Historically, heterozygous ATP1A3 mutations were initially described in rapid-onset dystonia–parkinsonism (RDP or DYT12) (MIM 128235).1 Advances in genetic techniques led to the subsequent discovery that abnormalities in the same gene were responsible for some forms of alternating hemiplegia of childhood (AHC) (MIM 614820),2 and also the CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) (MIM 601338).3 Although clinical features of RDP and AHC differ, on rare occasions patients have been reported with clinical features overlapping between the two,4,5 suggesting that RDP and AHC are disorders in the same spectrum4,6,7 rather than just allelic disorders as initially envisioned.8
In this paper, we present two unusual patients with ATP1A3-related disorders with clinical features overlapping between RDP and AHC. Our first patient carried a novel missense variant previously unknown in intermediate phenotypes or any ATP1A3-related disorders. Our second patient carried a known deleterious mutation and possessed an unusual phenotype never before reported in the intermediate form. These two unique patients illustrate the expanding phenotypic spectrum of ATP1A3-related disorders.
Written informed consent was obtained from the patients for publication of this case report and any accompanying images.
A 24-year-old female without family history of neurologic illness presented for evaluation of global developmental delay from early childhood and monthly alternating hemiplegic episodes lasting minutes to hours since her early teens. She usually recovered from these episodes after sleeping, but at age 14 she developed a severe episode that was not terminated by sleep. A diagnosis of “AHC” was made at this time, and a hospital evaluation for epilepsy was negative. Since that event, she developed continuous and unremitting posturing and functional impairment of the left arm, dysarthria, and lower cranial dystonia with marked drooling.
On examination a prominent risus sardonicus, marked dysarthria, and prominent drooling were evident (Video 1). Ocular motor examination was normal, and asymmetric dystonic posturing of the arms was present accompanied by parkinsonism. A rostrocaudal gradient of her dystonia was noted with only very mild involvement in her legs. Deep tendon reflexes were 3+ throughout.
Sanger sequencing of exons 1–23 in the ATP1A3 gene at a commercial laboratory revealed a novel heterozygous missense variant (NM_152296.4: c.2851G>A; NP_689509.1: p.E951K) in exon 21. This variant is not found in large publically available cohorts.9–11In silico, this variant is predicted to be damaging by SIFT (Sorting Intolerant From Tolerant) and probably damaging by PolyPhen-2 (with a score of 0.998).12,13 The position is highly conserved across multiple vertebrate species (from humans to zebrafish; Genomic Evolutionary Rate Profiling [GERP] score 2.91).14 Though not reported, this variant was also seen once in another patient with AHC in a research cohort in Utah (T. Newcomb, personal communication, June 12, 2015). Based on the new American College of Medical Genetics and Genomics standards and guidelines for interpretation of sequence variants, this variant is classified as likely to be pathogenic.15 Her parents elected not to pursue testing since they were asymptomatic. Botulinum toxin injection to the left arm provided temporary relief of dystonia.
A 10-year-old female presented to our office with her parents after being adopted from China 8 months prior. Information on her early development was limited. At age 1 year she was brought to an orphanage with obvious global developmental delay. When her adoptive mother met her in China, she was malnourished, immobile, mute, drooling, and unable to use her arms to feed herself but she could sit and walk. She seemed alert however, and after a few visits recognized her adoptive mother. She had experienced frequent episodes since childhood that had been labeled epileptiform (Video 2). Review of the video showed clear oculogyria with upward and lateral deviation of both eyes, accompanied by neck posturing. After her first evaluation in the United States, her referring neurologist started her on levodopa 200 mg/day, and the episodes dramatically improved, along with improved motor performance.
Examination in the office revealed a cooperative young girl with mildly soft and indistinct speech. Ocular motor examination was normal. There was symmetric mild dystonic posturing of both hands, with slow choreiform movements of her fingers, mild incoordination of the hands and no overt parkinsonism. She walked well with good arm swing. Deep tendon reflexes were 1+ throughout.
Owing to the dramatic response to levodopa and presence of oculogyria, our differential diagnosis included levodopa-responsive forms of aromatic L-amino acid decarboxylase (AADC)16 and tyrosine hydroxylase (TH) deficiency. Surprisingly, whole exome sequencing (and confirmed using the Sanger method) at a commercial laboratory revealed a known pathogenic heterozygous mutation (NM_152296.4: c.2401G>A; NP_689509.1: p.D801N) in exon 17 of the ATP1A3 gene.17–19 There were no mutations found in the DDC or GCH1 genes. Coverage for these two loci was at 100% and at least 10× (N. Alexander, personal communication, August 8, 2015). Since the TH gene was not well covered by whole exome sequencing, separate TH gene sequencing was performed at the same commercial laboratory using the Sanger method, which included all exons, flanking splice regions, and the cyclic adenosine monophosphate (cAMP) response element spanning c-74 to c-67 in the promoter region. TH deletion/duplication analysis was also performed via a dense exonic comparative genomic array. These methods did not detect any mutations, deletions, or duplications in the TH gene. Test method details for whole exome sequencing, TH sequencing, and deletion/duplication analysis can be found at the commercial laboratory’s website (www.genedx.com). Cerebrospinal fluid studies were not available.
We present two unusual patients with missense changes in the ATP1A3 gene whose clinical features overlapped between AHC and RDP. In classic AHC, patients experience symptom onset before 18 months of age, consisting of paroxysmal alternating hemiplegia events, developmental delay, and drooling. The classic RDP phenotype is often milder than AHC, with the main feature of rapid-onset parkinsonism over minutes to weeks, and stabilization of symptoms with minimal progression after a month. A rostrocaudal gradient of symptoms, asymmetric involvement, and prominent bulbar involvement including dysarthria and/or dysphagia is characteristic.
Our two patients’ clinical histories and examination overlapped between these two disorders (Table 1). In fact, Patient 1 started with an AHC phenotype, and her RDP phenotype emerged at age 14 years. Sasaki et al.5 reported and reviewed cases in the literature with intermediate phenotype between AHC and RDP,4,20 all of which (six patients) had D923N mutations in the ATP1A3 gene. Rosewich et al.6 later reported two patients with intermediate phenotype and the novel mutations I810F and W382R. The missense variant in our first patient, E951K, has never been reported in ATP1A3-related disorders, including the intermediate phenotype between AHC and RDP. The mutation in Patient 2, D801N, is one of the most common mutations reported with the classic AHC phenotype,21 but has never been reported in the intermediate form of AHC and RDP. Although almost all reported genetic derangements in ATP1A3-related disorders are de novo,22 parental genetic testing was not available in either of our patients. Phenotype–genotype correlations in ATP1A3-related disorders are summarized in Table 2.
|Clinical Feature||Patient 1||Patient 2|
|Paroxysmal alternating hemiplegia||+|
|Recovery of the episode with sleep||+|
|Mild bilateral hand dystonia||+1|
|Rostrocaudal gradient of dystonia||+1|
|Speech involvement||+1||+1 (mild)|
|Stabilization of the symptoms over time||+|
|I274T, E277K, 327Ldel, T370N, W382R, L417P, T613M, S684F, R756H, I758S, F780L, D810Y, D923N||D801N1, G867D, D923N, E951K1||S137Y, S137F, Q140L, I274N, E277K, V322D, C333F, T335P, G358C, L371P, G755A, G755S, G755C, L757P, T771N, S772R, N773S, N773I, D801E, D801N, T804I, D805E, M806R, I810F, I810S, S811P, E815K, 2542+1G>A (splice site), 919Vdel, D923N, D923Y, C927Y, C927F, C927W, G947R (2839G>A and 2839G>C), A955D, D992Y, 1013Ydup||E818K||E818K|
The ATP1A3 gene encodes the α3-subunit of the enzyme Na+/K+ ATPase. This enzyme functions to pump three molecules of Na+ out and two molecules of K+ into the cell to maintain the electrochemical gradient at the plasma membrane prior to depolarization. Both the E951K and D801N variants are located in the transmembrane regions of the ATP1A3 protein, which is also a cation-transporting ATPase region near the C-terminus. In previous studies, it was found that mutations causing AHC phenotypes tend to affect the transmembrane regions or functional domains compared to those causing RDP phenotypes,6 although this association cannot be applied in all cases.
Interestingly, Patient 2 presented with paroxysmal oculogyria dramatically responsive to levodopa, a phenomenon never reported before in AHC or RDP. AHC patients can have episodic ocular motor abnormalities, reported in up to 93% in one study,23 including nystagmus and intermittent esotropia or exotropia. In 1993, Dobyns et al.24 reported two out of 12 RDP patients with persistent (not paroxysmal) oculogyric crisis at the onset, lasting days or weeks. Genetic testing of the ATP1A3 gene was not available at that time, but subsequently one of them was found to have the I758S mutation in the ATP1A3 gene.25 Since then, oculogyria has not been reported in RDP. To our knowledge, this is the first patient reported with paroxysmal oculogyria associated with an ATP1A3 mutation. This atypical feature initially pointed us to other differential diagnoses of levodopa-responsive oculogyria in children, especially disorders in the monoamine synthetic pathway such as AADC and TH deficiencies. Given the dramatic improvement in our patient and in the other three patients in the same family with a novel AADC mutation,16 a trial of levodopa in children presenting with unexplained oculogyria seems warranted.
Our two cases expand our current knowledge of the phenotype–genotype variations and natural history of ATP1A3-related disorders, and emphasize that AHC and RDP are part of the same spectrum. Recognition of the overlapping phenotypes will help guide clinicians toward a correct molecular diagnosis for their patients.
1 Funding: Dr. Termsarasab received a clinical fellowship training grant from Dystonia Medical Research Foundation (DMRF).
2 Financial Disclosures: None.
3 Conflicts of Interest: The authors report no conflict of interest.
4 Ethics Statement: This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. The authors' institutional ethics committee has approved this study and all patients have provided written informed consent.
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