White matter and cerebellar involvement in alternating hemiplegia of childhood

Severino, Mariasavina; Pisciotta, Livia; Tortora, Domenico; Toselli, Benedetta; Stagnaro, Michela; Cordani, Ramona; Morana, Giovanni; Zicca, Anna; Kotzeva, Svetlana; Zanaboni, Clelia; Montobbio, Giovanni; Rossi, Andrea; Grandis, Elisa De

doi:10.1007/s00415-020-09698-3

Cited by 11 publications

(14 citation statements)

References 32 publications

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“…Although hydrocephalus is not typically observed in patients with ATP1A3 -related disorders, this zebrafish finding raises the possibility that NKA α 3 is involved in regulating brain volume ( Doğanlı et al, 2013 ). Zebrafish embryos may thus provide insight into the smaller total brain volume observed in both AHC and EIEE patients ( Paciorkowski et al, 2015 ; Severino et al, 2020 ). In response to tactile stimulation of the embryo trunk, atp1a3a KD embryos and atp1a3b KD embryos (60 hpf) both display brief distance recoils and occasional convulsions, which are delayed in atp1a3b KD embryos, in contrast to the burst swimming exhibited by control embryos ( Doğanlı et al, 2013 ).…”

Section: Animal Models Of Atp1a3 -Related Neurological Disordersmentioning

confidence: 99%

“…AHC, alternating hemiplegia of childhood; ASD, autism spectrum disorder; CAPOS, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss; COS, childhood-onset schizophrenia; CRA, childhood rapid-onset ataxia; D-DEMØ, dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø); NKA, Na + ,K + -ATPase; PMG, polymicrogyria; RDP, rapid-onset dystonia-parkinsonism; RECA, relapsing encephalopathy with cerebellar ataxia. G947R Bourgeois et al, 1993;Heinzen et al, 2012;Ito et al, 2018;Jasien et al, 2019;Panagiotakaki et al, 2010;Rosewich et al, 2012;Schirinzi et al, 2018a;Severino et al, 2020 Demos et al, 2014;Duat Rodriguez et al, 2017;Heimer et al, 2015;Maas et al, 2016;Potic et al, 2015;Rosewich et al, 2014c;Stenshorne et al, 2019 Brashear et al, 2012a;Cook et al, 2014;de Carvalho Aguiar et al, 2004;Dobyns et al, 1993;Haq et al, 2019;…”

Section: Human Nka α 3 Mutationsmentioning

confidence: 99%

“…Among 34 AHC patients evaluated with the Social Responsiveness Scale, 79% showed impaired social skills involving multiple domains and 26% were subsequently diagnosed with comorbid autism spectrum disorder (ASD) ( Uchitel et al, 2020 ). A study of 12 AHC patients revealed reduced total brain and white matter volumes, and a negative correlation between the volume of cerebellar grey matter and severity of ataxia and disability ( Severino et al, 2020 ). Among 87 patients with AHC, 60% exhibited resting electrocardiogram (ECG) abnormalities ( Balestrini et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Genetically altered animal models forATP1A3-related disorders

Ogbeta

Clapcote

2021

Disease Models &Amp; Mechanisms

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Within the past 20 years, particularly with the advent of exome sequencing technologies, autosomal dominant and de novo mutations in the gene encoding the neurone-specific α3 subunit of the Na+,K+-ATPase (NKA α3) pump, ATP1A3, have been identified as the cause of a phenotypic continuum of rare neurological disorders. These allelic disorders of ATP1A3 include (in approximate order of severity/disability and onset in childhood development): polymicrogyria; alternating hemiplegia of childhood; cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss syndrome; relapsing encephalopathy with cerebellar ataxia; and rapid-onset dystonia-parkinsonism. Some patients present intermediate, atypical or combined phenotypes. As these disorders are currently difficult to treat, there is an unmet need for more effective therapies. The molecular mechanisms through which mutations in ATP1A3 result in a broad range of neurological symptoms are poorly understood. However, in vivo comparative studies using genetically altered model organisms can provide insight into the biological consequences of the disease-causing mutations in NKA α3. Herein, we review the existing mouse, zebrafish, Drosophila and Caenorhabditis elegans models used to study ATP1A3-related disorders, and discuss their potential contribution towards the understanding of disease mechanisms and development of novel therapeutics.

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Section: Animal Models Of Atp1a3 -Related Neurological Disordersmentioning

confidence: 99%

Section: Human Nka α 3 Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetically altered animal models forATP1A3-related disorders

Ogbeta

Clapcote

2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…Recent clinical neuroscience research has begun to use referral methods to emphasize the importance of cerebellar microstructural changes in a wide range of psychopathological risks [9, 10]. Previous animal and human neuroimaging studies have provided converging evidence for the involvement of cerebellar function in a wide range of behaviors that are dependent on with multiple cerebral cortical regions [4, 10, 11]. Accumulating evidence supports, after the discovery of focal lesions of the cerebellum, the patient showed a series of cognitive deficits, including impaired executive function, spatial cognition, language processing, emotional regulation and personality changes[12].…”

Section: Introductionmentioning

confidence: 99%

Cerebellum models of psychosis implicate association nuclei in the pathogenesis of psychosis and mechanisms of cognitive impairment

Chang

Jia

Dong

et al. 2020

Preprint

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To comprehensively investigate the white matter (WM) features of cerebellum in patients with schizophrenia, and further assess the correlation between altered WM features and clinical and cognitive assessments. Forty-two patients and fifty-two matched healthy controls (HCs) of the Collaborative Informatics and Neuroimaging Suite Data Exchange tool were involved in this study. The cerebellar WM volume was calculated by voxel-based morphometry. And tract-based spatial statistics was used to analysis the diffusion changes in patients when compared to HCs. Furthermore, we investigated the correlation between altered imaging feature and clinical, cognitive assessments. Compared to HCs, the schizophrenia patients did not reveal difference in cerebellar WM volume and schizophrenia patients showed decreased fractional anisotropy and increased radial diffusivity in left middle cerebellar peduncles and inferior cerebellar peduncles in voxel-wise but not in tract-wise. Critically, these cerebellar changes were associated with disease duration in schizophrenia patients. And significant correlation between the altered cerebellar WM features and cognitive assessments only revealed in HCs but disrupted in schizophrenia patients. The present findings suggested that the voxel-wise WM integrity analysis might was the more sensitive way to investigate the structural abnormalities in schizophrenia patients. Middle cerebellar peduncles and inferior cerebellar peduncles may be a crucial neurobiological substrate of cognition and thus might be regarded as a biomarker for treatment.

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Brain structural changes in alternating hemiplegia of childhood using single‐case voxel‐based morphometry analysis

Arizono,

Sato,

Shigemoto

et al. 2023

Intl J of Devlp Neuroscience

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Background and purposeAlternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disease caused by ATP1A3 mutations. Using voxel‐based morphometry (VBM) analysis, we compared an AHC patient cohort with controls. Additionally, with single‐case VBM analysis, we assessed the associations between clinical severity and brain volume in patients with AHC.Materials and methodsTo investigate structural brain changes in gray matter (GM) and white matter (WM) volumes between 9 patients with AHC and 20 age‐matched controls, VBM analysis was performed using three‐dimensional T1‐weighted magnetic resonance imaging. Single‐case VBM analysis was also performed on nine patients with AHC to investigate the associations between the respective volumes of GM/WM differences and the motor level, cognitive level, and status epilepticus severity in patients with AHC.ResultsCompared with controls, patients with AHC showed significant GM volume reductions in both hippocampi and diffuse cerebellum, and there were WM reductions in both cerebral hemispheres. In patients with AHC, cases with more motor dysfunction, the less GM/WM volume of cerebellum was shown. Three of the six cases with cognitive dysfunction showed a clear GM volume reduction in the insulae. Five of the six cases with status epilepticus showed the GM volume reduction in hippocampi. One case had severe status epilepticus without motor dysfunction and showed no cerebellar atrophy.ConclusionWith single‐case VBM analysis, we could show the association between region‐specific changes in brain volume and the severity of various clinical symptoms even in a small sample of subjects.

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White matter and cerebellar involvement in alternating hemiplegia of childhood

Cited by 11 publications

References 32 publications

Genetically altered animal models forATP1A3-related disorders

Genetically altered animal models forATP1A3-related disorders

Cerebellum models of psychosis implicate association nuclei in the pathogenesis of psychosis and mechanisms of cognitive impairment

Brain structural changes in alternating hemiplegia of childhood using single‐case voxel‐based morphometry analysis

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