Alternating hemiplegia of childhood is a rare syndrome characterized by infantile onset of episodic hemi-or quadriplegia. Most cases are accompanied by dystonic posturing, choreoathetoid movements, abnormal ocular movements, developmental delay, and progressive cognitive impairment (summary by Heinzen et ... Alternating hemiplegia of childhood is a rare syndrome characterized by infantile onset of episodic hemi-or quadriplegia. Most cases are accompanied by dystonic posturing, choreoathetoid movements, abnormal ocular movements, developmental delay, and progressive cognitive impairment (summary by Heinzen et al., 2012). For discussion of genetic heterogeneity of alternating hemiplegia of childhood, see AHC1 (104290).
Verret and Steele (1971) first characterized alternating hemiplegia in childhood as a distinct condition. They reported 8 patients, including 2 sibs, with the disorder. All had intermittent hemiparesis of variable severity beginning in infancy or early childhood. Episodes ... Verret and Steele (1971) first characterized alternating hemiplegia in childhood as a distinct condition. They reported 8 patients, including 2 sibs, with the disorder. All had intermittent hemiparesis of variable severity beginning in infancy or early childhood. Episodes usually lasted minutes or hours, with a few patients having weakness for several days. Only 2 patients had intermittent seizures. Four patients had residual neurologic deficits including mental retardation and a movement disorder, such as dystonia and/or choreoathetosis. Attacks ceased spontaneously in 2 patients by age 4 years. EEG in all patients showed no constant focal abnormality or evidence of seizure activity. Some patients later developed headaches, and all had relatives with migraine headaches. Heinzen et al. (2012) reported 82 patients with AHC2 confirmed by genetic analysis. Affected individuals had infantile onset of hemiplegic attacks, usually associated with episodes of quadriparesis, abnormal eye movements, autonomic signs, seizures, dystonia, ataxia, chorea, and developmental delay. Most cases occurred sporadically, but there was 1 family of Puerto Rican origin in which 4 affected individuals were described in detail. One child in this family had onset at 2 months of age of tonic stiffening and eye deviation, but without loss of consciousness. By age 1 year, he had episodes of flaccid hemiplegia alternating with dystonia. He also had generalized tonic-clonic seizures that stopped by age 5 years. Hemiplegic episodes lasted from 5 to 30 minutes, and EEG showed no abnormalities during episodes. In childhood, he showed permanent neurologic sequelae, including mild cognitive impairment, ataxia, chorea, and dysarthria. At age 16 years, he had episodic severe dystonia and parkinsonism several times per month. This patient's brother developed whole body stiffening at age 3 years. Typical spells rendered him mute and unable to ambulate. In childhood, he had mild cognitive impairment, behavioral abnormalities, hypotonia, ataxia, dysarthria, and chorea. Since childhood, the father had episodic hemiplegic spells since childhood, accompanied by tonic or dystonic stiffening and abnormal eye movements. He also had rare generalized seizures. At age 41 years, he had neurocognitive deficits, depression, and anxiety. The father's brother had onset of hemi- and quadriplegia since age 6 months. As an adult, he continued to have episodes of flaccidity or parkinsonism-like rigidity.
In 82 of 105 patients with alternating hemiplegia of childhood, Heinzen et al. (2012) identified 19 different heterozygous mutations in the ATP1A3 gene (see, e.g., 182350.0009-182350.0012). The first mutations were identified through exome sequencing of affected individuals. Thirteen ... In 82 of 105 patients with alternating hemiplegia of childhood, Heinzen et al. (2012) identified 19 different heterozygous mutations in the ATP1A3 gene (see, e.g., 182350.0009-182350.0012). The first mutations were identified through exome sequencing of affected individuals. Thirteen of the 18 mutations observed in sporadic cases were confirmed to occur de novo in multiple cases. Since it was possible that some variants represented polymorphisms, Heinzen et al. (2012) estimated that mutations in the ATP1A3 gene may be responsible for up to 74% of patients with sporadic, typical AHC. Several mutations were recurrent, and some occurred within hypermutable sequences. In vitro functional expression studies of several of the mutations showed that they caused reductions in protein activity without affecting the level of protein expression.