Alternating hemiplegia of childhood (AHC), rapid‐onset dystonia parkinsonism (RDP), and cerebellar ataxia, arreflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome are phenotypic distinct entities that share mutations on a common gene, the ATP1A3, that encodes the α3 subunit of the Na+/K+‐ATPases.1
RDP symptoms start abruptly (hours to days), in previously healthy adolescents or young adults, with dystonia with a rostrocaudal pattern and parkinsonism.1 Symptoms are usually triggered by emotional or physical stress and do not respond to levodopa.1, 2 The ictal phase is followed by a chronic maintenance of acquired symptoms that rarely relapse.1
AHC usually begins within the first 6 months of life, triggered by physical and emotional stress, with sudden and transient episodes of hemiplegia combined with other paroxysmal symptoms, such as dystonia, nystagmus, autonomic disturbances, and seizures.1 Falling asleep can relieve symptoms.3 Nonparoxysmal symptoms ensue over the years. Developmental delay and intellectual disability are the most common, followed by dysarthria, ataxia, and choreoathetosis.1 Flunarizine may reduce the frequency of plegic attacks and motor deterioration.3
CAPOS syndrome is a symmetric ataxic encephalopathy of childhood recently associated with a mutation of ATP1A3 (c.2452G>A).4 As with RDP and AHC, it has an acute onset and physical stress as a trigger.1, 4 Optic atrophy and sensorineural hearing loss are distinct chronic features.4
Case Report
We present a case of a 5‐year‐old boy of a Caucasian Portuguese family with a normal early psychomotor development. At 3 years of age, he manifested a rapid‐onset course of left brachial‐predominant dystonia with a fixed flexion posture of the fingers and forearm. On subsequent days, a fluctuating course, aggravated by exercise and improving with rest, became evident. He did not respond to l‐dopa and inclusively deteriorated, presenting with severe dysarthria and dysphagia and onset of action tremor in the contralateral upper limb (see Video 1). After 3 months, he developed paroxysmal episodes of alternating hemiparesis, with a left‐side predilection. He also presented episodes of generalized hypotonia with lack of head control, anarthria, and oromandibular dystonia, lasting from hours to days. Physical exercise, cold, acute illness, and emotional excitement were trigger factors, and symptoms were relieved by rest and sleep. Between episodes, there was persistent anarthria, drooling, and left hemidystonia with choreoathetoic movements of the left foot and independent gait was impossible.
ATP1A3 gene was sequenced and a novel heterozygous mutation (NM_152296.4:c.1073G>A; p.Gly358Asp) was found. Several lines of evidence support its pathogenicity, in addition to the compatible phenotype: It is not known to ExAC, 1000 Genomes, ESP, or dbSNP databases; bioinformatics analysis with SIFT, Polyphen‐2, and Mutation Taster predict it is deleterious; it is not present in the healthy parents; and other mutations in the same codon are reported (p.1072G>T; p.1073G>T).3, 5
Treatment with oral flunarizine was started and hemiplegic attacks became less severe and frequent. He is now able to speak and to walk unaided, but maintains a general clumsiness, mild dysarthria, left brachial‐predominant dystonia with choreoathetoid movements, and mild psychomotor delay.
Discussion
This case presents features of AHC and RDP, but does not fulfil accepted criteria used to diagnose both conditions (Table 1). It presented with an acute‐onset dystonia, with bulbar symptoms, and progressed only 3 months after to a paroxysmal disorder similar to AHC. The patient did not have evidence of seizures or nystagmus and the paroxysmal attacks started later than usual for a typical AHC. On the other hand, the onset of dystonia is early for typical RDP and this condition is not associated with bulbar symptoms or paroxysmal attacks.
Table 1.
Clinical criteria for AHC and RDP
| AHC (Aicardi Criteria)11 | RDP12 |
|---|---|
| 1. Onset of AHC before 18 months of age | Minimal diagnostic criteria |
| 2. Repeated attacks of alternating hemiplegia | 1. Abrupt onset of dystonia with features of Parkinsonism (minutes to 30 days) |
| 3. Other paroxysmal disturbancesa | 2. Clear rostrocaudal (face > arm > leg) gradient of involvement |
| 4. Tetraplegic attacks | 3. Prominent bulbar findings |
| 5. Improvement of symptoms with sleep | Other suggestive features |
| 6. Evidence of developmental delay, mental retardation, choreoathetosis, dystonia, or ataxia | Minimal or no tremor at onset; occasional mild limb dystonia prior to the primary onset of RDP; common triggers associated with onset of symptoms; rare “second onsets” or abrupt worsening of symptoms later in life; stabilization of symptoms within a month; minimal improvement overall but with limited improvement in gait |
| 7. Not attributable to other disorders |
Tonic or dystonic spells, nystagmus or other oculomotor abnormalities, dyspnea, and various autonomic phenomena occurred during hemiplegic bouts or in isolation.
This distinct phenotype is consistent with other cases with phenotypes lying between AHC and RDP, resumed in Table 2.6, 7, 8, 9, 10 Case 4 had a similar installation of paroxysmal attacks after 18 months of age and a chronic maintenance of bulbar symptoms, oromotor dystonia, and severe dysarthria. Cases 2 and 3 resemble AHC, but with an age at onset after 18 months. Case 5, on the other hand, resembles RDP, but had an early onset and epilepsy. Cases 6 to 8 belong to a single family and show different atypical presentations of AHC over a single mutation. All had a later onset of symptoms and plegic attacks ended years after.
Table 2.
Clinical features of patients with intermediate forms of AHC and RDP
| Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | Case 6 | Case 7 | Case 8 | |
|---|---|---|---|---|---|---|---|---|
| Present Case | Rosewich (2014)7 | Sasaki (2014)6 | Anselm (2009)8 and Brashear (2012)9 | Brashear (2012)9 | Roubergue (2013)10 | Roubergue (2013)10 | Roubergue (2013)10 | |
| Sex | M | F | M | M | F | F | F | M |
| Early speech and motor development | Normal | Normal | Normal | Mild gross motor delay | Mild gross motor delay | NA | NA | NA |
| Age at onset | 3 y | 4 y, 6 mo | 2 y | 4 y | 9 mo | 3 y | 2 y | 2 y |
| Symptoms at onset | Dystonia | Plegic attacks | Plegic attacks | Dystonia | Hypotonia and dysphagia | Plegic attacks | Paroxysmal dystonia | Plegic attacks |
| Triggers | Physical and emotional stress | Physical and emotional stress | Fever and emotional excitement | Fever | Fever | NA | NA | Exercise |
| Alternating Hemiplegia | Yes | Yes | Yes | No | No | Yes | Yes | Yes |
| Quadriplegic episodes | Yes | Yes | No | No | Yes | No | No | Yes |
| Dystonia | Permanent | No | Episodic | Permanent | No | Episodic | Episodic | Episodic |
| Choreoathetosis | Yes | Yes | NA | NA | NA | NA | Yes | Yes |
| Abnormal ocular movements | No | Yes | NA | Yes | NA | NA | NA | NA |
| Seizures | No | NA | NA | NA | Yes | NA | NA | NA |
| Bulbar symptoms | Yes | Yes | Yes | Yes | Yes | Yes | NA | NA |
| Cognitive impairement | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes |
| Phenotype‐like | AHC | AHC | AHC | RDP | RDP | AHC | AHC | AHC |
| Nucleotide change | c.1073G>A | c.2600G>A | c.2767G>A | c.2767G>A | c.2267G>A | c.2767G>A | c.2767G>A | c.2767G>A |
| Protein change | p.Gly358Asp | p.Gly867Asp | p.Asp923Asn | p.Asp923Asn | p.Arg756His | p.Asp923Asn | p.Asp923Asn | p.Asp923Asn |
| Protein affected domain | Cytoplasmic P domain | Membrane domain | Membrane domain | Membrane domain | Membrane domain | Membrane domain | Membrane domain | Membrane domain |
F, female; M, male; y, years; mo, months; NA, not available.
Five of the patients discussed have the same mutation (p.Asp923Asn), and all patients but ours presented mutations on the transmembrane domain, where most of the already described AHC mutations are located. Interestingly, the 2 other patients reported to have a mutation on the same codon as our patient, located on the cytoplasmic P domain, had very severe AHC phenotypes, with seizures from day 1 after delivery and severe cognitive deficit.3, 4, 5 Thus, other genetic epiphenomena besides the location of amino acid changes may be involved in the clinical expression of intermediate phenotypes.
A strict use of classical diagnostic criteria may delay diagnosis. We think classical diagnostic criteria for all ATP1A3‐associated disorders, including CAPOS syndrome, should be revised, rather than trying to fit patients into separated groups.
Author Roles
The first two authors (P.P. and A.G.) have contributed equally to this article and made the initial draft and final revisions of the manuscript. J.P.M. is the main doctor of the patient.
(1) Case Report Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
P.P.: 1A, 1B, 1C, 3A, 3B
A.G.: 1A, 1B, 1C, 3A, 3B
M.F.: 1A, 1B, 1C, 3B
C.H.: 1A, 1B, 1C, 3B
J.P.: 1C, 3B
J.P.M.: 1A, 1B, 1C, 3B
Disclosures
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.
Supporting information
A video accompanying this article is available in the supporting information here.
Video 1. Segment 1: 2 months after the abrupt onset of symptoms. There is a persistent dystonia of the upper left limb. Segment 2: 2.5 months after onset of symptoms. There is a dystonic posture of the upper left limb, choreic movements of the left foot, and a intention tremor of the right hand. Segment 3: Filmed 1 day after the onset of a tetraplegic attack (already in recovery). The patient was usually unable to walk for long periods after these attacks (days to weeks).
Acknowledgments
The writing of the manuscript was done in Hospital Garcia de Orta, Almada, Portugal. Neither the whole nor part of the work has been presented previously.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid‐onset dystonia‐parkinsonism, CAPOS and beyond. Pediatr Neurol 2015;52:56–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al. Mutations in the Na+/K+‐ATPase α3 gene ATP1A3 are associated with rapid‐onset dystonia parkinsonism. Neuron 2004;43:169–175. [DOI] [PubMed] [Google Scholar]
- 3. Sasaki M, Ishii A, Saito Y, et al. Genotype‐phenotype correlations in alternating hemiplegia of childhood. Neurology 2014;82:482–490. [DOI] [PubMed] [Google Scholar]
- 4. Demos MK, Karnebeek CD, Ross CJ, et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 2014;9:15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Paciorkowski AR, McDaniel SS, Jansen LA, et al. Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 2015;56:422–430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Sasaki M, Ishii A, Saito Y, Hirose S. Intermediate form between alternating hemiplegia of childhood and rapid‐onset dystonia‐parkinsonism. Mov Disord 2014;29:153–154. [DOI] [PubMed] [Google Scholar]
- 7. Rosewich H, Baethmann M, Ohlenbusch A, et al. A novel ATP1A3 mutation with unique clinical presentation. J Neurol Sci 2014;341:133–135. [DOI] [PubMed] [Google Scholar]
- 8. Anselm IA, Sweadner KJ, Gollamudi S, Ozelius LJ, Darras BT. Rapid‐onset dystonia‐parkinsonism in a child with a novel ATP1A3 gene mutation. Neurology 2009;73:400–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Brashear A, Mink JW, Hill DF, et al. ATP1A3 mutations in infants: a new rapid‐onset dystonia‐Parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol 2012;54:1065–1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Roubergue A, Roze E, Vuillaumier‐Barrot S, et al. The multiple faces of the ATP1A3‐related dystonic movement disorder. Mov Disord 2013;28:1457–1459. [DOI] [PubMed] [Google Scholar]
- 11. Bourgeois M, Aicardi J, Goutières F. Alternating hemiplegia of childhood. J Pediatr 1993;122:673–679. [DOI] [PubMed] [Google Scholar]
- 12. Brashear A, Dobyns WB, de Carvalho P, Borg M, et al. The phenotypic spectrum of rapid‐onset dystonia‐parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 2007;130:828–835. [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
A video accompanying this article is available in the supporting information here.
Video 1. Segment 1: 2 months after the abrupt onset of symptoms. There is a persistent dystonia of the upper left limb. Segment 2: 2.5 months after onset of symptoms. There is a dystonic posture of the upper left limb, choreic movements of the left foot, and a intention tremor of the right hand. Segment 3: Filmed 1 day after the onset of a tetraplegic attack (already in recovery). The patient was usually unable to walk for long periods after these attacks (days to weeks).