Clinical Guidance

Although ATP1A3-related disorder is a continuum of neurologic manifestations, genotype-phenotype correlations for several ATP1A3 pathogenic variants have been reported . Phenotypes associated with certain pathogenic variants in multiple individuals include the following:

• AHC.

ATP1A3 pathogenic variant p.Asp801Asn is the most common variant, followed by pathogenic variants p.Glu815Lys and p.Gly947Arg . Individuals with the recurrent pathogenic variant p.Glu815Lys may have earlier onset of manifestations, more seizures, greater motor and cognitive impairment, and more rapid progression, including status epilepticus and respiratory paralysis, especially when compared to individuals with the other most common AHC pathogenic variant, p.Asp801Asn [, , , ].

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"

Diagnostic Criteria

No consensus diagnostic criteria for ATP1A3-related disorder have been published.

Suggestive Findings

ATP1A3-related disorder should be considered in individuals with features in any of the following four clinical categories .

Clinical category

• Paroxysmal neurologic episodes

• Hemiplegic events

• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy

• Seizures

• Abnormal eye movements

• Apnea

• Autonomic episodes

• Movement disorder

• Dystonia and/or chorea

• Ataxia

• Cognitive impairment. Mild to severe

• Neurobehavioral/psychiatric manifestations

• Behavioral difficulties

• Attention-deficit/hyperactivity disorder

• Autism spectrum disorder

• Childhood-onset schizophrenia

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"

Management Guidelines

No clinical practice guidelines for ATP1A3-related disorder have been published. In the absence of established clinical practice guidelines, the authors offer the recommendations discussed in this section based on their collective experience in working with more than 20 families over more than 15 years.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ATP1A3-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 6.

ATP1A3-Related Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval by neurologist experienced in movement disorders | Assess for:

• Episodic or persistent weakness;

• Movement disorders (e.g., dystonia, chorea, ataxia);

• Dysfunctions of speech swallowing;

• Hypo- or hypertonia;

• Cognitive manifestations (e.g., apraxia, frontal lobe dysfunction).

Obtain history of:

• Seizures;

• Headaches.

Musculoskeletal/ADL

| Orthopedics/ physical medicine rehab/ PT OT eval | Assess for:

• Gross motor fine motor skills;

• Contractures, pes cavus, kyphoscoliosis;

• Mobility, ADL, need for adaptive devices;

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills).

Speech

| Eval by speech-language pathologist | Assess for speech dyspraxia, dysphonia, /or dysarthria

Dysphagia/ Feeding difficulty

| Gastroenterology/ nutrition/ feeding team eval | • To incl eval of aspiration...

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"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 8. ATP1A3-Related Disorder: Recommended Surveillance

Source: GeneReviews — "ATP1A3-Related Disorder"