Glut1 deficiency and alternating hemiplegia of childhood.
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ABSTRACT:
SUBMITTER: Rotstein M
PROVIDER: S-EPMC2796456 | biostudies-literature | 2009 Dec
REPOSITORIES: biostudies-literature
Publications
Glut1 deficiency and alternating hemiplegia of childhood.
Rotstein M M Doran J J Yang H H Ullner P M PM Engelstad K K De Vivo D C DC
Neurology 20091201 23
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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: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
Project description:Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by recurrent paroxysmal hemiplegic attacks that affect one or the other side of the body. Up to 74% of patients with AHC have a pathologic variant in the ATP1A3 gene. After the introduction of next-generation sequencing, intermediate cases and atypical cases have expanded the clinical spectrum of ATP1A3-related disorders. Herein, we report the first case of AHC in Korea. A 33-year-old man visited our hospital with recurrent hemiplegic and dystonic episode after his first birthday. He was completely normal between episodes and did not have any ataxia, but brain magnetic resonance imaging showed cerebellar atrophy. He also had pes planovalgus deformity. Whole exome sequencing revealed a heterozygous G947R variant in the ATP1A3 gene (c.2839G > C, rs398122887), which is a known pathologic variant. This atypical case of AHC demonstrates the importance of the clinical approach in diagnosing ATP1A3-related disorders.
| S-EPMC7338211 | biostudies-literature
Project description:BackgroundAlthough described as non-progressive, alternating hemiplegia of childhood (AHC) can display a sudden deterioration, anecdotally reported mainly in childhood. Outcome in adulthood is uncertain.ObjectivesAim of this study is to describe the long-term follow-up of neurological function in adults with AHC.MethodsSeven adults with AHC were included in this retrospective single-center study. Clinical history and previous investigation data were gathered from the review of medical records. Video-documented neurological examination was performed at the last follow-up visit in four out of the seven reported indivisuals.ResultsOver a median follow-up of 16 years, neurological outcome and trajectories were heterogeneous. All individuals showed new neurological signs or symptoms. Three experienced a serious irreversible neurological deterioration after prolonged quadriplegic episodes and/or status epilepticus in their second or third decade. One patient died at age 29.ConclusionsThis video-series suggests that AHC in adulthood is not stationary; larger cohorts are needed to identify genotype-phenotype correlations and clinically useful outcome predictors.
| S-EPMC8810436 | biostudies-literature
Project description:Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.
| S-EPMC3442240 | biostudies-literature
Project description: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.
| S-EPMC8361420 | biostudies-literature
Project description:Study objectivesPatients 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.MethodsWe 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.ResultsOut 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.ConclusionsSleep dysfunction is common among children with AHC. Physicians should routinely screen for sleep pathology, with a low threshold to obtain a nocturnal PSG.
| S-EPMC6329557 | biostudies-literature
Project description: Not available
| S-EPMC1735877 | biostudies-literature