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Alternating hemiplegia of childhood is a rare neurological disease characterized by paroxysmal movement disorders and chronic neurological disturbances, with onset before 18 months of age. Mutations in theATP1A3gene have been identified in up to 80% of patients. Thirty-nine patients [20 females, 19 males, mean age 25.32 years (7.52–49.34)] have been recruited through the Italian Biobank and Clinical Registry for Alternating Hemiplegia of Childhood. Demographic data, genotype, paroxysmal movement disorders, chronic neurological features, and response to flunarizine have been analyzed.ATP1A3gene mutations have been detected in 92.3% of patients. Patients have been divided into three groups—p.Asp801Asn mutation patients (26%), p.Glu815Lys cases (23%), and patients with otherATP1A3mutations—and statistically compared. The Italian cohort has a higher percentage ofATP1A3gene mutation than reported in literature (92.3%). Our data confirm a more severe phenotype in patients with p.Glu815Lys mutation, with an earlier age of onset of plegic (p= 0.02 in the correlation with other mutations) and tonic attacks. P.Glu815Lys patients most frequently present altered muscle tone, inability to walk (p= 0.01 comparing p.Glu815Lys and p.Asp801Asn mutations), epilepsy, and a more severe grade of dystonia (p< 0.05 comparing p.Glu815Lys and p.Asp801Asn mutations). They have moderate/severe intellectual disability and severe language impairment (p< 0.05). Interestingly, flunarizine seems to be more efficacious in patients with p.Glu815Lys mutation than p.Asp801Asn. In conclusion, our research suggests a genotype–phenotype correlation and provides information on this disorder's features, clinical course, and treatment.

Aim of this study is to evaluate the impact of Precipitation Measurement Biases (PMBs) of tippingbucket rain gauges onto the hydraulic modelling of urban drainage networks. As a case study, the monitored experimental suburban catchment of Parco d’Orleans located in the University Campus of Palermo, Italy and managed since 1987 by the Department of Engineering of the University of Palermo is considered. . Two tipping-bucket rain gauges provide a good spatial coverage of the catchment area and an acoustic level gauge is installed at the outlet of the drainage network for flow mesaurements. Contemporary high temporal resolution rainfall and runoff data series are available between 1993 to 1998, and are used for the calibration of the hydraulic model in terms of roughness of the urban surfaces. The total drainage area is 12.8 ha with 68% of impervious areas; the drainage network is composed of circular and egg-shaped concrete conduits. In the present work, the sensitivity of this rapid response system to the accuracy of the rainfall input is studied, with reference to drainage failures and urban flooding issues. In order to quantify the instrumental mechanical error of the two available Tipping Bucket Rain-gauges, these were calibrated at the rain gauge laboratory of the WMO Lead Centre on Precipitation Intensity “B. Castelli” following the procedure described in the recent EN 17277:2019 standard on precipitation measurements. For each gauge a calibration curve was provided in order to quantify the measurement bias and the associated calibration uncertainty. For rainfall-runoff transformation in the urban drainage system, a conceptual model for urban catchment, which incorporates semi-distributed modelling concepts has been used. The urban basin is divided in external sub-catchments connected to the drainage network. Each external subcatchment is modelled as two separate conceptual linear elements, a reservoir and a channel, one for the pervious part, the other for the impervious part of the investigated area. The drainage network is schematized as a cascade of non-linear cells and the flood routing is simplified in the form of kinematic wave and represented as a flux transfer between adjacent cells. The sensitivity of this rapid response system to the accuracy of the rainfall input has been studied with reference to drainage failures and urban flooding issues. To examine the effects due to PMBs on the catchment response, a number of simulations were carried out using raw rainfall data and corrected data obtained after the application of the calibration curve for each rain gauge. Results, expressed in terms of comparisons between the hydrographs at catchment outlet, show a significant influence of the PMB on the peak flow and the total hydrograph volume.

Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve., Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term ‘alternating hemiplegia’. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

Item does not contain fulltext Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the alpha3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.

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