Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity

Lazarov, Elinor; Hillebrand, Merle; Schröder, Simone; Ternka, Katharina; Hofhuis, Julia; Ohlenbusch, Andreas; Barrantes‐Freer, Alonso; Pardo, Luis A.; Fruergaard, Marlene U.; Nissen, Poul; Brockmann, Knut; Gärtner, Jutta; Rosewich, Hendrik

doi:10.1016/j.nbd.2020.105012

Cited by 15 publications

(5 citation statements)

References 59 publications

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“…This suggested that missense mutations in intracellular domains had little effect on membrane protein expression and that there may be other mechanisms that contribute to the pathogenicity of these mutations. Similar results were obtained in the study of ATP1A3 [ 33 ], although AHC tends to be more severe than rapid-onset dystonia-parkinsonism, no difference in protein expression was found between groups. In this study, all mutations showed decreased cell survival under 1 µM ouabain compared with the WT, but there were no differences among the mutant groups.…”

Section: Discussionsupporting

confidence: 87%

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Tang

et al. 2021

J Headache Pain

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Background Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. Methods Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. Results Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. Conclusions ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

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Section: Discussionsupporting

confidence: 87%

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Tang

et al. 2021

J Headache Pain

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“…There are also reports of intermediate phenotypes or individuals showing atypical features not entirely fitting the classical signs of the disorders mentioned above. 39 , 49 , 89 …”

Section: Ahc and Atp1a3-related Disordersmentioning

confidence: 99%

Navigating the Complexity of Alternating Hemiplegia in Childhood: A Comprehensive Review

Rissardo,

Vora,

Singh

et al. 2024

Rambam Maimonides Med J

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Alternating hemiplegia of childhood (AHC) is a complex neurodevelopmental disorder characterized by paroxysmal and transient events of unilateral or bilateral paresis, usually occurring before 18 months of age. Mutations in the ATP1A3 gene, mainly p.Asp801Asn, p.Glu815Lys, and p.Gly947Arg at the protein level, are found in around 80% of the individuals with AHC. Interestingly, these mutations reflect the degree of severity of the neurological symptoms (p.Glu815Lys > p.Asp801Asn > p.Gly947Arg). Some channels involved in this disorder are N-type voltage-gated calcium channels, ATP-sensitive potassium channels, and the sodium/calcium exchanger. In this context, the management of AHC should be divided into the treatment of attacks, prophylactic treatment, and management of comorbidities commonly found in this group of individuals, including epilepsy, attention-deficit/hyperactivity disorder, aggressive behavior, cognitive impairment, movement disorders, and migraine. The importance of an integrated approach with a multidisciplinary team, such as neuropsychologists and dietitians, is worth mentioning, as well as the follow-up with a neurologist. In the present study, we propose new diagnostic criteria for AHC, dividing it into clinical, laboratory, supporting, and atypical features. Also, we review the location of the mutations in the ATP1A3 protein of individuals with AHC, rapid-onset dystonia-parkinsonism (RDP) variants, and early infantile epileptic encephalopathy (variants with hemiplegic attack). We also include a section about the animal models for ATP1A3 disorders.

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“…[60] Intermediate phenotypes or affected individuals with atypical features that do not completely express classical signs of the above-mentioned disorders have been reported. [61][62][63]…”

Section: Ahc and Atp1a3-related Disordersmentioning

confidence: 99%

Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

et al. 2022

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Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood–onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.

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Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity

Cited by 15 publications

References 59 publications

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Navigating the Complexity of Alternating Hemiplegia in Childhood: A Comprehensive Review

Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

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