CST); the callosal radiations (CR); and the superior, anterior, and posterior thalamic radiations were included in the significant voxels. No statistically significant results were found for Dav maps. CONCLUSIONS: These results highlight that, besides the already-evidenced FA increase in the CST and CR, the thalami and the thalamic radiations experience microstructural changes in the early development of the human brain.

Coexistence of Idiopathic Rolandic Epilepsy and CSWS in Two Families

Summary:  Purpose: To report two families combining benign childhood epilepsy with centrotemporal spikes (BCECS) and cryptogenic epilepsy with continuous spike–waves during sleep (CSWS) in first‐degree relatives.

Language development at 2 years is correlated to brain microstructure in the left superior temporal gyrus at term equivalent age: A diffusion tensor imaging study

This study aims at testing the hypothesis that neurodevelopmental abilities at age 2 years are related with local brain microstructure of preterm infants at term equivalent age. Forty-one preterm infants underwent brain MRI with diffusion tensor imaging sequences to measure mean diffusivity (MD), fractional anisotropy (FA), longitudinal and transverse diffusivity (λ// and λ[perpendicular]) at term equivalent age. Neurodevelopment was assessed at 2 years corrected age using the Bayley III scale. A voxel-based analysis approach, statistical parametric mapping (SPM8), was used to correlate changes of the Bayley III scores with the regional distribution of MD, FA, λ// and λ[perpendicular]. We found that language abilities are negatively correlated to MD, λ// and λ[perpendicular] in the left superior temporal gyrus in preterm infants. These findings suggest that higher MD, λ// and λ[perpendicular] values at term-equivalent age in the left superior temporal gyrus are associated with poorer language scores in later childhood. Consequently, it highlights the key role of the left superior temporal gyrus for the development of language abilities in children. Further studies are needed to assess on an individual basis and on the long term the prognostic value of brain DTI at term equivalent age for the development of language.

Gender Differences in Language and Motor-Related Fibers in a Population of Healthy Preterm Neonates at Term-Equivalent Age: A Diffusion Tensor and Probabilistic Tractography Study

BACKGROUND AND PURPOSE: Sex differences in white matter structure are controversial. In this MR imaging study, we aimed to investigate possible sex differences in language and motor-related tracts in healthy preterm neonates by using DTI and probabilistic tractography. MATERIALS AND METHODS: Thirty-eight preterm neonates (19 boys and 19 girls, age-matched), healthy at term-equivalent age and at 12 months were included. TBV was measured individually. Probabilistic tractography provided tract volumes, relative tract volumes (volume normalized to TBV), FA, MD, and λ⊥ in the SLF, in the TRs, and in the CSTs. Data were compared by using independent t tests, and Bonferroni corrections were performed to adjust for multiple comparisons. RESULTS: We showed that healthy preterm boys had larger TBV than girls. However, girls had statistically significantly larger relative tract volumes than boys bilaterally in the parieto-temporal SLF, and in the left CST. Moreover, in the left parieto-temporal SLF, a trend toward lower MD and λ⊥ was observed in females. CONCLUSIONS: Structural sex differences were found in preterm neonates at term-equivalent age in both sides of the parieto-temporal SLF and in the left CST. Further studies are necessary to investigate whether these structural differences are related to later sex differences in language skills and handedness or to the effect of prematurity.

Cutaneous histopathological findings of Aicardi–Goutières syndrome, overlap with chilblain lupus

We report a 2‐year‐old girl with developmental delay who, from the age of 1 year, developed perniotic lesions of the hands and feet initially diagnosed as chilblain lupus. Histological examination showed features of epidermal necrosis with intraepidermal bulla formation, interface dermatitis, lymphocytic vasculitis with fibrinoid necrosis and thrombi formation, both superficial and deep dermal lymphocytic infiltrate, lymphocytic eccrine hidradenitis and absence of marked dermal edema. Subsequent investigations suggested a clinical diagnosis of Aicardi–Goutières syndrome (AGS), a rare genetic leukoencephalopathy. Recently, both AGS and familial chilblain lupus, an autosomal dominant form of systemic lupus erythematosus (SLE), have been shown to be allelic thus suggesting a common pathogenic basis. In addition, a phenotypic overlap is apparent between SLE and AGS. To our knowledge, this is the first comprehensive dermatopathological report of the cutaneous lesions seen in AGS, and our paper highlights the importance of considering AGS in the differential diagnosis of perniosis and chilblain lupus.