Atp1a3-Related Neurologic Disorders

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 antiepileptic 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 antiepileptic 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 variant in ATP1A3 by molecular genetic testing (Table 1).

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 at the most reasonable cost 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 renal 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: moya-moya disease (OMIM PS252350); mitochondrial disorders such as pyruvate dehydrogenase deficiency (in which spells are typically accompanied by lactic acidosis; see OMIM PS312170); 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 (OMIM 608643) 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 (OMIM 608643), 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