Clinical characteristics: ATP1A3-related neurologic disorders represent a clinical continuum in which at least three distinct phenotypes have been delineated: rapid-onset dystonia-parkinsonism (RDP); alternating hemiplegia of childhood (ACH); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). However, some affected individuals have intermediate phenotypes or only a few features that do not fit well into one of these major phenotypes.
Diagnosis/testing: Diagnosis of an ATP1A3-related neurologic disorder is established in an individual with the clinical features of RDP, AHC, or CAPOS syndrome and/or by the identification of a heterozygous pathogenic variant in ATP1A3.
Management: Treatment of manifestations: Standard treatment of visual disturbance, hearing loss, seizure disorders, cardiac arrhythmia, and cardiomyopathy. Consideration of CPAP or BiPAP for those with sleep apnea. Those with severe dysphagia may require a gastrostomy tube. Physical therapy, occupational therapy, and speech therapy for motor dysfunction, ataxia, and dysarthria. Acute spasms may respond to chloral hydrate or other medication that induces sleep. Dystonia can be treated with benzodiazepines, dopamine agonists, or levo-dopa. Psychotherapy and standard pharmacotherapy for those with mood disorder or psychosis. Early referral for developmental support / special education. Prevention of primary manifestations: Prophylaxis for AHC episodes may include flunarizine, topiramate, a ketogenic diet, and sleep. A trial of high-dose benzodiazepines may be considered in individuals with RDP and AHC. Triggers that lead to acute attacks should be avoided. Prevention of secondary complications: When dystonia is present, physical therapy to prevent contractures in the hands and feet. Surveillance. Affected individuals should be monitored for the development of dysphagia (RDP and CAPOS syndrome), seizures (RDP and AHC), and psychiatric symptoms (RDP). Agents/circumstances to avoid: Pregnancy management: Affected pregnant women should be monitored for the development of symptoms of RDP. The number of pregnant women with RDP is small, but several reports of childbirth as a trigger have been noted. Exposure to antiepileptic medication may increase the risk to the fetus of adverse outcome; that risk, however, is often less than the risk to the fetus associated with exposure to an untreated maternal seizure disorder. Discussion of the risks and benefits of using a given antiepileptic medication during pregnancy should ideally take place before conception.
Genetic counseling: ATP1A3-related neurologic disorders are inherited in an autosomal dominant manner. ATP1A3 pathogenic variants may be inherited or occur de novo. In contrast to initial reports a familial history is not required for a diagnosis of RDP. In AHC, pathogenic variants are more commonly de novo than inherited; in both RDP and CAPOS syndrome both inherited and de novo pathogenic variants have been observed. Each child of an individual with an ATP1A3-related neurologic disorder has a 50% chance of inheriting the ATP1A3 pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the ATP1A3 pathogenic variant in the family is known. The variability of presentation within a family with a known ATP1A3 pathogenic variant further complicates genetic counseling. Lifelong asymptomatic individuals who harbor a heterozygous ATP1A3 pathogenic variant have been reported in families with RDP.
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