Familial childhood-onset progressive cerebellar syndrome associated with the
            <i>ATP1A3</i>
            mutation

Jaffer, Fatima; Fawcett, Katherine A.; Sims, David; Heger, Andreas; Houlden, Henry; Hanna, Michael G.; Kingston, Helen; Sisodiya, Sanjay M.

doi:10.1212/nxg.0000000000000145

Cited by 17 publications

(12 citation statements)

References 7 publications

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“…Recently, sudden unexpected death in epilepsy, cardiac structural abnormalities, episodic prolonged apnea, and postnatal microcephaly have been reported in patients with ATP1A3 -related disorders (Dard et al, 2015; Paciorkowski et al, 2015; Rosewich et al, 2012; Rosewich, Weise, Ohlenbusch, Gärtner, and Brockmann, 2014). Atypical and overlapping features of AHC, RDP, and CAPOS syndrome with intermediate phenotypes have been reported in patients with novel variants p.Arg756His and p.Arg756Cys in ATP1A3 (Jaffer et al, 2017; Kanemasa et al, 2016). While clinical diagnostic criteria for AHC and RDP have been established, supportive features remain the only diagnostic clues for CAPOS syndrome (Rosewich et al, 2017).…”

Section: | Discussionmentioning

confidence: 98%

Novel pregnancy‐triggered episodes of CAPOS syndrome

Chang

Adam

Jayadev

et al. 2017

American J of Med Genetics Pt A

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Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever-induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na /K ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied.

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Section: | Discussionmentioning

confidence: 98%

Novel pregnancy‐triggered episodes of CAPOS syndrome

Chang

Adam

Jayadev

et al. 2017

American J of Med Genetics Pt A

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“…To date, 57 cases with changes at residue 756 in the ATP1A3 gene have been reported, including 34 cases with c.2267G>A (p.Arg756His), 20 cases with c.2266C>T (p.Arg756Cys), and 3 cases with c.2267G>T (p.Arg756Leu) (Brashear et al, 2012 ; Dard et al, 2015 ; Fornarino et al, 2014 ; de Gusmao et al, 2016 ; Hully et al, 2017 ; Jaffer et al, 2017 ; Kanemasa et al, 2016 ; Nakamura et al, 2018 ; Sabouraud et al, 2019 ; Schirinzi et al, 2018 ; Sival et al, 2018 ; Sousa et al, 2017 ; Stagnaro et al, 2018 ; Tan et al, 2014 ; Yano et al, 2017 ). Some cases were described as intermediate or atypical phenotypes (Brashear et al, 2012 ; Hully et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…RECA and FIPWE were suggested as acronyms of the phenotype associated with variants at p.Arg756 (Dard et al, 2015 ; Sabouraud et al, 2019 ; Yano et al, 2017 ). Based on the study of our cases and the 33 cases discussed in literature (inclusion and exclusion criteria shown in appendices 1), we have described and defined the phenotype which is distinct from the AHC, RDP, and CAPOS phenotypes (Table 1 ) (Brashear et al, 2012 ; Dard et al, 2015 ; Fornarino et al, 2014 ; de Gusmao et al, 2016 ; Hully et al, 2017 ; Jaffer et al, 2017 ; Kanemasa et al, 2016 ; Nakamura et al, 2018 ; Sabouraud et al, 2019 ; Schirinzi et al, 2018 ; Sival et al, 2018 ; Sousa et al, 2017 ; Stagnaro et al, 2018 ; Sweney et al, 2015 ; Tan et al, 2014 ; Yano et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)—Report of two cases and literature review

Biela

Rydzanicz

Sztefko

et al. 2021

Molec Gen & Gen Med

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Background Variants in ATP1A3 cause well‐known phenotypes—alternating hemiplegia of childhood (AHC), rapid‐onset dystonia‐parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS), and severe early infantile epileptic encephalopathy. Recently, there has been growing evidence for genotype–phenotype correlations in the ATP1A3 variants, and a separate phenotype associated with variants in residue 756—two acronyms are proposed for the moment—FIPWE (fever‐induced paroxysmal weakness and encephalopathy) and RECA (relapsing encephalopathy with cerebellar ataxia). Materials and Methods Herein, we are describing two new pediatric cases with a p.Arg756His change in the ATP1A3 gene. Both patients have had more than one episode of a neurological decompensation triggered by fever with severe hypotonia and followed by ataxia. Thirty‐three cases from literature were analyzed to define and strengthen the genotype‐phenotype correlation of variants located in residue 756 (p.Arg756His, p.Arg756Cys, p.Arg756Leu). Conclusions Patients with a ATP1A3 variant in residue 756 are characterized by recurrent paroxysmal episodes of neurological decompensations triggered by fever, with severe hypotonia, ataxia, dysarthria, symptoms from the orofacial area (dysphagia, drooling) as well as with altered consciousness. Recovery is slow and usually not full with the persistent symptoms of cerebellar ataxia, dysarthria, dystonic and choreiform movements.

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“…Atypical phenotypes include paroxysms of unresponsiveness, bulbar signs, ataxia, fever-induced encephalopathy, prolonged flaccid tetraplegia with persistent choreo-athetosis between episodes, catastrophic epilepsy, and progressive childhood-onset cerebellar syndrome with step-wise deterioration [ 34 •, 39 – 41 ].…”

Section: Complex Hyperkinetic Movement Disorders Without Epilepsy As mentioning

confidence: 99%

Emerging Monogenic Complex Hyperkinetic Disorders

Carecchio

Mencacci

2017

Curr Neurol Neurosci Rep

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Purpose of ReviewHyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.Recent FindingsMutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,.SummaryThanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.

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Familial childhood-onset progressive cerebellar syndrome associated with the ATP1A3 mutation

Cited by 17 publications

References 7 publications

Novel pregnancy‐triggered episodes of CAPOS syndrome

Novel pregnancy‐triggered episodes of CAPOS syndrome

Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)—Report of two cases and literature review

Emerging Monogenic Complex Hyperkinetic Disorders

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