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

Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies

The spectrum of epilepsy with eyelid myoclonia: delineation of disease subtypes from a large multicenter study

Objective Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. Methods In this multicenter retrospective cohort study, we included 267 EEM patients from nine countries. Data on electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy, and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia involving body regions other than eyelids (body-MYO). Results Kernel density estimation revealed a trimodal distribution of AEO, and Fisher-Jenks optimization disclosed three EEM subgroups: early onset (EO-EEM), intermediate onset (IO-EEM), and late onset (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness, and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. Significance Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians toward a more accurate classification and prognostic profiling of EEM patients

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

Συσχέτιση των μοριακών διαταραχών του γονιδίου της νόσου Wilson (ATP7B) με τον κλινικό και βιοχημικό φαινότυπο της νόσου

Wilson disease is an autosomal recessive genetic condition, characterised by the accumulation of copper in the body and particularly in the liver and brain. Patients left without treatment (chelation therapy) present neurological signs and/or hepatic disease. Wilson disease is caused by mutations in the ATP7B gene and exhibits substantial allelic heterogeneity. In this study we report the results of molecular analysis of 93 patients from 69 unrelated families. Twenty different mutations accounted for 86% of the WND chromosomes. The most frequent were p.H1069Q (35%), p.R969Q (12%), c.2530delA (7%), p.L936X (7%), p.Q289X (7%), and p.I1148T (3%). We also present here a detailed phenotypic assessment, clinical and biochemical, for all patients. Thirty cases were homozygous for 9 different mutations, 13 of which were homozygous for p.H1069Q, and 7 for R969Q. Mutations p.H1069Q and p.R969Q appeared to confer a milder disease as patients showed disease onset at a later age, and were associated with milder severity. Predicted nonsense and frameshift mutations were associated with severe phenotypic expression with earlier disease onset and lower ceruloplasmin values. WND can be treated by copper-chelation therapy, particularly if the disease is diagnosed before irreversible tissue damage occurs and for that reason, early diagnosis is very important. With the development of a new methodology we succeeded a more rapid (DGGE method) and more accurate (sequencing) diagnosis of the disease. Our results on the genotype-phenotype correlation and on the effect of predicted nonsense and frameshift mutations are especially important for early medical intervention in presymptomatic infants and children with these genotypes.Η νόσος Wilson είναι μία αυτοσωματική υπολειπόμενη γενετική νόσος, η οποία έχει ως χαρακτηριστικό της τη συσσώρευση του χαλκού στον οργανισμό και ιδιαιτέρως στο ήπαρ και στον εγκέφαλο. Ασθενείς χωρίς θεραπεία (χηλικούς παράγοντες) εμφανίζουν νευρολογικά συμπτώματα και / ή ηπατική προσβολή. Προκαλείται από μεταλλάξεις στο γονίδιο ATP7B, το οποίο εμφανίζει πληθώρα διαφορετικών μεταλλάξεων. Στην παρούσα μελέτη αναφέρουμε τα αποτελέσματα της μοριακής ανάλυσης 93 ασθενών από 69 μη συγγενικές μεταξύ τους οικογένειες. Είκοσι διαφορετικές μεταλλάξεις είναι υπεύθυνες για το 86% των χρωμοσωμάτων της νόσου. Η πιο συχνές ήταν οι p.H1069Q (35%), p.R969Q (12%), c.2530delA (7%), p.L936X (7%), p.Q289X (7%) και p.I1148T (3%). Ο λεπτομερής κλινικός και βιοχημικός φαινότυπος καταγράφηκε για όλους τους ασθενείς. 30 ασθενείς ήταν ομοζυγώτες για 9 διαφορετικές μεταλλάξεις, 13 από αυτούς ήταν ομόζυγοι για τη μετάλλαξη p.H1069Q και 7 για την p.R969Q. Οι μεταλλάξεις p.H1069Q και p.R969Q φαίνεται ότι συνδυάζονται με μία ηπιότερη νόσο, καθώς οι ασθενείς εκδήλωσαν τη νόσο σε μεγαλύτερη ηλικία και είχαν μία ηπιότερη κλινική εικόνα. Οι ανερμηνεύσιμες μεταλλάξεις και οι μεταλλάξεις που αλλάζουν το πλαίσιο ανάγνωσης συνδυάσθηκαν με σοβαρή φαινοτυπική έκφραση με πιο πρώιμη εκδήλωση των κλινικών συμπτωμάτων και με χαμηλότερα επίπεδα σερουλοπλασμίνης. Η νόσος Wilson είναι μία από τις σπάνιες γενετικές νόσους για τις οποίες υπάρχει αποτελεσματική θεραπεία ιδιαιτέρως αν διαγνωσθεί προτού προκληθούν ανεπανόρθωτες ιστικές βλάβες και για αυτό το λόγο η έγκαιρη διάγνωσή της έχει ιδιαίτερη σημασία. Με την προτυποποίηση νέας μεθοδολογίας συμβάλλαμε στην ταχύτερη (μέθοδος DGGE) και πιο αποτελεσματικότερη (sequencing) διάγνωση της νόσου. Τα αποτελέσματά μας της συσχέτισης του γονοτύπου με το φαινότυπο και της επίδρασης των ανερμηνεύσιμων μεταλλάξεων και των μεταλλάξεων που αλλάζουν το πλαίσιο ανάγνωσης, είναι ιδιαιτέρως σημαντικά για μία ενωρίς ιατρική επέμβαση σε προσυμπτωματικά βρέφη και παιδιά με αυτό το γονότυπο

ALG3-CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation

Congenital disorders of glycosylation (CDG) are a group of inborn errors of metabolism presenting with heterogeneous multisystemic clinical manifestations. To date, more than 60 different types of CDG have been reported. ALG3-CDG is very rare, with only nine patients described so far. We report two affected siblings presenting prenatally with skeletal abnormalities associated with dysmorphic features, cerebellar vermis hypoplasia, corpus callosum agenesis, hepatic fibrosis and poor prognosis. This is the first detailed report of an affected fetus including clinical, radiographic and pathological findings. The patients showed some clinical features previously unreported in ALG3-CDG, such as bone dysplasia, cataract, corneal opacities, and pons hypoplasia. Both patients were homozygous for the previously unreported p.Gly96Arg mutation of the ALG3 gene. One patient showed chondrodysplasia punctata (CDP), which has not been previously reported in CDG. An exhaustive genetic and metabolic assessment, performed in order to rule out other possible causes of CDP, showed abnormally raised levels of anti-nuclear antibodies in the mother who, nevertheless, did not show any clinical sign of autoimmune disease during a 7 years follow-up. We speculate that the observed CDP may be explained by the maternal anti-nuclear antibodies; alternatively, a possible link to the underlying metabolic disorder cannot be ruled out. In conclusion, we report the clinical, pathological, biochemical and molecular characterization of two further patients affected by ALG3-CDG, expanding the phenotypic spectrum of this very rare disease. © 2015 Wiley Periodicals, Inc.status: publishe