Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood\u2014a study of 155 patients

Background: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. Methods: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. Results: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. Conclusions: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trial

Polyhandicap and aging

International audienc

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases

Euclid. I. Overview of the Euclid mission

The current standard model of cosmology successfully describes a variety of measurements, but the nature of its main ingredients, dark matter and dark energy, remains unknown. Euclid is a medium-class mission in the Cosmic Vision 2015-2025 programme of the European Space Agency (ESA) that will provide high-resolution optical imaging, as well as near-infrared imaging and spectroscopy, over about 14,000 deg^2 of extragalactic sky. In addition to accurate weak lensing and clustering measurements that probe structure formation over half of the age of the Universe, its primary probes for cosmology, these exquisite data will enable a wide range of science. This paper provides a high-level overview of the mission, summarising the survey characteristics, the various data-processing steps, and data products. We also highlight the main science objectives and expected performance

Euclid. I. Overview of the Euclid mission

International audienceThe current standard model of cosmology successfully describes a variety of measurements, but the nature of its main ingredients, dark matter and dark energy, remains unknown. Euclid is a medium-class mission in the Cosmic Vision 2015-2025 programme of the European Space Agency (ESA) that will provide high-resolution optical imaging, as well as near-infrared imaging and spectroscopy, over about 14,000 deg^2 of extragalactic sky. In addition to accurate weak lensing and clustering measurements that probe structure formation over half of the age of the Universe, its primary probes for cosmology, these exquisite data will enable a wide range of science. This paper provides a high-level overview of the mission, summarising the survey characteristics, the various data-processing steps, and data products. We also highlight the main science objectives and expected performance