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.
RDP has been characterized by: abrupt onset of dystonia over days to weeks with parkinsonism (primarily bradykinesia and postural instability); common bulbar involvement; and absence or minimal response to an adequate trial of L-dopa therapy, with few exceptions. Often fever, physiologic stress, or alcoholic binges trigger the onset of symptoms. After their initial appearance, symptoms often stabilize with little improvement; occasionally second episodes occur with abrupt worsening of symptoms. Rarely, affected individuals have reported a more gradual onset of symptoms over weeks to months. Anxiety, depression, and seizures have been reported. Age of onset ranges from four to 55 years, although a childhood variation of RDP with onset between ages nine and 14 months has been reported.
AHC is a complex neurodevelopmental syndrome most frequently manifesting in infancy or early childhood with paroxysmal episodic neurologic dysfunction including alternating hemiparesis or dystonia, quadriparesis, seizure-like episodes, and oculomotor abnormalities. Episodes can last for minutes, hours, days, or even weeks. Remission of symptoms occurs with sleep and immediately after awakening. Over time, persistent neurologic deficits including oculomotor apraxia, ataxia, choreoathetosis, dystonia, parkinsonism, and cognitive and behavioral dysfunction develop in the majority of those affected; more than 50% develop epilepsy in addition to their episodic movement disorder phenotype.
CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is characterized by episodes of ataxic encephalopathy and/or weakness during and after a febrile illness. Onset is between ages six months and four years. Some acute symptoms resolve; progression of sensory losses and severity vary.
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:
RDP. Triggers including alcohol, fever, psychological stress (e.g., childbirth), excessive exercise.
AHC. Triggers including psychological stress / excitement; environmental stressors (e.g., bright light, excessive heat or cold, excessive sound, crowds); water exposure (e.g., bathing, swimming); certain foods or odors (e.g., chocolate, food dyes); missed meals; excessive or atypically strenuous exercise; illness; irregular sleep (missing a nap, delayed bedtime).
CAPOS syndrome. Febrile illness, pregnancy.
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 anti-seizure 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 anti-seizure 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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