Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood-onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.