Clinical characteristics: ATP1A3-related disorder consists of heterogenous overlapping clinical findings that pertain to the four most common historically defined phenotypes: alternating hemiplegia of childhood (AHC); cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome; relapsing encephalopathy with cerebellar ataxia (RECA) / fever-induced paroxysmal weakness and encephalopathy (FIPWE); and rapid-onset dystonia-parkinsonism (RDP). These phenotypes exist on a spectrum and should be regarded as classifications of convenience.

AHC is characterized by onset prior to age 18 months of paroxysmal hemiplegic episodes, predominately involving the limbs and/or the whole body, lasting from minutes to hours to days (and sometimes weeks) with remission only during sleep, only to resume after awakening. Although paroxysmal episodic neurologic dysfunction predominates early in the disease course, with age increasingly persistent neurologic dysfunction predominates, including oculomotor apraxia and strabismus, dysarthria, speech and language delay, developmental delay, and impairment in social skills. Other system involvement may include cardiovascular (cardiac conduction abnormalities) and gastrointestinal (constipation, vomiting, anorexia, diarrhea, nausea, and abdominal pain) manifestations.

CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever. The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma. Usually, considerable recovery occurs within days to weeks; however, persistence of some degree of ataxia and other manifestations is typical.

RECA/FIPWE primarily presents with fever-induced episodes (infancy to age 5 years); however, first episodes can occur occasionally in young adults during illnesses such as mononucleosis. Recurrent fever-induced episodes may be ataxia-dominated RECA-like motor manifestations or FIPWE-like non-motor manifestations (encephalopathy) and can vary among affected individuals. Notably, RECA-like and FIPWE-like manifestations can occur in the same individual in different episodes. In some individuals episodes seem to decrease in frequency and severity over time, whereas others might experience worsening of manifestations.

RDP presents in individuals ages 18 months to 60 years and older with dystonia that is typically of abrupt onset over hours to several weeks, though some individuals report gradual onset over the course of months. A stress-related trigger is identifiable in up to 75% of individuals. Dystonia rarely improves significantly after onset; some individuals report mild improvement over time, whereas others can experience subsequent episodes of abrupt worsening months to years after onset. Limbs are usually the first to be affected, although by the time of diagnosis – typically many years after onset – individuals most commonly display a bulbar-predominant generalized dystonia. Exceptions are common and a rostrocaudal gradient is rare rather than typical. Migraines and seizures are also observed.

Diagnosis/testing: The diagnosis of ATP1A3-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in ATP1A3 identified by molecular genetic testing.

Management: There is no cure for ATP1A3-related disorder. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in neurology, developmental pediatrics, orthopedics, physical medicine and rehabilitation, speech-language therapy, psychology, mental health, ophthalmology, social work, and medical genetics.

Surveillance: Regularly scheduled evaluations by the treating specialists are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Agents/circumstances to avoid: To the extent possible, individuals who are heterozygous for an ATP1A3 pathogenic variant should avoid the known triggers for manifestations and/or episodes that include physical, psychological (e.g., missed meals, sleep deprivation), and emotional stress (e.g., excitement, fear); environmental stress (e.g., bright sunlight or fluorescent lighting, heat/cold, excessive noise, crowds); excessive or atypically strenuous exercise; and excessive use of alcohol.

Evaluation of relatives at risk: Clarification of the genetic status of apparently asymptomatic older and younger at-risk relatives is appropriate to identify as early as possible those who should be evaluated for cardiac conduction abnormalities and who should be advised about agents/circumstances to avoid.

Genetic counseling: ATP1A3-related disorder – including the four historically defined phenotypes of AHC, CAPOS syndrome, RECA/FIPWE, and RDP – is inherited in an autosomal dominant manner. Most individuals with a more severe ATP1A3-related phenotype (e.g., AHC) have the disorder as the result of a de novo pathogenic variant. About half of individuals with a relatively less severe ATP1A3-related phenotype (e.g., CAPOS syndrome or RDP) have the disorder as the result of a pathogenic variant inherited from an affected parent; about half of individuals have an apparently de novo pathogenic variant. Each child of an individual with ATP1A3-related disorder has a 50% chance of inheriting the pathogenic variant. Once the ATP1A3 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.