Opinion statement
The diagnosis and treatment of patients with Alternating Hemiplegia of Childhood (AHC) and related disorders should be provided by a multidisciplinary team experienced with the spectrum of presentations of this disease, with its related disorders, with its complex and fluctuating manifestations, and with cutting edge advances occurring in the field. Involvement in research to advance the understanding of this disease and partnership with international collaborators and family organizations are also important. An example of such an approach is that of The Duke AHC and Related Disorders Multi-Disciplinary Clinic and Program, which, in partnership with the Cure AHC Foundation, has developed and applied this approach to patients seen since early 2013. The program provides comprehensive care and education directly to AHC patients and their families and collaborates with referring physicians on the care of patients with AHC whether evaluated at Duke clinics or not. It also is involved in clinical and basic research and in collaborations with other International AHC Research Consortium (IAHCRC) partners. The clinic is staffed with physicians and experts from Neurology, Cardiology, Child Behavioral Health, Medical Genetics, Neurodevelopment, Neuropsychology, Nursing, Physical and Occupational Therapies, Psychiatry, Sleep Medicine, and Speech/Language Pathology. Patients are seen either for full comprehensive evaluations that last several days or for targeted evaluations with one or few appointments.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Neville BG, Ninan M. The treatment and management of alternating hemiplegia of childhood. Dev Med Child Neurol. 2007;49(10):777–80.
Verret S, Steele JC. Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics. 1971;47(4):675–80.
Lagman-Bartolome AM, Lay C. Pediatric migraine variants: a review of epidemiology, diagnosis, treatment, and outcome. Curr Neurol Neurosci Rep. 2015;15(6):34.
•• Heinzen EL et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012;44(9):1030–4. This study established that AHC in the majority of patients is caused by mutations of the ATP1A3 gene and that such mutations cause loss of function of enzyme activity without reducing the expression of that protein.
•• Rosewich H 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(9):764-73. This article, concurrently with above article, established that ATP1A3 mutations cause AHC.
Bottger P et al. Distribution of Na/K-ATPase alpha 3 isoform, a sodium-potassium P-type pump associated with rapid-onset of dystonia parkinsonism (RDP) in the adult mouse brain. J Comp Neurol. 2011;519(2):376–404.
•• Panagiotakaki E et al. Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients. Orphanet J Rare Dis. 2015;10:123. This article is the most recent study that provides a detailed study of the genotype-phenotype correlations in AHC.
•• Mikati MA et al. A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy; chromosomal studies; and physiologic investigations. Neurology. 1992;42(12):2251–7. This article reported the first family with AHC establishing genetic etiology of the disorder for the first time.
Mikati M, O’Tuama L, Dangond F. Autosomal dominant alternating hemiplegia of childhood. Alternating hemiplegia of childhood. 1995. p. 125–134.
Swoboda KJ et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol. 2004;55(6):884–7.
Bassi MT et al. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet. 2004;41(8):621–8.
Kramer U et al. Alternating hemiplegia of childhood in half-sisters. J Child Neurol. 2000;15(2):128–30.
Li M et al. A functional correlate of severity in alternating hemiplegia of childhood. Neurobiol Dis. 2015;77:88–93.
Viollet L et al. Alternating hemiplegia of childhood: retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry. PLoS ONE. 2015;10(5):e0127045.
Yang X et al. ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients. PLoS ONE. 2014;9(5):e97274.
Sasaki M et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology. 2014;82(6):482–90.
Heinzen EL et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 2014;13(5):503–14.
Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol. 2015;52(1):56–64.
Heimer G et al. CAOS-episodic cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss: a third allelic disorder of the ATP1A3 gene. J Child Neurol. 2015;30(13):1749–56.
Dard R et al. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation. Dev Med Child Neurol. 2015;57(12):1183–6.
Paciorkowski AR et al. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia. 2015;56(3):422–30.
Termsarasab P, Yang AC, Frucht SJ. Intermediate phenotypes of ATP1A3 mutations: phenotype-genotype correlations. Tremor Other Hyperkinet Mov (NY). 2015;5:336.
Demos MK et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014;9:15.
Bourgeois M, Aicardi J, Goutières F. Alternating hemiplegia of childhood. J Pediatr. 1993;122(5):673–9.
Mikati MA et al. Alternating hemiplegia of childhood: clinical manifestations and long-term outcome. Pediatr Neurol. 2000;23(2):134–41.
Andermann E et al. Benign familial nocturnal alternating hemiplegia of childhood. Neurology. 1994;44(10):1812–4.
Saito Y et al. A case of alternating hemiplegia of childhood with cerebellar atrophy. Pediatr Neurol. 1998;19(1):65–8.
Kansagra S, Mikati MA, Vigevano F. Alternating hemiplegia of childhood. Handb Clin Neurol. 2013;112:821–6.
Cornelio-Nieto JO et al. Acute hemiplegia in childhood and alternating hemiconvulsions secondary to Moya-Moya disease. Report of a case associated with Down’s syndrome. Bol Med Hosp Infant Mex. 1990;47(1):39–42.
Carlson CB, Harvey FH, Loop J. Progressive alternating hemiplegia in early childhood and basal arterial stenosis and telangiectasia (moyamoya syndrome). Neurology. 1973;23(7):734–44.
Montagna P et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology. 1988;38(5):751–4.
Mikati M, Fischman A. PET scan findings in alternating hemiplegia of childhood. Alternating hemiplegia of childhood. 1995. p. 109–114.
Dangond F et al. Focal brain dysfunction in a 41-year old man with familial alternating hemiplegia. Eur Arch Psychiatry Clin Neurosci. 1997;247(1):35–41.
Panagiotakaki E 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(Pt 12):3598–610.
•• Jaffer F et al. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype. Brain. 2015;138(Pt 10):2859–74. This study established that AHC patients have also cardiac abnormalities that potentially could prove to be contributing to the increased risks of motality in these patients.
•• Hunanyan AS et al. Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization. Epilepsia. 2015;56(1):82–93. This study described the, to date, the mouse model that most closely reproduces the human condition and characterized electrophysiological properties in it.
Tenney JR, Schapiro MB. Child neurology: alternating hemiplegia of childhood. Neurology. 2010;74(14):e57–9.
Sasaki M, Sakuragawa N, Osawa M. Long-term effect of flunarizine on patients with alternating hemiplegia of childhood in Japan. Brain Dev. 2001;23(5):303–5.
Pledger GW et al. Flunarizine for treatment of partial seizures: results of a concentration-controlled trial. Neurology. 1994;44(10):1830–6.
Chi LY et al. Alternating hemiplegia of childhood in chinese following long-term treatment with flunarizine or topiramate. Int J Neurosci. 2012;122(9):506–10.
Jiang W et al. Topiramate: a new agent for patients with alternating hemiplegia of childhood. Neuropediatrics. 2006;37(4):229–33.
Roubergue A et al. Excellent response to a ketogenic diet in a patient with alternating hemiplegia of childhood. JIMD Rep. 2015;15:7–12.
Vila-Pueyo M et al. Clinical and genetic analysis in alternating hemiplegia of childhood: ten new patients from Southern Europe. J Neurol Sci. 2014;344(1–2):37–42.
Haffejee S, Santosh PJ. Treatment of alternating hemiplegia of childhood with aripiprazole. Dev Med Child Neurol. 2009;51(1):74–7.
Badoe EV. Alternating hemiplegia in a child misdiagnosed as intractable epilepsy successfully treated with aripiprazole: a case report. West Afr J Med. 2011;30(2):140–4.
Wong VC, Kwong AK. ATP1A3 mutation in a Chinese girl with alternating hemiplegia of childhood--Potential target of treatment? Brain Dev. 2015;37(9):907–10.
Sone K et al. Successful trial of amantadine hydrochloride for two patients with alternating hemiplegia of childhood. Neuropediatrics. 2000;31(6):307–9.
Ju J et al. Treatment with oral ATP decreases alternating hemiplegia of childhood with de novo ATP1A3 mutation. Orphanet J Rare Dis. 2016;11(1):55.
Kirshenbaum GS et al. Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+, K+−ATPase alpha3 sodium pump. Proc Natl Acad Sci U S A. 2011;108(44):18144–9.
Ohnishi T et al. Na, K-ATPase alpha3 is a death target of Alzheimer patient amyloid-beta assembly. Proc Natl Acad Sci U S A. 2015;112(32):E4465–74.
Tanner GR et al. Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. J Neurosci. 2011;31(23):8689–96.
Holm TH et al. Cognitive deficits caused by a disease-mutation in the alpha3 Na(+)/K(+)-ATPase isoform. Sci Rep. 2016;6:31972.
Masoud M et al. Characterization and Analysis of Inter-relationships of Motor Function Domains in Patients with Alternating Hemiplegia of Childhood. Developmental Medicine and Child Neurology, in press.
Acknowledgements
This work was supported by Duke University and CureAHC funds. We would like to thank CureAHC for the funding of our laboratory and clinical research as well as for the partnership with them in AHC patient care. We thank the Irish and the Dutch AHC foundations for support of our lab research. We also would like to thank Melissa McLean, the Program research coordinator, the Iceland AHC Foundation, and all members of AHC and Related Disorders Multidisciplinary Clinic and Program at Duke as well as our partners in the International AHC Research Consortium (IAHCRC) and other researchers in the field. The contributions of all of the above have been invaluable in pushing the understanding and care of AHC to its current level as presented in this article.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Melanie Masoud, Lyndsey Prange, and Jeffrey Wuchich declare no conflict of interest.
Arsen Hunanyan reports receiving salary from Cure AHC grant.
Mohamad A. Mikati reports grants from Cure AHC, the Dutch AHC and the Irish AHC foundations during the conduct of the study.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Pediatric Neurology
Rights and permissions
About this article
Cite this article
Masoud, M., Prange, L., Wuchich, J. et al. Diagnosis and Treatment of Alternating Hemiplegia of Childhood. Curr Treat Options Neurol 19, 8 (2017). https://doi.org/10.1007/s11940-017-0444-7
Published:
DOI: https://doi.org/10.1007/s11940-017-0444-7