Real life retrospective study of cannabidiol therapy in alternating hemiplegia of childhood.

BACKGROUND: Many alternating hemiplegia of childhood (AHC) patients have received Cannabidiol (CBD) but, to our knowledge, there are no published data available. GOALS: Test the hypothesis that CBD has favorable effects on AHC spells. METHODS: Retrospective review of available data of AHC patients who received CBD. Primary analysis: Clinical Global Impression Scale of Improvement (CGI-I) score for response of AHC spells to CBD with calculation of 95% confidence interval (CI) for rejection of the null hypothesis. Secondary analyses, performed to achieve an understanding of the effect of CBD as compared to flunarizine, were CGI-I scores of 1) epileptic seizures to CBD, 2) AHC spells to flunarizine, 3) epileptic seizures to flunarizine. Also, Mann-Whitney test was done for comparison of CGI-I scores of CBD and flunarizine to both AHC spells and seizures. RESULTS: We studied 16 AHC patients seen at Duke University and University of Lyon. CI of CGI-I scores for AHC spells in response to CBD and to flunarizine, each separately, indicated a positive response to each of these two medications: neither overlapped with the null hypothesis score, 4, indicating significant positive responses with p < 0.05 for both. These two scores also did not differ (p = 0.84) suggesting similar efficacy of both: CBD score was 2 ± 1.1 with a 95% CI of 1.5-2.6 and flunarizine score was 2.3 ± 1.3 with a 95% CI of 1.7-3.1. In patients who had seizures, CI calculations indicated a positive effect of CBD on seizure CGI scores but not of flunarizine on seizure scores. CBD was well tolerated with no patients discontinuing it due to side effects and with some reporting positive behavioral changes. CONCLUSION: Our study indicates a real-life positive effect of CBD on AHC type spells.

Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na+/K+ ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1), SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.

Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease.

Here, we describe the process of development of the methodology for an international multicenter natural history study of alternating hemiplegia of childhood as a prototype disease for rare neurodevelopmental disorders. We describe a systematic multistep approach in which we first identified the relevant questions about alternating hemiplegia of childhood natural history and expected challenges. Then, based on our experience with alternating hemiplegia of childhood and on pragmatic literature searches, we identified solutions to determine appropriate methods to address these questions. Specifically, these solutions included development and standardization of alternating hemiplegia of childhood-specific spell video-library, spell calendars, adoption of tailored methodologies for prospective measurement of nonparoxysmal and paroxysmal manifestations, unified data collection protocols, centralized data platform, adoption of specialized analysis methods including, among others, Cohen kappa, interclass correlation coefficient, linear mixed effects models, principal component, propensity score, and ambidirectional analyses. Similar approaches can, potentially, benefit in the study of other rare pediatric neurodevelopmental disorders.

Development and testing of methods to record and follow up spells in patients with alternating hemiplegia of childhood.

BACKGROUND: Developing methods to record Alternating Hemiplegia of Childhood (AHC) spells is essential for clinical trials and patient care. OBJECTIVES: Test the following hypotheses: 1) Video-library training improves participants' ability to correctly identify AHC spells. 2) A custom-designed event-calendar with weekly reviews results in consistent documentation of such events over time. 3) Use of an electronic diary (e-Diary) to register events is a useful tool. METHODS: 1) A video-library of AHC type spells was developed along with specific training; the effect of the training was tested in 36 caregivers. 2) An event-calendar was similarly developed and provided to 5 caregivers with weekly videoconference meetings for 8 weeks. 3) An e-Diary was developed and offered to 33 patients; time of usage and caregivers' feedback (telephone interview) were analyzed. RESULTS: 1) Video-library training: Wilcoxon test showed improvement in caregiver identification of spells (p = 0.047), Cohen's Kappa demonstrated high degree of agreement between caregivers'-experts' classifications (>0.9). 2) Event-calendar: 96.42% of entries had complete information; this did not change during follow up (p = 0.804). 3) e-Diary: whereas 52% of respondents used the e-Diary when offered (duration: 10.5 ± 8.1 months), 96.3% indicated they would use it in future studies. Those who used it for 13 months, were very likely to use it during the rest of that year. CONCLUSIONS: Video-library training improved spell identification. Calendar with weekly reviews resulted in a sustained and consistent record keeping. Caregivers' e-Diary feedback was encouraging with long-term usage in many. These approaches could be helpful for AHC and, potentially, in similar disorders.

Alternating hemiplegia of childhood: evolution over time and mouse model corroboration.

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort (n = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool- mice at prepubescent and adult ages (n = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: P < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score (P = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score (P = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial (P = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score (P = 0.001) and first and last non-paroxysmal disability index score scores significantly differed (P = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3-related neurodegeneration.

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a 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 trials.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

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 <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

Biobanking from the patient perspective.

PLAIN ENGLISH SUMMARY: Biobanks are collections of donations of biological material (DNA, cells, tissue etc.) and related data which are very valuable for research into human diseases. A variety of biobanks exist for example within hospitals, research institutes, pharmaceutical companies and patient organisations. The role of patients in biobanking is changing from being seen simply as donors, to actual collaborators in the design, development and the running of biobanks. In this article, we provide a number of examples of patients acting as partners at the heart of biobanking, where their voice and perspective is being seen and used as a valuable resource for the biobank. Our aim is that these examples can be used by those who work with patients in biobank-based research, to design future strategies for patient and public involvement in all biobanks. ABSTRACT: Biobanks and biobanking research plays an increasingly important role in healthcare research and delivery as health systems become more patient-centred and medicine becomes more personalised. There is also growing acceptance and appreciation of the value that patients, patient advocacy organisations and the public can bring as stakeholders in biobanking and more generally in research. Therefore, the importance of active, early and sustained engagement and involvement of patient and public representatives in biobanks will become increasingly relevant. Organising and facilitating patient and public involvement in biobanking takes considerable time and effort for all stakeholders involved. Therefore, for any biobank operator considering involving patients and the public in their biobanking activities, consideration of best practices, current guidance, ethical issues and evaluation of involvement will be important. In this article, we demonstrate that patients are much more than donors to biobanks-they are collaborators at the heart of biobanking with an important voice to identify perspective, which can be an extremely valuable resource for all biobanks to utilise. The case studies herein provide examples of good practice of patient involvement in biobanking as well as outcomes from these practices, and lessons learned. Our aim is to provide useful insights from these efforts and potential future strategies for the multiple stakeholders that work with patients and the public involved in biobank-based research.

Alternating hemiplegia of childhood: metabolic studies in the largest European series of patients.

Alternating hemiplegia of childhood (AHC) is a rare disorder with diagnosis based on clinical criteria, as no laboratory, neuroradiological or genetic markers are currently available. The pathogenic mechanisms are still an enigma. Some hypotheses have been proposed such as hemiplegic migraine variant, epileptic mechanism, channelopathy and mitochondrial disorder, but none of these has been confirmed. Our aim was to analyze the results of metabolic studies performed on a series of 157 European patients who fulfilled diagnostic criteria for AHC. We tried to find a common metabolic abnormality, related with AHC. We did not find significant abnormalities in basic metabolic screening, at different ages. Neurotransmitters in cerebrospinal fluid (n = 26) were normal in all of the patients. Mitochondrial respiratory chain enzyme activities were analyzed in 19 muscle biopsies; in 4 cases, different MRC enzyme deficiencies were demonstrated, ranging from mild-unspecific deficiencies to more profound and probably primary defects. Although we did not find specific metabolic markers in our series, some metabolic disorders such as pyruvate dehydrogenase deficiency, MELAS, cerebral glucose transporter defect and neurotransmitter deficiency can exhibit symptoms similar to those of AHC and need to be ruled out before a diagnosis of AHC can be established. Further studies including high-throughput diagnostic technologies seem necessary to elucidate the etiology of this severe and enigmatic disorder.

Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults.

Alternating hemiplegia of childhood is a neurological disorder characterized by episodes of hemiplegia, various non-epileptic paroxysmal events and global neurological impairment. Characterization of the evolution and outcome into adulthood has not been sufficiently investigated. The goal of this study was to elucidate the natural history of alternating hemiplegia within a large cohort of 157 patients, as part of the European Network for Research on Alternating Hemiplegia project. A questionnaire was formulated to determine the severity of both paroxysmal and global neurological impairment and address progression of the disorder by allocating data to specific age epochs up to and over 24 years of age. Patients in early age groups were consistently present in subsequent later age groups and for each patient, data were collected for each corresponding age epoch. The study was based on predominantly retrospective and, for a period of 2 years, prospective data. At inclusion, patients were aged from 9 months to 52 years. The median age at diagnosis was 20 months. All patients experienced hemiplegic attacks; 86.5% reported episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation. When data over the course of the illness were examined for the whole cohort, the severity of symptoms did not appear to change, with the exception of abnormal ocular movements and hypotonia that regressed, but did not disappear into adulthood (from 86 to 36% and 76 to 36%, respectively). No statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurological outcome was identified. Seven patients died, some of whom experienced severe plegic attacks or epileptic seizures at the time of death. History of severe plegic/dystonic attacks was not found to be an aggravating factor for deceased patients. Our results provide evidence that the natural history of alternating hemiplegia is highly variable and unpredictable for individual patients. However, we did not find evidence to support a steadily progressive and degenerative course of the disorder when patients were analysed as a group. For a minority of patients, a risk of sudden death was associated with more severe neurological impairment. The European Network for Research on Alternating Hemiplegia Registry, validated by our study, includes all major neurological signs and symptoms of alternating hemiplegia and may thus be used as a precedent for the progressive inclusion and follow-up of patients as well as a reference for genetic studies and treatment trials.