Clinical characteristics.

ATP1A3-related neurologic disorders represent a clinical continuum in which at least three distinct phenotypes have been delineated: rapid-onset dystonia-parkinsonism (RDP); alternating hemiplegia of childhood (ACH); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). However, some affected individuals have intermediate phenotypes or only a few features that do not fit well into one of these major phenotypes.

• RDP has been characterized by: abrupt onset of dystonia over days to weeks with parkinsonism (primarily bradykinesia and postural instability); common bulbar involvement; and absence or minimal response to an adequate trial of L-dopa therapy, with few exceptions. 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. Rarely, affected individuals have reported a more gradual onset of symptoms over weeks to months. Anxiety, depression, and seizures have been reported. Age of onset ranges from four to 55 years, although a childhood variation of RDP with onset between ages nine and 14 months has been reported.
• 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 including oculomotor apraxia, ataxia, choreoathetosis, dystonia, parkinsonism, and cognitive and behavioral dysfunction develop in the majority of those affected; more than 50% develop epilepsy in addition to their episodic movement disorder phenotype.
• CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is characterized by episodes of ataxic encephalopathy and/or weakness during and after a febrile illness. Onset is between ages six months and four years. Some acute symptoms resolve; progression of sensory losses and severity vary.

Diagnosis/testing.

Diagnosis of an ATP1A3-related neurologic disorder is established in an individual with the clinical features of RDP, AHC, or CAPOS syndrome and/or by the identification of a heterozygous pathogenic variant in ATP1A3.

Management.

Treatment of manifestations: Standard treatment of visual disturbance, hearing loss, seizure disorders, cardiac arrhythmia, and cardiomyopathy. Consideration of CPAP or BiPAP for those with sleep apnea. Those with severe dysphagia may require a gastrostomy tube. Physical therapy, occupational therapy, and speech therapy for motor dysfunction, ataxia, and dysarthria. Acute spasms may respond to chloral hydrate or other medication that induces sleep. Dystonia can be treated with benzodiazepines, dopamine agonists, or levo-dopa. Psychotherapy and standard pharmacotherapy for those with mood disorder or psychosis. Early referral for developmental support / special education.

Prevention of primary manifestations: Prophylaxis for AHC episodes may include flunarizine, topiramate, a ketogenic diet, and sleep. A trial of high-dose benzodiazepines may be considered in individuals with RDP and AHC. Triggers that lead to acute attacks should be avoided.

Prevention of secondary complications: When dystonia is present, physical therapy to prevent contractures in the hands and feet.

Surveillance. Affected individuals should be monitored for the development of dysphagia (RDP and CAPOS syndrome), seizures (RDP and AHC), and psychiatric symptoms (RDP).

Agents/circumstances to avoid:

• RDP. Triggers including alcohol, fever, psychological stress (e.g., childbirth), 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, pregnancy.

Pregnancy management: Affected pregnant women should be monitored for the development of symptoms of RDP. The number of pregnant women with RDP is small, but several reports of childbirth as a trigger have been noted. Exposure to anti-seizure medication may increase the risk to the fetus of adverse outcome; that risk, however, is often less than the risk to the fetus associated with exposure to an untreated maternal seizure disorder. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before conception.

Genetic counseling.

ATP1A3-related neurologic disorders are inherited in an autosomal dominant manner. ATP1A3 pathogenic variants may be inherited or occur de novo. In contrast to initial reports a familial history is not required for a diagnosis of RDP. In AHC, pathogenic variants are more commonly de novo than inherited; in both RDP and CAPOS syndrome both inherited and de novo pathogenic variants 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. The variability of presentation within a family with a known ATP1A3 pathogenic variant further complicates genetic counseling. Lifelong asymptomatic individuals who harbor a heterozygous ATP1A3 pathogenic variant have been reported in families with RDP.

Suggestive Findings

ATP1A3-related neurologic disorders should be suspected in individuals with the following clinical features (by age) and neuroimaging findings [Rosewich et al 2017].

Establishing the Diagnosis

The diagnosis of an ATP1A3-related neurologic disorder is established in a proband with classic clinical features of RDP, AHC, or CAPOS syndrome (see Clinical Description) and/or by the identification of a heterozygous pathogenic (or likely pathogenic) variant in ATP1A3 by molecular genetic testing (Table 1).

Note: 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 section is understood to include likely pathogenic variants.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, or comprehensive genomic testing:

• Single-gene testing. Sequence analysis of ATP1A3 is performed.
• A multigene panel that includes ATP1A3 and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel 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. (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.
• Comprehensive genomic testing (when available) including exome and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

ATP1A3-related neurologic disorders represent a clinical continuum in which three main phenotypes have been described: rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Individuals with intermediate phenotypes or with only a few features have also been described (see Genotype-Phenotype Correlations).

Pathophysiology

Neuropathology specimens from persons with RDP show changes in neuronal pathways, suggesting involvement of cerebral and cerebellar connections necessary for motor control [Oblak et al 2014].

Genotype-Phenotype Correlations

Review of published studies has shown that the same pathogenic variant may lead to different phenotypes (e.g., RDP in one family but AHC in another), suggesting that ATP1A3-related disorders truly represent a continuum of phenotypes [de Carvalho Aguiar et al 2004, Zanotti-Fregonara et al 2008, Heinzen et al 2012, Roubergue et al 2013, Boelman et al 2014, Rosewich et al 2014b, Yang et al 2014, Viollet et al 2015].

AHC. Individuals with AHC and the pathogenic variant p.Glu815Lys may have earlier onset of symptoms and greater motor and cognitive impairment, and more often experience status epilepticus and respiratory paralysis [Sasaki et al 2014b, Yang et al 2014, Panagiotakaki et al 2015, Viollet et al 2015].

Intermediate and atypical phenotypes

• Intermediate phenotypes, often with onset in the childhood years, have also been reported in individuals with the following pathogenic variants: p.Gly358Asp, p.Arg756His, p.Gly867Asp, p.Asp923Asn, and p.Glu951Lys [Anselm et al 2009, Brashear et al 2012b, Roubergue et al 2013, Rosewich et al 2014a, Sasaki et al 2014a, Panagiotakaki et al 2015, Pereira et al 2015, Termsarasab et al 2015, Jaffer et al 2017].
• Childhood-onset schizophrenia with long-standing mild motor delays, selective mutism, and aggression was reported in a child age six years who was heterozygous for the p.Val129Met variant [Smedemark-Margulies et al 2016].
• One individual with catastrophic infantile-onset epileptic encephalopathy who died at age 16 months had a novel heterozygous p.Gly358Val variant in ATP1A3. Another individual with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental delays had a novel heterozygous p.Ile363Asn variant in ATP1A3 [Paciorkowski et al 2015].
• Rapid-adult-onset ataxia with profound dysarthria and progressive cerebellar degeneration was reported in a single individual with a de novo heterozygous p.Gly316Ser pathogenic variant [Sweadner at al 2016].
• Approximately 12 individuals with different pathogenic variants in the amino acid residue p.Arg756 [Yano et al 2017] have atypical features that may represent a definable phenotype that is distinct from RDP, AHC, and CAPOS:
  • All affected individuals had an episodic course with fever-induced encephalopathy as a key defining feature. Varying associated motor deficits including hypotonia, paresis, weakness, ataxia, dystonia, and dysphagia were described.
  • For those with more prominent ataxia, the name "relapsing encephalopathy with cerebellar ataxia" (designated RECA) has been proposed [Dard et al 2015, Hully et al 2017].
  • Those whose primary feature is weakness have been given the designation of FIPWE: fever-induced paroxysmal weakness and encephalopathy [Yano et al 2017].

Penetrance

RDP. Penetrance is incomplete. The small number of families with RDP studied to date limits the estimate of penetrance; however, several members of the larger reported families have had a heterozygous ATP1A3 pathogenic variant but no symptoms [Kramer et al 1999, de Carvalho Aguiar et al 2004, Brashear et al 2007].

AHC. Penetrance is even more uncertain, as most ATP1A3 pathogenic variants reported to date have occurred de novo.

CAPOS syndrome. There is no evidence of incomplete penetrance in the families/individuals reported to date [Demos et al 2014, Maas et al 2016, Duat Rodriguez et al 2017].

Nomenclature

The nomenclature of all three well-described phenotypes, based on early clinical categorization, is useful for highlighting symptoms that provide a starting point for diagnosis.

Rapid-onset dystonia-parkinsonism (RDP) was first recognized and named by Dobyns et al [1993] in a girl age 15 years with an abrupt onset of dystonia with severe bulbar symptoms and some signs of parkinsonism (postural instability with bradykinesia). Cerebrospinal fluid levels of dopamine metabolites were low; thus, the term "RDP" was used to describe what later came to be known as "DYT12 caused by pathogenic variants in ATP1A3" (DYT12 is also referred to as DYT-ATP1A3; see Dystonia Overview). 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 symptoms, and the disorder is classified as combined dystonia (previously called dystonia-plus) [Albanese et al 2013].

Alternating hemiplegia of childhood (AHC) was named for its most striking and diagnostic motor symptom; however, the range of manifestations show it to be a CNS disorder affecting function broadly in various brain circuits, and the disease evolves with age.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome was named for a unique cluster of symptoms. It is now recognized to share characteristics with RDP and AHC; however, the fact that to date the same ATP1A3 pathogenic variant has been observed in the nine unrelated families/individuals, some of whom have a de novo pathogenic variant, supports the continued use of the term.

Prevalence

RDP. The prevalence is not known. RDP has been described in individuals and families from the US, Europe, and Asia, and in individuals of African descent [Webb et al 1999, de Carvalho Aguiar et al 2004, Brashear et al 2007, Lee et al 2007, Blanco-Arias et al 2009, Tarsy et al 2010, de Gusmao et al 2016].

AHC. The prevalence has been estimated at 1:1,000,000.

CAPOS syndrome. The prevalence is not known.

Rapid-Onset Dystonia-Parkinsonism (RDP)

The physician needs to exclude more common and treatable forms of dystonia-parkinsonism (see Dystonia Overview and Parkinson Disease Overview). Evaluations should include brain MRI and assessment for Wilson disease. Additionally administration of L-dopa should be trialed. In RDP, the MRI is normal and the response to L-dopa is usually minimal or none, with only one reported exception [Termsarasab et al 2015].

The differential diagnosis of RDP includes the following:

• Dopa-responsive dystonia (DRD) differs from RDP in the response to L-dopa, which is minimal in those with RDP [Bressman et al 2002, Kabakci et al 2005, Geyer & Bressman 2006], with only one exception [Termsarasab et al 2015]. Furthermore, DRD typically presents in the leg and, in some reports, has been confused with cerebral palsy [Nygaard et al 1994]. "DRD" refers to the following disease entities: autosomal dominant GTPCH1-deficient DRD, autosomal recessive TH-deficient DRD, and autosomal recessive sepiapterin reductase-deficient DRD.
• DYT1 dystonia, unlike RDP, has a more caudal to rostral gradient. Onset of DYT1 dystonia in older individuals is rare, whereas RDP may present abruptly after age 30 years.
• Young-onset parkinsonism. Individuals with young-onset parkinsonism may have limb dystonia as an early manifestation; however, unlike persons with RDP, they should have a significant and sustained response to L-dopa. Other genetic forms of Parkinson disease including PINK1 type of young-onset Parkinson disease and parkin type of early-onset Parkinson disease (both inherited in an autosomal recessive manner) should be considered.
• Possible locus heterogeneity. Although no other genes or loci are known to be associated with RDP, not all individuals with a phenotype consistent with RDP have an ATP1A3 pathogenic variant; therefore, it is possible that pathogenic variants in another gene or genes cause RDP.
  A clinical diagnosis of RDP in a kindred of eight individuals who have neither a pathogenic variant in ATP1A3 nor linkage to chromosome 19q in the DYT12 region is apparently a phenocopy [Kabakci et al 2005]. The proband presented at age six years with overnight onset of dysphonia, dysphagia, orofacial dystonia, and dystonia of all four limbs, findings that meet the diagnostic criteria for RDP. However, five of the eight affected individuals had renal disease consisting of renal hypoplasia, renal cysts, and/or end-stage kidney disease, which has not been observed in individuals with RDP and ATP1A3 pathogenic variants.

Alternating Hemiplegia of Childhood (AHC)

Given the early onset and protean neurologic symptoms in affected infants and young children, the differential diagnosis of 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 (Glut1-DS), which responds to a ketogenic diet.

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 infantile-onset epileptic encephalopathy syndromes (OMIM PS308350).

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

Specific disorders and alternative genetic etiologies to consider include the following:

• Pyruvate dehydrogenase deficiency (OMIM PS312170), MELAS, and other mitochondrial disorders
• Glut1-DS
• Inborn errors of neurotransmitter biosynthesis and metabolism [Sweney et al 2009], especially disorders with deficient dopamine biosynthesis including aromatic L-amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, dihydropteridine reductase deficiency (OMIM 261630), and 6-pyruvoyl-tetrahydrobiopterin synthase deficiency (OMIM 261640).
• ATP1A2-related disorders. Three neurologic diseases associated with pathogenic variants in the homologous gene ATP1A2 have some overlapping clinical manifestations: infantile seizures, familial hemiplegic migraine (FHM2), and familial common migraine [De Fusco et al 2003, Vanmolkot et al 2003, Bassi et al 2004, Kaunisto et al 2004, Swoboda et al 2004, Ambrosini et al 2005, Todt et al 2005]. Despite the related genes and manifestations of hemiplegia and seizure, ATP1A2 is expressed mainly in astrocytes instead of neurons [McGrail et al 1991], and the underlying pathophysiology is likely to be different from that of ATP1A3-related disorders [Swoboda et al 2004, Jen et al 2007].
• CACNA1A-related disorders (familial hemiplegic migraine 1, episodic ataxia 2 (OMIM 108500), and spinocerebellar ataxia type 6)
• SLC1A3 glutamate transporter-related disorders [Jen et al 2005] (episodic ataxia 6; see Hereditary Ataxia Overview)
• SCN1A-related disorders [Kim et al 2013, Weller et al 2014] (SCN1A-related seizure disorders and familial hemiplegic migraine 3)
• ADCY5-related disorders [Westenberger et al 2017], which include familial dyskinesia with facial myokymia (OMIM 606703)

Locus heterogeneity in AHC is strongly suggested by the identification of infants and children with a phenotype meeting the classic clinical criteria for AHC but in whom no apparent pathogenic variant involving ATP1A3 or its locus have been identified.

In several large studies of individuals with features of AHC [Panagiotakaki et al 2015, Viollet et al 2015], 82%-85% had pathogenic variants in ATP1A3, suggesting a different (unknown) genetic cause for disease in approximately 15%-20% of individuals in these cohorts.

CAPOS Syndrome

CAPOS syndrome is unique, and each of its major symptoms has multiple etiologies as separate conditions. The combination of features, particularly sensorineural hearing loss in association with pes cavus deformity, elicits a rather broad differential diagnosis including mitochondrial and peroxisomal disorders.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an ATP1A3-related neurologic disorder, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

Note: Pallidal deep brain stimulation has not been effective [Deutschländer et al 2005; Kamm et al 2008; Brücke et al 2014; Brashear A, personal communication].

Prevention of Secondary Complications

When dystonia is present, physical therapy to prevent contractures in the hands and feet is appropriate.

Surveillance

RDP. Monitor for evidence of the following:

• Dysphagia, which (rarely) requires use of a feeding tube
• Psychiatric symptoms
• Seizures, which are reported in some individuals following acute onset of RDP

AHC. Monitor for evidence of seizures, which occur over time in a large proportion of affected individuals.

CAPOS syndrome. Monitor for evidence of swallow dysfunction to reduce the risk of aspiration.

Agents/Circumstances to Avoid

At-risk family members and asymptomatic individuals with an ATP1A3 pathogenic variant are cautioned to avoid alcohol and excessive exercise.

Infections and fever are also common triggers; while practical preventive strategies are lacking, unnecessary exposure should be avoided. There is no known reason to avoid vaccinations.

RDP. Triggers associated with the abrupt onset of RDP that should be avoided include (but are not limited to) the following:

• Alcohol
• Fever
• Psychological stress (e.g., childbirth)
• Excessive exercise (e.g., running track)

AHC. Triggers associated with inducing paroxysmal episodes in AHC [Sweney et al 2009] include the following:

• Psychological stress
• Emotional excitement
• Environmental stressors: bright light (sunlight or fluorescent lighting), excessive heat or cold, situations associated with excessive noise, crowds
• Water exposure in the form of bathing, swimming, shampooing
• Certain foods or odors: chocolate, food dyes
• Missed meals
• Excessive or atypically strenuous exercise (e.g., walking farther than usual, use of a playground swing)
• Illness
• Irregular sleep, missing a nap, delayed bedtime

CAPOS syndrome. Febrile illness can trigger an episode of ataxic encephalopathy and/or weakness. Pregnancy can also trigger worsening of symptoms in women with CAPOS syndrome [Chang et al 2018].

Evaluation of Relatives at Risk

It is appropriate to evaluate the at-risk family members of an affected individual in order to identify as early as possible those who should avoid triggers such as alcohol and excessive exercise (see Agents/Circumstances to Avoid).

Evaluations can include the following:

• Molecular genetic testing if the pathogenic variant in the family is known
• Neurologic evaluation if the pathogenic variant in the family is not known

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

Pregnancy Management

The pregnancy of a woman should be monitored for symptoms of RDP, onset of which has followed childbirth in some (not all) women who are heterozygous for an ATP1A3 pathogenic variant.

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 during pregnancy reduces this risk. However, exposure to anti-seizure medication 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 anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place before conception. Transitioning to a lower-risk medication before pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Other

Levodopa and dopamine agonists usually provide little benefit, but are an important part of the diagnostic evaluation.

There is no known way to prevent the abrupt onset of symptoms in RDP. During the abrupt onset, no acute treatment other than symptomatic relief of dystonia is available.

Mode of Inheritance

ATP1A3-related neurologic disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• A proband with an ATP1A3-related neurologic disorder may have an affected parent.
  • Many individuals diagnosed with a relatively less severe ATP1A3-related neurologic disorder (e.g., RDP or CAPOS) inherited an ATP1A3 pathogenic variant from an affected parent [de Carvalho Aguiar et al 2004, Demos et al 2014]. In some families, an affected individual may inherit an ATP1A3 pathogenic variant from a heterozygous, asymptomatic parent; this is more frequently observed when the affected individual has RDP.
  • Very rarely, an individual with a more severe ATP1A3-related neurologic disorder (e.g., AHC) inherited an ATP1A3 pathogenic variant from an affected parent.
• A proband with an ATP1A3-related neurologic disorder may have the disorder as the result of a de novo pathogenic variant (i.e., neither parent is heterozygous for the ATP1A3 pathogenic variant).
  • De novo pathogenic variants are common in RDP.
  • CAPOS syndrome is known to have resulted from a de novo pathogenic variant in at least three individuals [Demos et al 2014, Rosewich et al 2014a, Maas et al 2016].
  • AHC is usually the result of a de novo pathogenic variant.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant (i.e., neither parent is known to be affected with an ATP1A3-related neurologic disorder) include obtaining a detailed medical and family history, examination by a movement disorder specialist, and molecular genetic testing of both parents for the ATP1A3 pathogenic variant identified in the proband.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (germline mosaicism has been reported [Hully et al 2017]).
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation or reduced penetrance (reduced penetrance is seen in RDP but has not been reported in CAPOS syndrome; penetrance in AHC is currently unknown). Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and genetic testing have been performed.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 has an ATP1A3 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Sibs who inherit the ATP1A3 pathogenic variant typically share the same phenotypic features as the proband; however, reduced penetrance (see Penetrance) and intrafamilial variability have been observed. In one family, affected individuals were described as having typical and atypical AHC (i.e., intermediate phenotypes between AHC and RDP) [Roubergue et al 2013]. The occurrence of both mild and severe forms of ATP1A3-related neurologic disorders have been reported in the same family.
• If the parents have not been tested for the ATP1A3 pathogenic variant but are clinically unaffected, sibs of a proband are still at increased risk for an ATP1A3-related neurologic disorder because of the possibility of reduced penetrance in a heterozygous parent (see Penetrance) or the possibility of parental germline mosaicism (germline mosaicism has been reported [Hully et al 2017]).

Offspring of a proband. Each child of an individual with RDP, AHC, or CAPOS syndrome 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

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the ATP1A3 pathogenic variant in the family.

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].

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the ATP1A3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

Virtually all pathogenic variants that have been studied experimentally make one-residue changes to the protein and reduce activity, Na⁺ affinity, or the stability of the protein. There is a tendency for high inhibition with stable protein to manifest as AHC, while pathogenic variants associated with RDP retain some activity or result in poor protein expression [reviewed in Heinzen et al 2014].

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.

Na,K-ATPase has three types of subunits (alpha, beta, and FXYD), and each subunit has multiple isoforms.

• The catalytic alpha subunit has three isoforms (alpha 1, 2, and 3) that are expressed in the CNS by three distinct genes [Moseley et al 2003]. Although it is found in a few peripheral cell types, the alpha 3 isoform is expressed exclusively in neurons in the CNS [McGrail et al 1991].
• Three beta subunits required for Na,K-ATPase function are also expressed in the CNS.
• The FXYD subunit regulates and modifies the properties of the complex; at least three FXYD subunits are expressed in the CNS.

A review [Heinzen et al 2014] includes information on animal models of rapid-onset dystonia-parkinsonism.

Gene structure. ATP1A3 comprises 23 exons; NM_152296.4 is the predominant transcript. Additional transcripts have been described; for a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Several common coding SNPs are reported in dbSNP.

Pathogenic variants

• RDP. To date, at least 20 missense or small indel variants have been described as causative of RDP in both familial cases and simplex cases (resulting from a de novo pathogenic variant) [Heinzen et al 2014, Rosewich et al 2014b]. The variant most frequently reported in RDP is p.Thr613Met (~26% both de novo and familial occurrence) [de Carvalho Aguiar et al 2004, Brashear et al 2007, Lee et al 2007, McKeon et al 2007, Barbano et al 2012].
• AHC. To date, pathogenic variants reported in individuals with the classic AHC phenotype are largely different from those reported with RDP; however, some overlap exists.
  More than 85 pathogenic variants have been reported to result in an AHC phenotype. Most affected individuals have a de novo pathogenic variant; however, at least two familial cases with autosomal dominant inheritance have been reported as well as affected identical twins. Three pathogenic variants – p.Asp801Asn (~40%), p.Glu815Lys (~20%), and p.Gly947Arg (~10%) – account for more than two thirds of the de novo pathogenic variants observed to date [Panagiotakaki et al 2015, Viollet et al 2015].
• CAPOS syndrome. All reported families and individuals with CAPOS syndrome have the same unique missense variant, p.Glu818Lys [Duat Rodriguez et al 2017].

Normal gene product. ATP1A3 encodes the alpha 3 subunit of the sodium/potassium-transporting ATPase (Na,K-ATPase), which comprises 1,013 amino acid residues.

Abnormal gene product. Both functional studies and structural analysis of the alpha 3 subunit of the Na,K-ATPase suggest that missense variants impair enzyme activity or stability [de Carvalho Aguiar et al 2004, Heinzen et al 2012]; however, it is not known whether this loss of function occurs by haploinsufficiency or dominant-negative effects.

Functional biochemical studies with several pathogenic variants associated with the RDP phenotype all show reduced Na⁺ affinity suggesting that defects in the handling of Na⁺ may be a major factor in the development and pathology of RDP [Rodacker et al 2006, Blanco-Arias et al 2009, Einholm et al 2010].

Author Notes

Wake Forest School of Medicine: Rapid-Onset Dystonia-Parkinsonism

To obtain up-to-date help, a report of possible diagnosis should be made to one of the AHC or RDP organizations listed in Resources. There, contacts with experienced clinicians can be found as well as information about known pathogenic variants, and novel pathogenic variants can be considered. For AHC, parent organizations in several countries provide advice and support, raise funding for research, and hold family meetings.

Novel variants and novel symptoms associated with ATP1A3 variants should also be reported to these organizations. The identification of non-pathogenic genetic variants is also possible in patients with other disease etiologies, and is important to arrive at a correct diagnosis. Equally important are reports of patients with typical manifestations but without a pathogenic variant in ATP1A3, who might have a pathogenic variant in a second causative gene.

Acknowledgments

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

Revision History

• 22 February 2018 (ma) Comprehensive update posted live
• 6 November 2014 (me) Comprehensive update posted live; title changed
• 13 September 2012 (ab/tb) Revision: alternating hemiplegia of childhood added as a genetically related disorder
• 25 August 2011 (me) Comprehensive update posted live
• 19 March 2009 (cd) Revision: sequence analysis available clinically
• 7 February 2008 (me) Review posted live
• 5 October 2007 (ab) Original submission

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