ATP1A3-Related Neurologic Disorders

The spectrum of ATP1A3-related neurologic disorders includes rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. While early reports emphasized the distinctness of RDP and AHC, it is increasingly evident that these conditions represent a spectrum related to mutation of ATP1A3. Because only ten individuals from three families and one individual with a de novo mutation have been described with CAPOS syndrome to date, its phenotype is less defined; however, some features overlap with RDP and AHC as well. RDP is characterized by abrupt onset of dystonia with parkinsonism (primarily bradykinesia and postural instability); a clear rostrocaudal (face>arm>leg) topological gradient of involvement; bulbar involvement; and absence of response to an adequate trial of L-dopa therapy. 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. Anxiety, depression, and seizures have been reported. Age of onset is four to 55 years. 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 develop in the majority of those affected, including oculomotor apraxia, ataxia, choreoathetosis, dystonia, parkinsonism, and cognitive and behavioral dysfunction; more than 50% develop epilepsy in addition to their episodic movement disorder phenotype. CAPOS syndrome (a mnemonic for cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss) is characterized by episodes of ataxic encephalopathy and/or weakness after a febrile illness. Onset is between ages six months and five years. Some acute symptoms resolve; disease progression and severity vary.
Diagnosis of an ATP1A3-related neurologic disorder is suspected in an individual with the classic clinical features of RDP, AHC, or CAPOS syndrome and confirmed by detection of a heterozygous pathogenic variant in ATP1A3.
Treatment of manifestations: RDP. High-dose benzodiazepines in some, and standard treatment for seizures, dysphagia, and depression and anxiety. AHC. Avoiding triggers; reducing the frequency and/or severity of recurrent paroxysmal episodes with medication (e.g., flunarizine, topiramate) or by sleep (either natural or induced with medications such as benzodiazepines or chloral hydrate). Standard treatment of seizures. CAPOS syndrome. Treatment of manifestations apart from hearing and visual aids has not been reported. Management includes physical therapy to prevent contractures and monitoring of swallow function to reduce the risk for aspiration. Agents/circumstances to avoid: RDP. Triggers including alcohol, fever, psychological stress, 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 .
ATP1A3-related neurologic disorders are inherited in an autosomal dominant manner. ATP1A3 mutations may be inherited or de novo. In AHC, de novo mutations are more common than inherited; in both RDP and CAPOS syndrome both inherited and de novo mutations 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.
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