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.

Suggestive Findings

ATP1A3-related disorder should be considered in individuals with features in any of the following four clinical categories [Vezyroglou et al 2022].

Clinical category

• Paroxysmal neurologic episodes
  • Hemiplegic events
  • Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [Termsarasab et al 2015]
  • 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 [Smedemark-Margulies et al 2016, Vezyroglou et al 2022]

Imaging findings. Most individuals have a normal brain MRI; however, focal atrophies have been reported [Arizono et al 2023]. A less common finding is cerebellar atrophy that sometimes occurs in conjunction with ataxia.

Family history may suggest autosomal dominant inheritance with affected males and females in multiple generations (more commonly observed in association with relatively less severe phenotypes), or a proband may be the only family member known to be affected (more commonly observed with more severe phenotypes). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of ATP1A3-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ATP1A3 identified by molecular genetic testing (Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous ATP1A3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include comprehensive genomic testing (exome sequencing, genome sequencing) or gene-targeted testing (multigene panel). Comprehensive genomic testing does not require that the clinician determine which gene(s) are likely involved, whereas use of a multigene panel does.

Note: (1) Single-gene testing (sequence analysis of ATP1A3, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. (2) Given the broad phenotypic spectrum of this disorder (see Scope), use of a multigene panel may also be too restrictive.

• Comprehensive genomic testing. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of ATP1A3 pathogenic variants reported (e.g., missense, splice, and in-frame codon insertion/deletions) are within the coding region and are likely to be identified on exome sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel that includes ATP1A3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Following the initial description of rapid-onset dystonia-parkinsonism (RDP) by Dobyns et al [1993] 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 Salles & Fernandez [2020] to conceptualize ATP1A3-related disorder as encompassing "a broadly heterogeneous continuum of features" shared among the historical clinically defined phenotypes (see Figure 1).

Figure 1.

The overlapping clinical findings in the most common historically defined phenotypes of ATP1A3-related disorder: 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)

Adapted with permission from Salles & Fernandez [2020]

RDP

The RDP phenotype was initially named because its delayed and rapid onset was thought to be distinctive; however, over time it became apparent that dystonia and bradykinesia, its predominant manifestations, are common in the other ATP1A3-related phenotypes [Haq et al 2019].

Acute presentation. The acute onset of RDP may be preceded by mild nonspecific manifestations of dystonia, including limb cramping (most often the hands or arms) [Haq et al 2019].

Primary onset occurs between ages four and 55 years (range: 9 months to >60 years) with dystonia characterized by the following (see Haq et al [2019] and Figure 2):

Figure 2.

In a cohort of individuals with ATP1A3-related rapid-onset dystonia-parkinsonism (RDP), persons progressed to diffuse involvement without rostrocaudal gradient. Predominance of any dystonia at onset is seen on the left and at initial study visit is seen (more...)

• Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [Haq et al 2019].
• Prominent bulbar findings include impairment of speech, voice, and swallowing [Haq et al 2019, Moya-Mendez et al 2020].
• There is minimal or no tremor at onset.
• Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [Haq et al 2019].

Progression typically stops at or before one month after onset with little subsequent improvement.

Subsequent disease course

• Dystonia. Although 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. These events resemble the primary onset, with worsening of bulbar, arm, and leg manifestations over a similar time course; however, because only a few affected individuals have been reexamined over an extended time, documentation of subsequent events is incomplete.
  Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
• Non-motor features include the following:
  • Cognitive impairment, a relatively common finding, often precedes motor onset. This can include difficulty with memory and learning, psychomotor speed, attention, and executive functioning. These differences persist after controlling for psychomotor speed and severity of depressive symptoms [Cook et al 2014].
  • Neurobehavioral/psychiatric manifestations. Although their scores are in the normal range, individuals with RDP frequently report anxiety, depression, general mood disorders, and substance abuse (though not at frequencies significantly higher than those in familial controls). Psychosis was more frequently reported in individuals with RDP (20% vs 0% in familial controls) [Haq et al 2019].
  • Headaches are significantly more common among individuals with RDP than familial controls (68% vs 40%) [Haq et al 2019].

Prognosis. Life expectancy, to date, has been normal. Level of neurologic functioning is highly variable.

Genotype-Phenotype Correlations

Although ATP1A3-related disorder is a continuum of neurologic manifestations, genotype-phenotype correlations for several ATP1A3 pathogenic variants have been reported [Salles & Fernandez 2020, Vezyroglou et al 2022] (see Table 9).

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 [Uchitel et al 2021].
  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 [Sasaki et al 2014b, Yang et al 2014, Panagiotakaki et al 2015, Viollet et al 2015].
• CAPOS syndrome. A unique correlation has been reported between the p.Glu818Lys pathogenic variant and its fever-induced ataxia phenotype [Demos et al 2014, Tranebjærg et al 2018]. While glutamate 818 is in a short cytoplasmic loop near glutamate 815, which is mutated in many individuals with AHC, CAPOS syndrome has little clinical overlap with AHC. Some individuals with the p.Glu818Lys pathogenic variant manifest only the auditory neuropathy phenotype of CAPOS syndrome [Tranebjærg et al 2018, Lee et al 2020, Lax et al 2021, Wang et al 2021]. However, individuals and family members with the p.Glu818Lys pathogenic variant should be considered at risk of disease progression and development of other features of CAPOS syndrome.
• RECA/FIPWE is due to alternative pathogenic variants of the single ATP1A3 residue p.Arg756 that has been mutated to His, Cys, or Leu [Brashear et al 2012a, Dard et al 2015, Yano et al 2017, Sabouraud et al 2019, Zhang et al 2022].

Intermediate phenotypes (those showing overlap across disease phenotypes), often with onset in childhood, have been reported in individuals with the following ATP1A3 pathogenic variants: p.Gly358Asp, p.Gly867Asp, p.Asp923Asn, and p.Glu951Lys [Anselm et al 2009, Brashear et al 2012b, Roubergue et al 2013, Rosewich et al 2014, Panagiotakaki et al 2015, Pereira et al 2015, Termsarasab et al 2015, Jaffer et al 2017].

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 [Demos et al 2014, Maas et al 2016, Duat Rodriguez et al 2017, Tranebjærg et al 2018]. 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 [Brashear et al 2007, Oblak et al 2014, Haq et al 2019].

Nomenclature

Rapid-onset dystonia-parkinsonism (RDP) is also referred to as DYT/PARK-ATP1A3 (formerly DYT12). Because classic signs of Parkinson disease, such as tremor, are unusual in individuals with RDP, the term "parkinsonism" in the designation "RDP" represents a subset of parkinsonian manifestations, and the disorder is classified as combined dystonia (previously called dystonia-plus). See Hereditary Dystonia Overview for more information.

Prevalence

The prevalence of ATP1A3-related disorder is unknown. However, because AHC is by far the most common phenotype in ATP1A3-related disorder, the estimated prevalence of AHC at 1:1,000,000 should be close to the overall prevalence of this disorder [Uchitel et al 2021]. More than 1,000 individuals with ATP1A3-related disorder have been reported in the literature Vezyroglou et al [2022].

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. The paroxysmal nature of features in AHC can also mimic inborn errors of neurotransmitter biosynthesis and metabolism such as aromatic L-amino acid decarboxylase deficiency and tyrosine hydroxylase deficiency. Studies of cerebrospinal fluid neurotransmitters are necessary to exclude this group of disorders early in the clinical course (and prior to ATP1A3 molecular genetic testing), since targeted treatments for these disorders (e.g., neurotransmitter precursors and pyridoxine or dopamine receptor agonist therapy) are available.

The often prolonged episodes of hemiparesis, dystonia, or quadriplegia observed early in the course of AHC are typically not associated with epileptiform activity on EEG, a finding that can help to distinguish AHC from early-infantile developmental and epileptic encephalopathy (OMIM PS308350).

Specific disorders and alternative genetic etiologies to consider include those listed in Table 4. Of note, pathogenic variants in several genes have been identified in individuals with phenotypes consistent with AHC but without pathogenic variants in ATP1A3, including CLDN5, SCN2A, TANGO2, and TBC1D24.

CAPOS Syndrome

The combination of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss is unique to CAPOS syndrome. However, an individual with the CAPOS syndrome-related ATP1A3 pathogenic variant p.Glu818Lys may present with a subset of these features (e.g., sensorineural hearing loss in association with areflexia; or cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing without pes cavus) or may present with a single feature (e.g., apparently isolated hearing loss [Lee et al 2020, Lax et al 2021]). (Note: Individuals with the p.Glu818Lys pathogenic variant and only a single feature, or a subset of CAPOS syndrome-related features, should be considered at risk for progression.) Subsets of features seen in CAPOS syndrome and the individual features themselves elicit a broad differential diagnosis including mitochondrial and peroxisomal disorders.

RECA/FIPWE

The differential diagnosis of fever-induced manifestations such as weakness and ataxia is broad and includes the episodic ataxias (see Hereditary Ataxia Overview) [Olszewska et al 2023] and numerous other genetic and non-genetic causes of ataxia. Acute infection and autoimmune disease in particular must be excluded from the differential diagnosis of relapsing encephalopathy with cerebellar ataxia (RECA) / fever-induced paroxysmal weakness and encephalopathy (FIPWE).

Rapid-Onset Dystonia-Parkinsonism

Forms of dystonia-parkinsonism that are more common than rapid-onset dystonia-parkinsonism (RDP) (see Hereditary Dystonia Overview and Parkinson Disease Overview) and potentially treatable must be excluded from the differential diagnosis. Evaluations should include brain MRI and assessment for Wilson disease. Additionally, administration of levodopa should be trialed; in RDP, the brain MRI is grossly normal and the response to levodopa is usually transient or minimal, with only one reported exception [Termsarasab et al 2015].

The differential diagnosis of RDP includes the genes listed in Table 5.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ATP1A3-related disorder, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for ATP1A3-related disorder. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 7.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Agents/Circumstances to Avoid

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 [Sweney et al 2009], 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.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with ATP1A3-related disorder in order to identify as early as possible those who should be evaluated for cardiac conduction abnormalities (see Table 6) and who should avoid triggers such as excessive alcohol and exercise (see Agents/Circumstances to Avoid).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

It is recommended that during pregnancy a woman with ATP1A3-related disorder be monitored for manifestations of RDP, onset of which has followed childbirth in some (not all) women who are heterozygous for an ATP1A3 pathogenic variant. Pregnancy can also trigger worsening of symptoms in women with CAPOS syndrome [Chang et al 2018].

In principle, abortion or cesarean section could be sufficiently stressful to trigger an episode.

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place before conception. Transitioning to a lower-risk ASM before pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

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.

Mode of Inheritance

ATP1A3-related disorder – including the four historically defined phenotypes of 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) – is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Individuals with ATP1A3-related disorder may have the disorder as the result of a pathogenic variant inherited from a parent.
  • Very rarely, individuals with a more severe ATP1A3-related phenotype (e.g., AHC) have the disorder as the result of an ATP1A3 pathogenic variant inherited from an affected parent [Heinzen et al 2012].
  • About half of individuals diagnosed with a relatively less severe ATP1A3-related phenotype (e.g., CAPOS syndrome or RDP) have the disorder as the result of an ATP1A3 pathogenic variant inherited from an affected parent [de Carvalho Aguiar et al 2004, Demos et al 2014].
  • Some individuals with RDP have the disorder as the result of an ATP1A3 pathogenic variant inherited from an asymptomatic heterozygous parent [Dobyns et al 1993, Haq et al 2019].
• Individuals with ATP1A3-related disorder may have the disorder as the result of a de novo pathogenic variant.
  • Most individuals with AHC have the disorder as the result of a de novo pathogenic variant [Heinzen et al 2012, Rosewich et al 2012].
  • About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [Vezyroglou et al 2022], FIPWE/RECA [Biela et al 2021, Vezyroglou et al 2022, Sano et al 2023], or RDP [Haq et al 2019] have an apparently de novo pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the ATP1A3 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited an ATP1A3 pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [Hully et al 2017, Yang et al 2019, Vezyroglou et al 2022, Li et al 2023]. * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an ATP1A3 pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with ATP1A3-related disorder may appear to be negative because of a milder phenotypic presentation or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the ATP1A3 pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of a proband is affected and/or is known to have an ATP1A3 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Sibs who inherit an ATP1A3 pathogenic variant typically share the same phenotypic features as the proband; however, severity varies.
• If the ATP1A3 pathogenic variant identified in the proband cannot be detected in either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism [Hully et al 2017].
• If the parents have not been tested for the ATP1A3 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for ATP1A3-related disorder because of the possibility of reduced penetrance [Oblak et al 2014] in a heterozygous parent and the possibility of parental gonadal mosaicism [Hully et al 2017, Yang et al 2019, Vezyroglou et al 2022, Li et al 2023].

Offspring of a proband. Each child of an individual with ATP1A3-related disorder has a 50% chance of inheriting the ATP1A3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the ATP1A3 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the ATP1A3 pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Issues unique to RDP. Because of the sudden onset of RDP, at-risk individuals may become hypervigilant about symptoms. Serious psychological issues have been observed in families [Brashear et al 2012a, Haq et al 2019].

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the ATP1A3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ATP1A3 encodes the alpha-3 subunit of the sodium/potassium-transporting ATPase (Na⁺/K⁺-ATPase). Na⁺/K⁺-ATPase has three types of subunits (alpha, beta, and FXYD), each of which has multiple isoforms. The catalytic alpha subunit has three isoforms (alpha-1, alpha-2, and alpha-3) expressed in the central nervous system (CNS) by three distinct genes, ATP1A1, ATP1A2, and ATP1A3, respectively [Moseley et al 2003, Sweadner et al 2019]. Although found in a few peripheral cell types, ATP1A3 is expressed exclusively in neurons in the CNS [McGrail et al 1991, Sweadner et al 2019].

The Na⁺/K⁺-ATPases convert metabolic energy by moving Na⁺ ions out of the cell and K⁺ ions into the cell, restoring the ion gradients reduced by the activity of ion channels and Na⁺-dependent carriers. In the central nervous system (CNS), the Na⁺/K⁺-ATPase is harnessed for reuptake of glutamate and other transmitters, extracellular K⁺ buffering, extrusion of Ca²⁺ by Na⁺/Ca²⁺ exchange, and the regulation of cell volume. Because it transports three Na⁺ ions out of the cell for every two K⁺ ions transported in, it is electrogenic and makes a small direct hyperpolarizing contribution to membrane potential.

Mechanism of disease causation. Both functional studies and structural analysis of the alpha-3 subunit of the Na⁺/K⁺-ATPase suggest that missense ATP1A3 variants impair enzyme activity or stability [de Carvalho Aguiar et al 2004, Heinzen et al 2012, Sweadner et al 2019]; however, this loss of function can occur by haploinsufficiency or by dominant-negative effects.

ATP1A3-specific laboratory technical considerations. The 5' end of the three reported ATP1A3 transcripts differ in length, often resulting in conflicting variant numbering in online databases (i.e., ClinVar) and the literature (e.g., several publications reported known variants as "novel" variants). Thus, the authors recommend that all reports use the "MANE select" (Matched Annotation from NCBI and EMBL-EBI) transcript numbering for both cDNA and protein variant identification, as to date it is the only transcript whose expression in the brain has been validated (see www.gtexportal.org). The reference sequence for the MANE select transcript is NM_152296 (NCBI) or ENST00000648268.1 (ensemble) and the encoded protein (NCBI: NP_689509) is 1,013 amino acids long.

Author Notes

Drs Brashear and Haq are actively involved in clinical research regarding individuals with ATP1A3-related disorder. They would be happy to communicate with persons who have any questions regarding diagnosis of ATP1A3-related disorder or other considerations.

Contact Drs Sweadner and Ozelius to inquire about review of ATP1A3 variants of uncertain significance.

Acknowledgments

The authors would like to thank Dr William B Dobyns and Dr Vicki Wheelock for their contributions to this research and all the families and patients who participated in this research.

Author History

Allison Brashear, MD (2008-present)
Jared F Cook, MA; Wake Forest University School of Medicine (2014-2024)
Ihtsham Haq, MD (2024-present)
Eleonora Napoli, PhD (2024-present)
Laurie Ozelius, PhD (2008-present)
Kathleen J Sweadner, PhD (2008-present)
Kathryn J Swoboda, MD; Massachusetts General Hospital (2014-2024)

Revision History

• 5 December 2024 (bp) Comprehensive update posted live; title changed
• 22 February 2018 (ma) Comprehensive update posted live
• 6 November 2014 (me) Comprehensive update posted live; title changed
• 25 August 2011 (me) Comprehensive update posted live
• 7 February 2008 (me) Review posted live
• 5 October 2007 (ab) Original submission

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