Alternating hemiplegia of childhood in Denmark: Clinical manifestations and ATP1A3 mutation status

Published:October 07, 2013DOI:


      Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by early-onset recurrent distinctive hemiplegic episodes commonly accompanied by other paroxysmal features and developmental impairment. De novo mutations in ATP1A3 were recently identified as a genetic cause of AHC. To describe the entire Danish cohort of paediatric AHC patients we approached neuropaediatricians nationwide. All currently acknowledged Danish patients ≤16 years with AHC were genetically tested and seen by the same child neurologist (PU). Ten patients; seven girls and three boys were identified. Mean present age was 10.0 years (range 1–16). Mean age at presentation was 7.4 months (range 1–18 months). Sequencing of ATP1A3 in all ten patients revealed a pathogenic mutation in seven. Two females with moderate psychomotor impairment were heterozygous for the known p.G947R mutation, whereas one severely retarded boy was heterozygous for the common p.E815K mutation. The prevalent p.D801N mutation was identified in two moderate to severely retarded children. Interestingly, in a set of monochorionic male twins a novel p.D801E mutation was identified, underscoring that the asparagine at position 801 is a mutation hotspot. Three girls aged 5–13 years did not reveal any ATP1A3 mutations. They were rather mildly clinically affected and displayed a normal or near-normal psychomotor development. This is the first study of AHC in the Danish paediatric population. The patients harboured a wide range of psychomotor difficulties. Patients with no mutation detected tended to be less severely affected. Prevalence was approximately 1 per 100,000 children.



      ADHD (attention deficit/hyperactivity disorder), AHC (alternating hemiplegia of childhood), Atyp (atypical case), DNA (deoxyribonucleic acid), DYT12 (dystonia 12), EDTA (ethylenediaminetetraacetic acid), EEG (electroencephalography), Nd (no mutation detected), Na (not analysed), PCR (polymerase chain reaction), Typ (typical case)
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        • Verret S.
        • Steele J.C.
        Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy.
        Pediatrics. 1971; 47: 675-680
        • Neville B.G.
        • Ninan M.
        The treatment and management of alternating hemiplegia of childhood.
        Dev Med Child Neurol. 2007; 49: 777-780
        • Tenney J.R.
        • Schapiro M.B.
        Child neurology: alternating hemiplegia of childhood.
        Neurology. 2010; 74: e57-e59
        • Sasaki M.
        • Sakuragawa N.
        • Osawa M.
        Long-term effect of flunarizine on patients with alternating hemiplegia of childhood in Japan.
        Brain Dev. 2001; 23: 303-305
        • Heinzen E.L.
        • Swoboda K.J.
        • Hitomi Y.
        • et al.
        De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.
        Nat Genet. 2012; 44: 1030-1034
        • Rosewich H.
        • Thiele H.
        • Ohlenbusch A.
        • et al.
        Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study.
        Lancet Neurol. 2012; 11: 764-773
        • Fons C.
        • Campistol J.
        • Panagiotakaki E.
        • et al.
        Alternating hemiplegia of childhood: metabolic studies in the largest European series of patients.
        Eur J Paediatr Neurol. 2012; 16: 10-14
        • Ishii A.
        • Saito Y.
        • Mitsui J.
        • et al.
        Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients.
        PLoS One. 2013; 8: e56120
        • Dobretsov M.
        • Stimers J.R.
        Neuronal function and alpha3 isoform of the Na/K-ATPase.
        Front Biosci. 2005; 10: 2373-2396
        • Lingrel J.B.
        • Williams M.T.
        • Vorhees C.V.
        • Moseley A.E.
        Na, K-ATPase and the role of alpha isoforms in behaviour.
        J Bioenerg Biomembr. 2007; 39: 385-389
        • De Carvalho Aguiar P.
        • Sweadner K.J.
        • Penniston J.T.
        • et al.
        Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.
        Neuron. 2004; 43: 169-175
        • Anselm I.A.
        • Sweadner K.J.
        • Gollamudi S.
        • Ozelius L.J.
        • Darras B.T.
        Rapid-onset dystonia-parkinsonism in a child with a novel atp1a3 gene mutation.
        Neurology. 2009; 73: 400-401
        • Blanco-Arias P.
        • Einholm A.P.
        • Mamsa H.
        • et al.
        A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia-parkinsonism.
        Hum Mol Genet. 2009; 18: 2370-2377
        • Brashear A.
        • Mink J.W.
        • Hill D.F.
        • et al.
        ATP1A3 mutations in infants: a new rapid-onset dystonia-parkinsonism phenotype characterised by motor delay and ataxia.
        Dev Med Child Neurol. 2012; 54: 1065-1067
        • Krageloh I.
        • Aicardi J.
        Alternating hemiplegia in infants: report of five cases.
        Dev Med Child Neurol. 1980; 22: 784-791
        • Bourgeois M.
        • Aicardi J.
        • Goutiéres F.
        Alternating hemiplegia of childhood.
        J Pediatr. 1993; 122: 673-679
        • Sweney M.T.
        • Silver K.
        • Gerard-Blanluet M.
        • et al.
        Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome.
        Pediatrics. 2009; 123: e534-e541
      1. Statistics Denmark:

        • Sasaki M.
        • Sakuma H.
        • Fukushima A.
        • Yamada K.
        • Ohnishi T.
        • Matsuda H.
        Abnormal cerebral glucose metabolism in alternating hemiplegia of childhood.
        Brain Dev. 2009; 31: 20-26
        • Mikati M.A.
        • Kramer U.
        • Zupanc M.L.
        • Shanahan R.J.
        Alternating hemiplegia of childhood: clinical manifestations and long-term outcome.
        Pediatr Neurol. 2000; 23: 134-141
        • Panagiotakaki E.
        • Gobbi G.
        • Neville B.
        • et al.
        Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults.
        Brain. 2010; 133: 3598-3610
        • Chaves-Vischer V.
        • Picard F.
        • Andermann E.
        • Dalla Bernardina B.
        • Andermann F.
        Benign nocturnal alternating hemiplegia of childhood: six patients and long-term follow-up.
        Neurology. 2001; 57: 1491-1493
        • Villéga F.
        • Picard F.
        • Espil-Taris C.
        • Husson M.
        • Michel V.
        • Pedespan J.M.
        Benign nocturnal alternating hemiplegia of childhood: two cases with positive evolution.
        Brain Dev. 2011; 33: 525-529
        • Wagener-Schimmel L.J.J.C.
        • Nicolai J.
        Child neurology: benign nocturnal alternating hemiplegia of childhood.
        Neurology. 2012; 79: e161-e163
        • DeAndrade M.P.
        • Yokoi F.
        • van Groen T.
        • Lingrel J.B.
        • Li Y.
        Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism.
        Behav Brain Res. 2011; 216: 659-665
        • Clapcote S.J.
        • Duffy S.
        • Xie G.
        • et al.
        Muatation I810N in the alpha3 isoform of Na+, K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS.
        Proc Natl Acad Sci U S A. 2009; 106: 14085-14090