Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Jaffer, Fatima; Avberšek, Andreja; Vavassori, Rosaria; Fons, Carmen; Campistol, Jaume; Stagnaro, Michela; Grandis, Elisa De; Veneselli, Edvige; Rosewich, Hendrik; Gianotta, Melania; Zucca, Claudio; Ragona, Francesca; Granata, Tiziana; Nardocci, Nardo; Mikati, Mohamad A.; Helseth, Ashley; Boelman, Cyrus; Minassian, Berge A.; Johns, Sophia; Garry, Sarah; Scheffer, Ingrid E.; Gourfinkel‐An, Isabelle; Carrilho, Inês; Aylett, Sarah; Parton, M.; Hanna, Michael G.; Houlden, Henry; Neville, Brian; Kurian, Manju A.; Nový, Jan; Sander, Josemir W.; Lambiase, Pier D.; Behr, Elijah R.; Schyns, Tsveta; Arzimanoglou, Alexis; Cross, J. Helen; Kaski, Juan Pablo; Sisodiya, Sanjay M.

doi:10.1093/brain/awv243

Cited by 31 publications

(31 citation statements)

References 49 publications

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“…Regarding non-neurological symptoms, our patient has never presented with arrhythmic episodes or abnormal features on electrocardiography. However, systematic reviews of the cardiac function must be conducted for successful long-term management, as recently reported [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis

et al. 2016

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BackgroundAlternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes.Case presentationA 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins.ConclusionsThis study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0680-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis

et al. 2016

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“…AHC has been associated with an increased risk of sudden death that may be caused by lethal cardiac arrhythmias (10). Cardiac dysfunction may account for some of the unexplained premature mortality of patients with AHC (6).…”

Section: A F T E R T H E F I R S T D E S C R I P T I O N O F a H C ( mentioning

confidence: 99%

“…AHC is considered to be associated with autonomic nervous dysfunction because of symptoms of heart rate fluctuations, sweating, conjunctival injection, lacrimation and so on (6,7). However, frequency analysis of heart rate variability (HRV) widely used to evaluate autonomic nervous function has not yet been reported in patients with this disorder.…”

Section: Introductionmentioning

confidence: 99%

Heart rate variability in a patient with alternating hemiplegia

Nakashima

Yasuda

Kobayashi

et al. 2019

IRDR

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“…The potential causal relationships between transcriptomic signatures and specific morphological, physiological and functional properties remain to be elucidated [103]. Furthemore, extending the phenotypic analysis to organs than the brain, ideally at the individualwide scale, is also relevant for 'personalised' treatment, as some genetic defects affect multiple organs, and broad phenotyping can inform diagnostic and therapeutic management [104].…”

Section: Taming Complexity: the Role Of Deep Phenotypingmentioning

confidence: 99%

Personalized treatment in the epilepsies: challenges and opportunities

Balestrini

Sisodiya

2018

Expert Review of Precision Medicine and Drug Development

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Introduction. 'Personalised' medicine is not a new construct. Indeed, the science of medicine has been historically focused around notions of subgroups and categorization. A few decades ago the Human Genome Project provided a complete resource of detailed information about the structure, organization, and function of the full set of human genes. This has enabled implementation of the idea that treatments could be targeted to genetically-defined subgroups of individuals. Areas covered. We provide an overview of the current pitfalls and opportunities of 'personalised' treatment in epilepsy. Development of targeted therapeutics has been so far mainly by re-purposing drugs already available on the market but not necessarily approved for the treatment of epilepsy. Most genomic findings have not yet translated into widespread utilisation for therapy. Expert opinion/Commentary. Genotypic and phenotypic heterogeneity, epigenetic modulation, variable penetrance and expressivity, environmental influence, post-translational changes are all factors that increase the complexity of genomic networks and generate pitfalls in the application of the 'personalised' treatment paradigm. Unravelling the multiple layers of biological complexity through new collaborative and computational approaches, and deep and multimodal phenotyping, is becoming fundamental for a better understanding of disease biology and in turn better tailored treatment strategies.

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Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Cited by 31 publications

References 49 publications

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis

Heart rate variability in a patient with alternating hemiplegia

Personalized treatment in the epilepsies: challenges and opportunities

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