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BACKGROUND: ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. AIM: We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. METHODS: A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. RESULTS: Patients (age 2.5-20â¯years) had symptom onset at an early age (6â¯days-1â¯year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3â¯years, range 6â¯weeks-4.8â¯years) with some improvements reported in all five. CONCLUSIONS: Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.
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Encefalopatías , Epilepsia , Adolescente , Adulto , Niño , Preescolar , Humanos , Mutación/genética , Estudios Retrospectivos , ATPasa Intercambiadora de Sodio-Potasio/genética , Adulto JovenRESUMEN
AIM: To evaluate presence and severity of social impairments in alternating hemiplegia of childhood (AHC) and determine factors that are associated with social impairments. METHOD: This was a retrospective analysis of 34 consecutive patients with AHC (19 females, 15 males; mean age: 9y 7mo, SD 8y 2mo, range 2y 7mo-40y), evaluated with the Social Responsiveness Scale, Second Edition (SRS-2). RESULTS: SRS-2 scores, indicating level of social impairment, were higher than population means (75, SD 14 vs 50, SD 10, p<0.001). Of these, 27 out of 34 had high scores: 23 severe (>76), four moderate (66-76). All subscale domains, including social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior, had abnormal scores compared to population means (p<0.001). High SRS-2 scores were associated with the presence of autism spectrum disorder (ASD) and epilepsy (p=0.01, p=0.04), but not with other scales of AHC disease symptomatology. All nine patients who received formal evaluations for ASD, because they had high SRS-2 scores, were diagnosed with ASD. INTERPRETATION: Most patients with AHC have impaired social skills involving multiple domains. ASD is not uncommon. High SRS-2 scores in patients with AHC support referral to ASD evaluation. Our findings are consistent with current understandings of the pathophysiology of AHC and ASD, both thought to involve GABAergic dysfunction. WHAT THIS PAPER ADDS: Most patients with alternating hemiplegia of childhood (AHC) have impaired social skills involving multiple domains. These impairments are significant compared to population means. Most patients with AHC have high Social Responsiveness Scale, Second Edition (SRS-2) scores. Patients with AHC with high SRS-2 scores are likely to have autism spectrum disorder.
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Trastorno del Espectro Autista/diagnóstico , Epilepsia/diagnóstico , Hemiplejía/diagnóstico , Discapacidad Intelectual/diagnóstico , Escalas de Valoración Psiquiátrica , Percepción Social , Habilidades Sociales , Adolescente , Adulto , Trastorno del Espectro Autista/etiología , Niño , Preescolar , Femenino , Hemiplejía/complicaciones , Humanos , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
AIM: To determine the neuropsychological abnormalities that occur in alternating hemiplegia of childhood (AHC) and report on our experience in managing them. METHOD: Patients underwent evaluations according to our standardized AHC pathway. Data were entered into our prospective AHC database and then analyzed. RESULTS: Of the cohort of 25 consecutive patients (ages 15mo-42y), eight had initial chief complaints about cognition, 14 language, five attention, and 11 behavior. As compared to population norms means, neuropsychological and behavioral assessment tools (including Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, and Wechsler Intelligence Quotient tests) showed significant impairments in multiple domains: cognition, expressive and receptive language, executive function/attention, and behavior (p<0.05 in all comparisons). Evaluations generated management recommendations in all patients. Twenty had neuropsychiatric diagnoses: 10 attention-deficit/hyperactivity disorder (ADHD), seven disruptive behavior, and three anxiety disorder. Eight out of nine patients with ADHD who were prescribed medications responded to pharmacotherapy. INTERPRETATION: Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. This supports the hypothesis that the underlying AHC pathophysiology involves diffuse neuronal dysfunction. Testing generated recommendations to help manage these difficulties. Patients with AHC also have a range of neuropsychiatric diagnoses, the most common being ADHD which responds to pharmacotherapy. WHAT THIS PAPER ADDS: Patients with alternating hemiplegia of childhood (AHC) have developmental difficulties with underlying neuropsychological impairments. The findings in this study are consistent with an underlying AHC pathophysiology which involves diffuse neuronal, probably largely GABAergic, dysfunction. Patients with AHC have a range of neuropsychiatric diagnoses, the most common being attention-deficit/hyperactivity disorder.
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Adaptación Psicológica/fisiología , Trastorno por Déficit de Atención con Hiperactividad/etiología , Trastornos del Conocimiento/etiología , Manejo de la Enfermedad , Hemiplejía , Adolescente , Adulto , Niño , Preescolar , Trastornos del Conocimiento/terapia , Femenino , Hemiplejía/complicaciones , Hemiplejía/genética , Hemiplejía/psicología , Hemiplejía/terapia , Humanos , Lactante , Inteligencia , Pruebas de Inteligencia , Masculino , Mutación/genética , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , ATPasa Intercambiadora de Sodio-Potasio/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: To characterize motor function profiles in alternating hemiplegia of childhood, and to investigate interrelationships between these domains and with age. METHOD: We studied a cohort of 23 patients (9 males, 14 females; mean age 9y 4mo, range 4mo-43y) who underwent standardized tests to assess gross motor, upper extremity motor control, motor speech, and dysphagia functions. RESULTS: Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure-88 (GMFM-88), Manual Ability Classification System (MACS), and Revised Melbourne Assessment (MA2) scales manifested predominantly mild impairments; motor speech, moderate to severe; Modified Dysphagia Outcome and Severity Scale (M-DOSS), mild-to moderate deficits. GMFCS correlated with GMFM-88 scores (Pearson's correlation, p=0.002), MACS (p=0.038), and MA2 fluency (p=0.005) and accuracy (p=0.038) scores. GMFCS did not correlate with motor speech (p=0.399), MA2 dexterity (p=0.247), range of motion (p=0.063), or M-DOSS (p=0.856). Motor speech was more severely impaired than the GMFCS (p<0.013). There was no correlation between any of the assessment tools and age (p=0.210-0.798). INTERPRETATION: Our data establish a detailed profile of motor function in alternating hemiplegia of childhood, argue against the presence of worse motor function in older patients, identify tools helpful in evaluating this population, and identify oropharyngeal function as the more severely affected domain, suggesting that brain areas controlling this function are more affected than others.
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Hemiplejía , Trastornos del Movimiento , Índice de Severidad de la Enfermedad , Trastornos del Habla , Adolescente , Adulto , Niño , Preescolar , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Femenino , Hemiplejía/complicaciones , Hemiplejía/diagnóstico , Hemiplejía/fisiopatología , Humanos , Lactante , Masculino , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/etiología , Trastornos del Movimiento/fisiopatología , Trastornos del Habla/diagnóstico , Trastornos del Habla/etiología , Trastornos del Habla/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Non-sleep related apnea (NSA) has been observed in alternating hemiplegia of childhood (AHC) but has yet to be characterized. GOALS: Investigate the following hypotheses: 1) AHC patients manifest NSA that is often severe. 2) NSA is usually triggered by precipitating events. 3) NSA is more likely in patients with ATP1A3 mutations. METHODS: Retrospective review of 51 consecutive AHC patients (ages 2-45 years) enrolled in our AHC registry. NSAs were classified as mild (not needing intervention), moderate (needing intervention but not perceived as life threatening), or severe (needing intervention and perceived as life threatening). RESULTS: 19/51 patients (37 %) had 52 NSA events (6 mild, 11 moderate, 35 severe). Mean age of onset of NSA (± Standard Error of the Mean (SEM)): 3.8 ± 1.5 (range 0-24) years, frequency during follow up was higher at younger ages as compared to adulthood (year 1: 2.2/year, adulthood: 0.060/year). NSAs were associated with triggering factors, bradycardia and with younger age (p < 0.008 in all) but not with mutation status (p = 0.360). Triggers, observed in 17 patients, most commonly included epileptic seizures in 9 (47 %), anesthesia, AHC spells and intercurrent, stressful, conditions. Management included use of pulse oximeter at home in nine patients, home oxygen in seven, intubation/ventilatory support in seven, and basic CPR in six. An additional patient required tracheostomy. There were no deaths or permanent sequalae. CONCLUSIONS: AHC patients experience NSAs that are often severe. These events are usually triggered by seizures or other stressful events and can be successfully managed with interventions tailored to the severity of the NSA.
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Apnea , Epilepsia , Niño , Humanos , Mutación , Hemiplejía/genética , Convulsiones , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
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.
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Cannabidiol , Hemiplejía , Humanos , Cannabidiol/uso terapéutico , Cannabidiol/efectos adversos , Cannabidiol/administración & dosificación , Estudios Retrospectivos , Hemiplejía/tratamiento farmacológico , Hemiplejía/etiología , Femenino , Masculino , Niño , Preescolar , Adolescente , Flunarizina/uso terapéutico , Resultado del TratamientoRESUMEN
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.
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Hemiplejía , Trastornos del Neurodesarrollo , Niño , Humanos , Estudios Prospectivos , Hemiplejía/diagnóstico , Convulsiones , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/diagnósticoRESUMEN
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.
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Hemiplejía , Convulsiones , Humanos , Estudios de Seguimiento , Hemiplejía/diagnóstico , Hemiplejía/etiología , CuidadoresRESUMEN
Mutations in the ATP1A3 gene (which encodes the main α subunit in neuronal Na+/K+-ATPases) cause various neurological syndromes including alternating hemiplegia of childhood. This rare disorder is characterized by paroxysmal episodes of hemiplegia, dystonia, oculomotor abnormalities, and occasionally developmental regression. Approximately 50% of alternating hemiplegia of childhood patients also have epilepsy, which is either focal or generalized. Seizures are often drug resistant. We report a 10-year-old girl with the D801N ATP1A3 mutation and alternating hemiplegia of childhood who manifested with drug-resistant focal seizures as an infant and throughout childhood. At the age of about10.5 years, her epilepsy evolved into electrical status epilepticus in sleep with generalized discharges. These changes coincided with developmental regression consistent with epileptic encephalopathy. Additionally, MRI and MR spectroscopy showed new cortical atrophy and markedly depressed N-acetyl aspartate peaks compared to previous normal studies. Electrical status epilepticus in sleep resolved after medication adjustments. She, now, only four months after her diagnosis of electrical status epilepticus in sleep, has regained most of the skills that were lost only a few months earlier. Our observations document that alternating hemiplegia of childhood can result in the above-described unique features; particularly, progression of focal epilepsy to electrical status epilepticus in sleep with generalized features and reversible epileptic encephalopathy.
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Epilepsias Parciales , Epilepsia Generalizada , Hemiplejía , Sueño , Estado Epiléptico , Niño , Progresión de la Enfermedad , Epilepsias Parciales/genética , Epilepsias Parciales/fisiopatología , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatología , Femenino , Hemiplejía/genética , Hemiplejía/fisiopatología , Humanos , Mutación , Sueño/fisiología , ATPasa Intercambiadora de Sodio-Potasio/genética , Estado Epiléptico/genética , Estado Epiléptico/fisiopatologíaRESUMEN
BACKGROUND: Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. GOALS: Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications. METHODS: Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency). STATISTICS: Fisher Exact test, Spearman correlations. RESULTS: These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation. CONCLUSIONS: During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.
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Anestesia , Apnea , Anestesia/efectos adversos , Hemiplejía , Humanos , Convulsiones , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
BACKGROUND: Many central nervous system disorders result in hypothalamic-pituitary (HP) axis dysfunction. Alternating Hemiplegia of Childhood (AHC) is usually caused by mutations in the ATP1A3 subunit of the Na+/K+ ATPase, predominantly affecting GABAergic interneurons. GABAergic interneurons and the ATP1A3 subunit are both important for function of the hypothalamus. However, whether HP dysfunction occurs in AHC and, if so, how such dysfunction manifests remains to be investigated. METHODS: We conducted a retrospective review of a cohort of 50 consecutive AHC patients for occurrence of HP related manifestations and analyzed the findings of the 6 patients, from that cohort, with such manifestations. RESULTS: Six out of 50 AHC patients manifested HP dysfunction. Three of these patients were mutation positive and 3 were mutation negative. Of the 6 patients with HP dysfunction, 3 had central precocious puberty. A fourth had short stature due to growth hormone deficiency. Two other patients had recurrent episodes of fever of unknown origin (FUO) diagnosed, after workups, as being secondary to central fever. All patients were evaluated and co-managed by pediatric neurology and endocrinology or rheumatology. CONCLUSION: AHC was associated with HP dysfunction in about 12% of patients. Awareness of such dysfunction is important for anticipatory guidance and management particularly in the case of FUO which often presents a diagnostic dilemma. Our findings are also consistent with current understandings of the underlying pathophysiology of AHC and of the HP axis.
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Hemiplejía/complicaciones , Enfermedades Hipotalámicas/epidemiología , Enfermedades Hipotalámicas/etiología , Sistema Hipotálamo-Hipofisario , Adolescente , Adulto , Anciano , Niño , Preescolar , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Background Pathogenic variation in the ATP1A3-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12-lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype-negative status, and significantly shorter in patients with the ATP1A3-D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3-D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3-D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype-negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3-D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life-threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.
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Bradicardia , Hemiplejía , ATPasa Intercambiadora de Sodio-Potasio , Fibrilación Ventricular , Arritmias Cardíacas , Bradicardia/genética , Preescolar , Susceptibilidad a Enfermedades , Femenino , Genotipo , Hemiplejía/genética , Humanos , Masculino , Mutación , ATPasa Intercambiadora de Sodio-Potasio/genética , Fibrilación Ventricular/genéticaRESUMEN
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.
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BACKGROUND: Alternating hemiplegia of childhood often manifests severe or extreme behavioral problems, the nature of which remains to be fully characterized. METHODS: We analyzed 39 consecutive patients with alternating hemiplegia of childhood for occurrence of behavioral problems and categorized those by severity: mild (not requiring intervention), moderate (requiring intervention but no risk), severe (minor risk to self, others, or both), and extreme (major risk). We then analyzed behavioral manifestations, concurrent morbidity, and medication responses in patients with severe or extreme symptoms. RESULTS: Two patients had mild behavioral problems, five moderate, 10 severe, six extreme, and 16 none. Extreme cases exhibited disruptive behaviors escalating to assaults. Triggers, when present, included peer-provocation, low frustration tolerance, limits set by others, and sleep disruption. Reversible psychotic symptoms occurred in two patients: in one triggered by infection and trihexyphenidyl, and in another triggered by sertraline. Of the 16 patients with severe or extreme symptoms, 13 had concurrent neuropsychiatric diagnoses. Occurrence of severe or extreme symptoms did not correlate with age, puberty, severity of intellectual disability, or mutation status (P > 0.05). A multidisciplinary team including mental health professionals comanaged all patients with severe or extreme symptoms with either behavioral therapy, medications, or both. When considering medications prescribed to more than four patients, medicines that demonstrated efficacy or partial efficacy in more than 50% of patients were alpha-adrenergic agonists and selective-serotonin-reuptake-inhibitors. CONCLUSIONS: Patients with alternating hemiplegia of childhood (41%) often experience severe or extreme behavioral problems and, rarely, medication-triggered psychotic symptoms. These observations are consistent with current understanding of underlying alternating hemiplegia of childhood brain pathophysiology. Increasing awareness of these behavioral problems facilitates alternating hemiplegia of childhood management and anticipatory guidance.
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Síntomas Conductuales/etiología , Hemiplejía/complicaciones , Trastornos Psicóticos/etiología , Adolescente , Adulto , Agresión/fisiología , Síntomas Conductuales/fisiopatología , Niño , Preescolar , Femenino , Hemiplejía/genética , Hemiplejía/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/fisiopatología , Conducta Autodestructiva/etiología , Conducta Autodestructiva/fisiopatología , Índice de Severidad de la Enfermedad , Ideación Suicida , Violencia , Adulto JovenRESUMEN
BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is caused by mutations of the ATP1A3 gene which is expressed in brain areas that include structures controling autonomic, gastrointestinal, gut motility and GABAergic functions. We aimed to investigate, in a cohort of 44 consecutive AHC patients, two hypotheses: 1) AHC patients frequently manifest gastrointestinal, particularly motility, problems. 2) These problems are often severe and their severity correlates with neurological impairments. RESULTS: 41/44 (93%) exhibited gastrointestinal symptoms requiring medical attention. For these 41 patients, symptoms included constipation (66%), swallowing problems (63%), vomiting (63%), anorexia (46%), diarrhea (44%), nausea (37%), and abdominal pain (22%). Symptoms indicative of dysmotility occurred in 33 (80%). The most common diagnoses were oropharyngeal dysphagia (63%) and gastroesophageal reflux (63%). 16 (39%) required gastrostomy and two fundoplication. Severity of gastrointestinal symptoms correlated with non-paroxysmal neurological disability index, Gross Motor Function Classification System scores, and with the presence/absence of non-gastrointestinal autonomic dysfunction (p = 0.031, 0.043, Spearman correlations and 0.0166 Cramer's V, respectively) but not with the paroxysmal disability index (p = 0.408). CONCLUSIONS: Most AHC patients have gastrointestinal problems. These are usually severe, most commonly are indicative of dysmotility, often require surgical therapies, and their severity correlates with that of non-paroxysmal CNS manifestations. Our findings should help in management-anticipatory guidance of AHC patients. Furthermore, they are consistent with current understandings of the pathophysiology of AHC and of gastrointestinal dysmotility, both of which involve autonomic and GABAergic dysfunction.
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Hemiplejía , ATPasa Intercambiadora de Sodio-Potasio , Humanos , Mutación , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
OBJECTIVE: To describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset. METHODS: Review and analysis of clinical and genetic data. RESULTS: Patients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia. CONCLUSIONS: D-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.
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Quantitative MRI is increasingly being used as a biomarker in neurological disorders. Cerebellar atrophy occurs in some Alternating Hemiplegia of Childhood (AHC) patients. However, it is not known if cerebellar atrophy can be a potential biomarker in AHC or if quantitative MRI is a reliable method to address this question. Here we determine the reproducibility of an MRI-volumetrics method to investigate brain volumes in AHC and apply it to a population of 14 consecutive AHC patients (ages 4-11 years). We studied method reproducibility in the first 11 patients and then performed correlation of cerebellar volumes, relative to published normal population means, with age in all 14. We used FreeSurfer 6.0.0 to automatically segment MRI images, then performed manual resegmentation correction by two different observers. No significant differences were observed in any of ten brain regions between the two reviewers: p > .591 and interclass Correlation Coefficient (ICC) ≥0.975 in all comparisons. Additionally, there were no significant differences between the means of the two reviewers and the automatic segmentation values: p ≥ .106 and ICC ≥0.994 in all comparisons. We found a negative correlation between cerebellar volume and age (R = -0.631, p = .037), even though only one patient showed any cerebellar atrophy upon formal readings of the MRIs by neuroradiology. Sample size did not allow us to rule out potential confounding variables. Thus, findings from this cross-sectional study should be considered as exploratory. Our study supports the prospective investigation of quantitative MRI-volumetrics of the cerebellum as a potential biomarker in AHC.
Asunto(s)
Cerebelo/diagnóstico por imagen , Hemiplejía/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Cerebelo/patología , Niño , Preescolar , Estudios Transversales , Femenino , Hemiplejía/patología , Humanos , Masculino , Proyectos Piloto , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
Asunto(s)
Ataxia Cerebelosa/genética , Deformidades Congénitas del Pie/genética , Pérdida Auditiva Sensorineural/genética , Hemiplejía/genética , Mutación/genética , Atrofia Óptica/genética , Reflejo Anormal/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Adolescente , Adulto , Ataxia Cerebelosa/metabolismo , Ataxia Cerebelosa/terapia , Niño , Preescolar , Estudios de Cohortes , Femenino , Deformidades Congénitas del Pie/metabolismo , Deformidades Congénitas del Pie/terapia , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/terapia , Hemiplejía/diagnóstico , Hemiplejía/terapia , Humanos , Lactante , Masculino , Persona de Mediana Edad , Atrofia Óptica/metabolismo , Atrofia Óptica/terapia , Fenotipo , Convulsiones/terapia , Adulto JovenRESUMEN
OBJECTIVE: To report our experience and investigate 5 original hypotheses: (1) multiple types of epileptic seizures occur in alternating hemiplegia of childhood (AHC), and these can be the initial presentation; (2) epileptiform abnormalities often appear well after clinical seizures; (3) nonepileptic reduced awareness spells (RAS) occur frequently; (4) epilepsy is commonly drug resistant but may respond to vagal nerve stimulation (VNS); and (5) status epilepticus (SE) is common and is usually refractory and recurrent. METHODS: We analyzed a cohort of 51 consecutive patients with AHC. RESULTS: Thirty-two of 51 patients had epilepsy: 18 focal seizures, frontal more frequently than temporal, and then posterior. Eleven had primary generalized seizures (tonic-clonic, myoclonic, and/or absence). Epileptic seizures preceded other AHC paroxysmal events in 8 (lag 5.63 ± 6.55 months; p = 0.0365). In 7 of 32, initial EEGs were normal, with the first epileptiform EEG lagging behind by 3.53 ± 4.65 years (p = 0.0484). RAS occurred equally in patients with epilepsy (16 of 32) and patients without epilepsy (10 of 19, p = 1.0). Twenty-eight patients had video-EEG; captured RAS showed no concomitant EEG changes. Nineteen patients (59%) were drug resistant. VNS resulted in >50% reduction in seizures in 5 of 6 (p < 0.04). Twelve patients (38%) had SE (9 of 12 multiple episodes), refractory/superrefractory in all (p < 0.001), and 4 of 12 had regression after SE. CONCLUSIONS: Epilepsy in AHC can be focal or generalized. Epileptic seizures may be the first paroxysmal symptom. EEG may become epileptiform only on follow-up. Epilepsy, although frequently drug resistant, can respond to VNS. RAS are frequent and nonepileptic. SE often recurs and is usually refractory/superrefractory. Our observations are consistent with current data on AHC-ATP1A3 pathophysiology.
Asunto(s)
Epilepsia/fisiopatología , Hemiplejía/fisiopatología , Convulsiones/fisiopatología , Estado Epiléptico/etiología , Adolescente , Adulto , Niño , Preescolar , Electroencefalografía/métodos , Epilepsia/diagnóstico , Femenino , Hemiplejía/diagnóstico , Humanos , Lactante , Recién Nacido , Masculino , Convulsiones/diagnóstico , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Estado Epiléptico/fisiopatología , Estimulación del Nervio Vago/efectos adversos , Adulto JovenRESUMEN
STUDY OBJECTIVES: Patients with alternating hemiplegia of childhood (AHC) experience bouts of hemiplegia and other paroxysmal spells that resolve during sleep. Patients often have multiple comorbidities that could negatively affect sleep, yet sleep quality and sleep pathology in AHC are not well characterized. This study aimed to report sleep data from both polysomnography (PSG) and clinical evaluations in children with AHC. METHODS: We analyzed nocturnal PSG and clinical sleep evaluation results of a cohort of 22 consecutive pediatric patients with AHC who were seen in our AHC multidisciplinary clinic and who underwent evaluations according to our comprehensive AHC clinical pathway. This pathway includes, regardless of presenting symptoms, baseline PSG and evaluation by a board-certified pediatric sleep specialist. RESULTS: Out of 22 patients, 20 had at least one type of sleep problem. Six had obstructive sleep apnea as documented on polysomnogram, of whom two had no prior report of sleep-disordered breathing symptoms. Patients had abnormal mean overall apnea-hypopnea index of 5.8 (range 0-38.7) events/h and an abnormal mean arousal index of 15.0 (range 4.8-46.6) events/h. Based on sleep history, 16 patients had difficulty falling asleep, staying asleep, or both; 9 had behavioral insomnia of childhood; and 2 had delayed sleep-wake phase syndrome. CONCLUSIONS: Sleep dysfunction is common among children with AHC. Physicians should routinely screen for sleep pathology, with a low threshold to obtain a nocturnal PSG.