Clinical Guidance

Following the initial description of rapid-onset dystonia-parkinsonism (RDP) by prior to knowledge of its genetic cause, the understanding of the scope of ATP1A3-related disorder subsequently expanded to include four 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 RDP. The widespread use of exome and genome sequencing (i.e., non-hypothesis-driven molecular genetic testing) led to conceptualize ATP1A3-related disorder as encompassing "a broadly heterogeneous continuum of features" shared among the historical clinically defined phenotypes .

Source: GeneReviews — "ATP1A3-Related Disorder"

Penetrance

AHC and FIPWE. Penetrance is uncertain, as to date most individuals with these phenotypes have a de novo ATP1A3 pathogenic variant. CAPOS syndrome. There is no evidence of reduced penetrance in the families/individuals reported to date [, , , ]. At current writing more than half of CAPOS syndrome case reports include families with more than one affected member. RDP. The small number of families with RDP studied to date limits the estimate of penetrance; however, several members of larger reported families have had a heterozygous ATP1A3 pathogenic variant but no clinical manifestations .

Source: GeneReviews — "ATP1A3-Related Disorder"

Differential Diagnosis

Alternating Hemiplegia of Childhood

Given the early onset and protean neurologic manifestations in affected infants and young children, the differential diagnosis of alternating hemiplegia of childhood (AHC) is unavoidably broad. It is particularly important early in the diagnostic evaluation of an individual suspected of having AHC to exclude metabolic disorders or vascular syndromes that could benefit from specific therapeutic approaches, including moyamoya disease (OMIM PS252350); mitochondrial disorders such as pyruvate dehydrogenase deficiency (in which spells are typically accompanied by lactic acidosis; see Primary Pyruvate Dehydrogenase Complex Deficiency Overview); and glucose transporter type 1 deficiency syndrome, in which seizures tend to respond to a ketogenic diet.

Source: GeneReviews — "ATP1A3-Related Disorder"

Clinical Guidance

To the extent possible, individuals who are heterozygous for an ATP1A3 pathogenic variant should avoid agents/circumstances known to trigger onset of ATP1A3-related disorder manifestations and/or episodes , including the following:

• 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 (e.g., walking farther than usual)

• Alcohol binges

Illness, infections, and fever are common triggers. While practical preventive strategies are lacking, unnecessary exposure should be avoided. Helmets and protective devices to prevent head injuries should be worn when participating in activities with risk of fall. There is no known reason to avoid vaccinations.

Source: GeneReviews — "ATP1A3-Related Disorder"

Therapies Under Investigation

A clinical trial studying the variable phenotypic presentations of ATP1A3-related disorder is recruiting (NCT00682513). Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "ATP1A3-Related Disorder"