Novel E815K knock-in mouse model of alternating hemiplegia of childhood

Helseth, Ashley; Hunanyan, Arsen; Adil, Syed M; Linabarger, Molly; Sachdev, Monisha; Abdelnour, Elie; Arehart, Eric; Szabo, Marlee; Richardson, Jarrett W.; Wetsel, William C.; Hochgeschwender, Ute; Mikati, Mohamad A.

doi:10.1016/j.nbd.2018.07.028

Cited by 34 publications

(34 citation statements)

References 72 publications

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“…This novel knockin mouse model (Atp1a3 E815K+/-, Matoub, Matb +/-) expresses the E815K mutation of the Atp1a3 gene (the most severe common phenotype of AHC). 83 In their elegant study, authors clearly demonstrated that mutated mice expressed behavioural and neurophysiological features, resembling the most severe form of AHC. In particular, the motor initiative was poor, the motor performance was deeply impaired (e.g.…”

Section: Animal In Vivo Studiesmentioning

confidence: 99%

“…coordination, balance, abnormal gait), and interestingly, other than epilepsy, many mice were observed to pass during spontaneous seizure or provoked seizures for sudden unexpected death in epilepsy (SUDEP). 83 Of note, the hemiplegia and dystonia episodes were both spontaneous and induced by high level of stress (e.g. water contact or cage change), likely in the human phenotype.…”

Section: Animal In Vivo Studiesmentioning

confidence: 99%

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<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Capuano¹,

Garone²,

Tiralongo³

et al. 2020

TACG

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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.

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Section: Animal In Vivo Studiesmentioning

confidence: 99%

Section: Animal In Vivo Studiesmentioning

confidence: 99%

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

Capuano¹,

Garone²,

Tiralongo³

et al. 2020

TACG

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“… 16 – 18 They also lead to increased excitability in the brain and abnormal cerebellar Purkinje cell and deep nuclei neuronal firing. 19 – 21 Most ATP1A3 mutations causing AHC affect an amino acid located within a transmembrane domain, changing the configuration of the protein, and therefore affecting several factors such as binding to Na + and K + , or transport of these ions in and out of the cell. 5 , 16 , 22 In RDP, which has a phenotype milder than AHC, mutations are more evenly distributed across the ATPA13 protein.…”

Section: Discussionmentioning

confidence: 99%

D-DEMØ, a distinct phenotype caused by ATP1A3 mutations

et al. 2020

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ObjectiveTo 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.MethodsReview and analysis of clinical and genetic data.ResultsPatients 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.ConclusionsD-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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“…Furthermore, many other central nervous system disorders that manifest gastrointestinal motility problems, including mitochondrial disease and Rett syndrome, also have been shown to manifest prominent GABAergic dysfunction [29]. Lastly, cerebellar function contributes to gastrointestingal motility, and cerebellar dysfuntion is very common in AHC [4][5][6][7][30][31][32].…”

Section: Diagnoses and Interventionsmentioning

confidence: 99%

Alternating Hemiplegia of Childhood: gastrointestinal manifestations and correlation with neurological impairments

Pratt

Uchitel

McGreal

et al. 2020

Orphanet J Rare Dis

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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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Novel E815K knock-in mouse model of alternating hemiplegia of childhood

Cited by 34 publications

References 72 publications

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

<p>Alternating Hemiplegia of Childhood: Understanding the Genotype–Phenotype Relationship of ATP1A3 Variations</p>

D-DEMØ, a distinct phenotype caused by ATP1A3 mutations

Alternating Hemiplegia of Childhood: gastrointestinal manifestations and correlation with neurological impairments

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