scholarly journals Expanding Phenotype of ATP1A3 - Related Disorders: A Case Series

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110480
Author(s):  
Jelena De Vrieze ◽  
Ingrid M.B.H. van de Laar ◽  
Johanneke F. de Rijk-van Andel ◽  
Erik-Jan Kamsteeg ◽  
Irene A.W. Kotsopoulos ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Cerebellar Ataxia ◽  
De Novo ◽  
Early Stage ◽  
Case Series ◽  
Rapid Onset ◽  
Sudden Onset ◽  
Intermediate Phenotype ◽  
Alternating Hemiplegia Of Childhood ◽  
Neurologic Disorders

Neurologic disorders caused by mutations in the ATP1A3 gene were originally reported as three distinct rare clinical syndromes: Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Opticus atrophy and Sensorineural hearing loss (CAPOS). In this case series, we describe 3 patients. A mother and her daughter showed an intermediate phenotype different from each other with the same heterozygous missense mutation (p.[R756C]), recently described in literature as Relapsing Encephalopathy With Cerebellar Ataxia (RECA). In addition, a third patient showed an intermediate AHC-RDP phenotype and had a likely pathogenic novel de novo missense mutation (p.[L100 V]). These patients support the growing evidence that AHC, RDP and RECA are part of a continuous ATP1A3 mutation spectrum that is still expanding. Three common features were a sudden onset, asymmetrical neurological symptoms, as well as the presence of triggering factors. When present, the authors argue to perform exome sequencing in an early stage.

A De Novo Dominant Negative Mutation in DNM1L Causes Sudden Onset Status Epilepticus with Subsequent Epileptic Encephalopathy

2019 ◽  
Vol 50 (03) ◽  
pp. 197-201
Author(s):  
S. Schmid ◽  
M. Wagner ◽  
C. Goetz ◽  
C. Makowski ◽  
P. Freisinger ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Missense Mutation ◽  
De Novo ◽  
Mitochondrial Fission ◽  
Refractory Status Epilepticus ◽  
Sudden Onset ◽  
Epileptic Encephalopathy ◽  
Neurologic Outcome ◽  
Dominant Negative Mutation ◽  
Refractory Status

AbstractMitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.

scholarly journals Recognition and management of rapid-onset gluten ataxias: case series

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Laurence Newrick ◽  
Nigel Hoggard ◽  
Marios Hadjivassiliou
Keyword(s):  
Cerebellar Ataxia ◽  
Case Series ◽  
Rapid Onset ◽  
Rapid Progression ◽  
Gluten Sensitivity ◽  
Gluten Ataxia ◽  
Early Access ◽  
Immune Mediated ◽  
Cerebellar Ataxias ◽  
Case Presentations

Abstract Background Most immune-mediated cerebellar ataxias, including those associated with gluten sensitivity (Gluten Ataxia), tend to present subacutely and usually progress gradually. Acute presentations with rapid progression outside the context of paraneoplastic cerebellar degeneration require prompt diagnosis and early access to disease-modifying immunotherapy in order to avert severe and permanent neurological disability. Case presentations We describe three cases of rapid-onset Gluten Ataxia, an immune-mediated cerebellar ataxia due to gluten sensitivity. We detail their presentation, clinical and neuroimaging findings, and our treatment strategy with immunotherapy. Conclusions Our cases highlight the potential for immune-mediated cerebellar ataxias to present acutely, with rapid-onset symptoms and devastating neurological consequences. We caution against the diagnosis of ‘post-infective cerebellitis’ in adults, and advocate early consideration of an immune-mediated cerebellar ataxia and initiation of immunotherapy to prevent irreversible cerebellar damage.

Acute Cerebellar Ataxia

PEDIATRICS ◽  
1957 ◽  
Vol 20 (5) ◽  
pp. 781-781
Keyword(s):  
Cerebrospinal Fluid ◽  
Differential Diagnosis ◽  
Cerebellar Ataxia ◽  
Rapid Onset ◽  
Sudden Onset ◽  
Demyelinating Diseases ◽  
Cerebellar Tumor ◽  
Intention Tremor ◽  
Acute Cerebellar Ataxia ◽  
Principal Source

This is a report of seven cases of acute cerebellar ataxia and an analysis of 33 cases from the literature. The syndrome is characterized by a sudden onset of ataxia in a previously well child. It occurs usually in children less than 5 years of age. The symptoms include staggering, falling, a drunken and uncertain gait; gross intention tremor, staccato speech and nystagmus are frequently present. There are no abnormal findings in the cerebrospinal fluid and fever is absent. Recovery usually takes place in a period from a few days to 6 months. The principal source of concern in the differential diagnosis is a posterior fossa tumor. The rapid onset of symptoms and absence of increase in pressure of the cerebrospinal fluid serve to distinguish the condition from a cerebellar tumor. Because of the favorable outcome, the nature of the pathologic process is not known. In some cases there was an increase in protein in the cerebrospinal fluid at some time during the later course of the disorder. The differential diagnosis from brain tumor, labyrinthine ataxia, and acute demyelinating diseases is discussed.

Acute Cerebellar Ataxia in Pediatric Legionellosis

PEDIATRICS ◽  
1983 ◽  
Vol 72 (6) ◽  
pp. 847-849
Author(s):  
Giovanni Nigro ◽  
Maddalena Castellani Pastoris ◽  
Mirella Mazzotti Fantasia ◽  
Mario Midulla
Keyword(s):  
Cerebellar Ataxia ◽  
Sudden Onset ◽  
Unknown Etiology ◽  
Laboratory Findings ◽  
Neurologic Disorders ◽  
Acute Cerebellar Ataxia ◽  
Csf Levels ◽  
Systemic Symptoms ◽  
Muscle Hypotonia

Acute-phase and convalescent-phase sera of 66 children, aged 3 months to 12 years, with neurologic disorders of unknown etiology were tested against Legioneila pneumophila polyvalent and monovalent antigens (groups 1 to 4). Three significant antibody titer increases were obtained, all in childlren with acute cerebellar ataxia. This neurologic syndrome was characterized by sudden onset of muscle hypotonia and inability to sit or walk, with no other specific neurologic or systemic symptoms. Persisting pharyngitis always preceded ataxia. Fever of short duration was still present. Gastrointestinal disturbance occurred in two of the three children. Abnormal laboratory findings were, not always simultaneously, high ESR and leukocytosis with lymphocytosis. CSF levels and electromyographic findings were normal in two of the children. Two children received oral betamethasone. Recovery was complete within seven to ten days without antibiotic treatment. These studies indicate the possible etiologic role of L pneumophila in acute cerebellar ataxia.

scholarly journals Not all SCN1A epileptic encephalopathies are Dravet syndrome

Neurology ◽  
2017 ◽  
Vol 89 (10) ◽  
pp. 1035-1042 ◽  
Author(s):  
Lynette G. Sadleir ◽  
Emily I. Mountier ◽  
Deepak Gill ◽  
Suzanne Davis ◽  
Charuta Joshi ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Missense Mutation ◽  
De Novo ◽  
Age At Onset ◽  
Case Series ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Developmental Impairment ◽  
Hyperkinetic Movement Disorder

Objective:To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.Methods:A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.Results:We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.Conclusions:Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

scholarly journals Research conference summary from the 2014 International Task Force on ATP1A3-Related Disorders

2017 ◽  
Vol 3 (2) ◽  
pp. e139 ◽  
Author(s):  
Hendrik Rosewich ◽  
Matthew T. Sweney ◽  
Suzanne DeBrosse ◽  
Kevin Ess ◽  
Laurie Ozelius ◽  
...  
Keyword(s):  
Genetic Testing ◽  
International Research ◽  
Task Force ◽  
Rapid Onset ◽  
Acute Management ◽  
Care Providers ◽  
Preventative Measures ◽  
Alternating Hemiplegia Of Childhood ◽  
Neurologic Disorders ◽  
Clinical Conditions

Objective:ATP1A3-related neurologic disorders encompass a broad range of phenotypes that extend well beyond initial phenotypic criteria associated with alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism.Methods:In 2014, the Alternating Hemiplegia of Childhood Foundation hosted a multidisciplinary workshop intended to address fundamental challenges surrounding the diagnosis and management of individuals with ATP1A3-related disorders.Results:Workshop attendees were charged with the following: (1) to achieve consensus on expanded diagnostic criteria to facilitate the identification of additional patients, intended to supplement existing syndrome-specific diagnostic paradigms; (2) to standardize definitions for the broad range of paroxysmal manifestations associated with AHC to disseminate to families; (3) to create clinical recommendations for common recurrent issues facing families and medical care providers; (4) to review data related to the death of individuals in the Alternating Hemiplegia of Childhood Foundation database to guide future efforts in identifying at-risk subjects and potential preventative measures; and (5) to identify critical gaps where we most need to focus national and international research efforts.Conclusions:This report summarizes recommendations of the workshop committee, highlighting the key phenotypic features to facilitate the diagnosis of possible ATP1A3 mutations, providing recommendations for genetic testing, and outlining initial acute management for common recurrent clinical conditions, including epilepsy.

scholarly journals De novo ATP1A3 variants cause polymicrogyria

2021 ◽  
Vol 7 (13) ◽  
pp. eabd2368
Author(s):  
Satoko Miyatake ◽  
Mitsuhiro Kato ◽  
Takuma Kumamoto ◽  
Tomonori Hirose ◽  
Eriko Koshimizu ◽  
...  
Keyword(s):  
De Novo ◽  
Sensorineural Deafness ◽  
Rapid Onset ◽  
Severe Form ◽  
Brain Diseases ◽  
Pes Cavus ◽  
Cortical Malformation ◽  
Alternating Hemiplegia Of Childhood ◽  
Whole Exome ◽  
Malformation Of Cortical Development

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

scholarly journals Genetically altered animal models for ATP1A3-related disorders

2021 ◽  
Vol 14 (10) ◽  
Author(s):  
Hannah W. Y. Ng ◽  
Jennifer A. Ogbeta ◽  
Steven J. Clapcote
Keyword(s):  
Cerebellar Ataxia ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Unmet Need ◽  
Rapid Onset ◽  
Childhood Development ◽  
Model Organisms ◽  
Potential Contribution ◽  
De Novo Mutations

ABSTRACT 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.

Alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism: Phenotypic spectrum of ATP1A3-associated disorders

2013 ◽  
Vol 44 (02) ◽  
Author(s):  
K Brockmann ◽  
H Rosewich ◽  
H Thiele ◽  
U Maschke ◽  
P Huppke ◽  
...  
Keyword(s):  
Rapid Onset ◽  
Alternating Hemiplegia Of Childhood ◽  
Phenotypic Spectrum
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