Correction: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.
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SUBMITTER: Viollet L
PROVIDER: S-EPMC4554723 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Correction: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.
Viollet Louis L Glusman Gustavo G Murphy Kelley J KJ Newcomb Tara M TM Reyna Sandra P SP Sweney Matthew M Nelson Benjamin B Andermann Frederick F Andermann Eva E Acsadi Gyula G Barbano Richard L RL Brown Candida C Brunkow Mary E ME Chugani Harry T HT Cheyette Sarah R SR Collins Abigail A DeBrosse Suzanne D SD Galas David D Friedman Jennifer J Hood Lee L Huff Chad C Jorde Lynn B LB King Mary D MD LaSalle Bernie B Leventer Richard J RJ Lewelt Aga J AJ Massart Mylynda B MB Mérida Mario R MR Ptáček Louis J LJ Roach Jared C JC Rust Robert S RS Renault Francis F Sanger Terry D TD Sotero de Menezes Marcio A MA Tennyson Rachel R Uldall Peter P Zhang Yue Y Zupanc Mary M Xin Winnie W Silver Kenneth K Swoboda Kathryn J KJ
PloS one 20150831 8
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Project description:Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.
| S-EPMC4440742 | biostudies-literature
Project description: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 the ATP1A3 gene 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. ATP1A3 gene 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 other ATP1A3 mutations-and statistically compared. The Italian cohort has a higher percentage of ATP1A3 gene 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.
| S-EPMC8060701 | biostudies-literature
Project description:Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na+/K+ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p.Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na+/K+ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.
| S-EPMC7125306 | biostudies-literature
Project description:Alternating hemiplegia of childhood (AHC) is a rare and severe neurological disorder. ATP1A3 was recently identified as the causative gene. Here we report the first genetic study in Chinese AHC cohort. We performed whole-exome sequencing on three trios and three unrelated patients, and screened additional 41 typical cases and 100 controls by PCR-Sanger sequencing. ATP1A3 mutations were detected in 95.7% of typical AHC patients. At least 93.3% were de novo. Four late onset, atypical AHC patients were also mutation positive, suggesting the need for testing ATP1A3 mutations in atypical cases. Totally, 13 novel missense mutations (T370N, G706R, L770R, T771N, T771I, S772R, L802P, D805H, M806K, P808L, I810N, L839P and G893R) were identified in our study. By homology modeling of the mutant protein structures and calculation of an extensive list of molecular features, we identified two statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. A logistic regression classifier achieved 92.9% accuracy by the average of 100 times of five-fold cross validations. Genotype-phenotype correlation analysis showed that patients with epilepsy were more likely to carry E815K mutation. In summary, ATP1A3 is the major pathogenic gene of AHC in Chinese patients; mutations have distinctive molecular features that discriminate them from neutral variants and are correlated with phenotypes.
| S-EPMC4026576 | biostudies-literature
Project description: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.
| S-EPMC4671482 | biostudies-literature
Project description:ObjectiveAlternating Hemiplegia of Childhood (AHC) is characterised by paroxysmal hemiplegic episodes and seizures. Remission of hemiplegia upon sleep is a clinical diagnostic feature of AHC. We investigated whether: 1) Hemiplegic events are associated with spectral EEG changes 2) Sleep in AHC is associated with clinical or EEG spectral features that may explain its restorative effect.MethodsWe retrospectively performed EEG spectral analysis in five adults with AHC and twelve age-/gender-matched epilepsy controls. Five-minute epochs of hemiplegic episodes and ten-minute epochs of four sleep stages were selected from video-EEGs. Arousals were counted per hour of sleep.ResultsWe found 1) hemispheric differences in pre-ictal and ictal spectral power (p = 0.034), during AHC hemiplegic episodes 2) 22% reduced beta power (p = 0.017) and 26% increased delta power (p = 0.025) during wakefulness in AHC versus controls. There were 98% more arousals in the AHC group versus controls (p = 0.0003).ConclusionsThere are hemispheric differences in spectral power preceding hemiplegic episodes in adults with AHC, and sleep is disrupted.SignificanceSpectral EEG changes may be a potential predictive tool for AHC hemiplegic episodes. Significantly disrupted sleep is a feature of AHC.
| S-EPMC9524638 | biostudies-literature
Project description: Not available
| S-EPMC2796456 | biostudies-literature
Project description:Alternating hemiplegia of childhood (AHC) is a rare and severe neurodevelopmental disorder characterized by recurrent hemiplegic episodes. Most AHC cases are sporadic and caused by de novo ATP1A3 pathogenic variants. In this study, the aim was to identify the origin of ATP1A3 pathogenic variants in a Chinese cohort. In 105 probands including 101 sporadic and 4 familial cases, 98 patients with ATP1A3 pathogenic variants were identified, and 96.8% were confirmed as de novo. Micro-droplet digital polymerase chain reaction was applied for detecting ATP1A3 mosaicism in 80 available families. In blood samples, four asymptomatic parents, including two paternal and two maternal, and one proband with a milder phenotype were identified as mosaicism. Six (7.5%) parental mosaicisms were identified in multiple tissues, including four previously identified in blood and two additional cases identified from paternal sperms. Mosaicism was identified in multiple tissues with varied mutant allele fractions (MAFs, 0.03%-33.03%). The results suggested that MAF of mosaicism may be related to phenotype severity. This is the first systematic report of ATP1A3 mosaicism in AHC and showed mosaicism as an unrecognized source of previously considered "de novo" AHC. Identifying ATP1A3 mosaicism provides more evidence for estimating recurrence risk and has implications in genetic counseling of AHC.
| S-EPMC6850116 | biostudies-literature
Project description:BackgroundAlternating of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months with recurrent hemiplegia of one or either sides of the body or quadriplegia. The disorder is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene. In AHC neurological co-morbidities are various and frequently reported including developmental delay, epilepsy, tonic or dystonic spells, nystagmus,autonomic manifestations with intrafamilial variability.Case presentationClinical and genetic findings of a couple of twins (Family 1: Case 1 and Case 2) and a couple of siblings (Family 2: Case 3 and Case 4) coming from two different Italian families affected by AHC were deeply examined. In twins of Family 1, a pathogenic variant in ATP1A3 gene (c.2318A>G) was detected. In siblings of Family 2, the younger brother showed a novel GRIN2A variant (c.3175 T > A), while the older carried the same GRIN2A variant, and two missense mutations in SCNIB (c.632 > A) and KCNQ2 (1870 G > A) genes. Clinical manifestations of the four affected children were reported along with cases of AHC drawn from the literature.ConclusionsHemiplegic episode is only a sign even if the most remarkable of several and various neurological comorbidities in AHC affected individuals. Molecular analysis of the families here reported showed that clinical features of AHC may be also the result of an unexpected genetic heterogeneity.
| S-EPMC8851838 | biostudies-literature
Project description: Not available
| S-EPMC5874472 | biostudies-literature