ORPHA: 2131; DO: 0050635;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.2 | Alternating hemiplegia of childhood 1 | 104290 | Autosomal dominant | 3 | ATP1A2 | 182340 |
A number sign (#) is used with this entry because of evidence that alternating hemiplegia of childhood-1 (AHC1) is caused by heterozygous mutation in the ATP1A2 gene (182340) on chromosome 1q23.
Familial hemiplegic migraine-2 (FHM2; 602481) is an allelic disorder with some overlapping features.
Alternating hemiplegia of childhood is a rare syndrome of episodic hemi- or quadriplegia lasting minutes to days. Most cases are accompanied by dystonic posturing, choreoathetoid movements, nystagmus, other ocular motor abnormalities, autonomic disturbances, and progressive cognitive impairment (Mikati et al., 1992).
The disorder may mimic or overlap with other disorders, including familial hemiplegic migraine (FHM1; 141500) and GLUT1 deficiency syndrome (606777) (Rotstein et al., 2009).
Genetic Heterogeneity of Alternating Hemiplegia of Childhood
See also AHC2 (614820), caused by mutation in the ATP1A3 gene (182350).
Mikati et al. (1992) reported what appeared to be the first instance of familial occurrence of alternating hemiplegia of childhood. Inheritance appeared to be autosomal dominant. The proband, a 9-year-old boy, presented with developmental retardation, rare tonic-clonic seizures and frequent episodes of flaccid alternating hemiplegia that had been presumed to represent postictal paralysis. The hemiplegia spells, which started in his first year, did not respond to multiple antiepileptics. Between attacks, there was choreoathetosis and dystonic posturing. A brother, the father, a paternal uncle, and the maternal grandmother had similar histories of alternating hemiplegia. Investigations included negative CT and metabolic studies. EEG and SPECT scanning failed to reveal any significant slowing or major changes in cortical perfusion during hemiplegia as compared with nonhemiplegic periods. The karyotype demonstrated a balanced reciprocal translocation, 46,XY,t(3;9)(p26;q34) in the patient, in all the affected living relatives, and in 1 apparently unaffected sib. The asymptomatic mother had a normal karyotype. Both affected sibs were treated with and responded to flunarizine, a calcium-entry blocker, with a greater than 70% decrease in attack frequency.
Among a group of 22 presumably unrelated patients with alternating hemiplegia of childhood, Bourgeois et al. (1993) described onset before 18 months of age, repeated episodes of hemiplegia lasting from a few minutes to several days, the occurrence of tonic or dystonic attacks, nystagmus, dyspnea, cognitive impairment, and choreoathetosis. All of the patients also had episodes of quadriplegia that occurred either when a hemiplegia was shifting from one side to the other or as an isolated phenomenon. Six patients also had epileptic seizures, but Bourgeois et al. (1993) considered the 2 disorders to be distinct. Treatment with flunarizine was partially effective.
Kramer et al. (2000) reported 2 half sisters with alternating hemiplegia of childhood who had the same mother and different fathers. The authors ruled out mitochondrial abnormalities and suggested autosomal dominant inheritance.
Kanavakis et al. (2003) reported a family with alternating hemiplegia of childhood inherited in an autosomal dominant pattern. The proband was a 9-year-old boy with mental retardation, tonic-clonic seizures, dystonic attacks, and episodes of alternating hemiplegia starting at age 2.5 years. His mother, 3 brothers, and maternal uncle had similar symptoms. Other clinical features included autonomic changes in affected limbs and abnormal extraocular movements. Brain imaging, cytogenetic analysis, and mitochondrial DNA analysis were normal. Headache was not a feature. Flunarizine treatment reduced the severity of episodes.
Clinical Variability
Sampedro Castaneda et al. (2018) reported a 9-year-old Brazilian boy with episodic flaccid muscle weakness. At age 2 months, he showed absence seizures that evolved to status epilepticus, but were eventually controlled with medication with difficulty. He had global developmental delay: he walked just before 3 years of age and had speech delay and learning difficulties. At age 2 years, he developed tetraparesis and dysphagia associated with a respiratory tract infection. The episodes, which were bilateral, continued, lasting hours to days. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. Electrophysiologic studies showed reduced compound muscle action potentials (CMAPs), suggesting peripheral impairment of neuromuscular function. The symptoms improved with potassium, but worsened with acetazolamide. There was no family history of a similar disorder. Sampedro Castaneda et al. (2018) noted the phenotypic similarities to hypokalemic periodic paralysis (see 170400) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations.
The transmission pattern of AHC1 in the family reported by Kanavakis et al. (2003) and Swoboda et al. (2004) was consistent with autosomal dominant inheritance.
In affected members of the family reported by Kanavakis et al. (2003), Swoboda et al. (2004) identified a thr378-to-asn mutation in the ATP1A2 gene (T378N; 182340.0005). Mutation analysis in 8 sporadic patients and affected subjects from 5 additional kindreds with alternating hemiplegia of childhood did not identify additional mutations in the ATP1A2 gene.
In 4 affected members of a Greek family with alternating hemiplegia of childhood, Bassi et al. (2004) identified the T378N mutation in the ATP1A2 gene. Mutation analysis of the ATP1A2 gene in 10 sporadic patients was negative.
In a 9-year-old Brazilian boy with episodic flaccid muscle weakness that was responsive to potassium supplementation, Sampedro Castaneda et al. (2018) identified a de novo heterozygous S779N variant (182340.0023) in the highly conserved K+ binding site of the enzyme. The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis.
Bassi, M. T., Bresolin, N., Tonelli, A., Nazos, K., Crippa, F., Baschirotto, C., Zucca, C., Bersano, A., Dolcetta, D., Boneschi, F. M., Barone, V., Casari, G. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J. Med. Genet. 41: 621-628, 2004. [PubMed: 15286158] [Full Text: https://doi.org/10.1136/jmg.2003.017863]
Bourgeois, M., Aicardi, J., Goutieres, F. Alternating hemiplegia of childhood. J. Pediat. 122: 673-679, 1993. [PubMed: 8496742] [Full Text: https://doi.org/10.1016/s0022-3476(06)80003-x]
Kanavakis, E., Xaidara, A., Papathanasiou-Klontza, D., Papadimitiou, A., Velentza, A., Youroukos, S. Alternating hemiplegia of childhood: a syndrome inherited with an autosomal dominant trait. Dev. Med. Child Neurol. 45: 833-836, 2003. Note: Erratum: Dev. Med. Child Neurol. 46: 288 only, 2004. [PubMed: 14667076] [Full Text: https://doi.org/10.1017/s0012162203001543]
Kramer, U., Nevo, Y., Margalit, D., Shorer, Z., Harel, S. Alternating hemiplegia of childhood in half-sisters. J. Child Neurol. 15: 128-130, 2000. [PubMed: 10695898] [Full Text: https://doi.org/10.1177/088307380001500212]
Mikati, M. A., Maguire, H., Barlow, C. F., Ozelius, L., Breakefield, X. O., Klauck, S. M., Korf, B., O'Tuama, S. L. A., Dangond, F. A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy; chromosomal studies; and physiologic investigations. Neurology 42: 2251-2257, 1992. [PubMed: 1361034] [Full Text: https://doi.org/10.1212/wnl.42.12.2251]
Rotstein, M., Doran, J., Yang, H., Ullner, P. M., Engelstad, K., De Vivo, D. C. GLUT1 deficiency and alternating hemiplegia of childhood. Neurology 73: 2042-2044, 2009. [PubMed: 19996082] [Full Text: https://doi.org/10.1212/WNL.0b013e3181c55ebf]
Sampedro Castaneda, M., Zanoteli, E., Scalco, R. S., Scaramuzzi, V., Marques Caldas, V., Conti Reed, U., da Silva, A. M. S., O'Callaghan, B., Phadke, R., Bugiardini, E., Sud, R., McCall, S., Hanna, M. G., Poulsen, H., Mannikko, R., Matthews, E. A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms. Brain 141: 3308-3318, 2018. [PubMed: 30423015] [Full Text: https://doi.org/10.1093/brain/awy283]
Swoboda, K. J., Kanavakis, E., Xaidara, A., Johnson, J. E., Leppert, M. F., Schlesinger-Massart, M. B., Ptacek, L. J., Silver, K., Youroukos, S. Alternating hemiplegia of childhood or familial hemiplegic migraine?: a novel ATP1A2 mutation. Ann. Neurol. 55: 884-887, 2004. [PubMed: 15174025] [Full Text: https://doi.org/10.1002/ana.20134]