{'fraction_non_alphanumeric': 0.026718703092164516, 'fraction_numerical': 0.022215550885619936, 'mean_word_length': 5.204841713221602, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The multiple faces of the ATP1A3‐related dystonic movement disorder

Alternating hemiplegia of childhood (AHC) and rapidonset dystonia-parkinsonism (RDP/DYT12) are 2 rare disorders caused by dominant mutations in ATP1A3 encoding the neuron-specific Na/K-ATPase a3 subunit. AHC is characterized by episodes of alternating hemiplegia/quadriplegia and dystonic or tonic attacks that are associated with permanent neurological deficits including intellectual disability and movement disorders. Paroxysmal events typically start before 18 months of age and are often precipitated by specific triggers. RDP is characterized by abrupt onset of dystonia within hours to weeks, associated with parkinsonism. Onset can be precipitated by triggers similar to AHC and usually occurs in adolescence or early adulthood. None of the ATP1A3 mutations detected in AHC (n 5 26) was reported in RDP (n 5 11), suggesting that AHC and RDP are allelic disorders due to mutations with distinct effects on ATP1A3 activity. Nevertheless, some overlap exists because permanent dystonia is found in most AHC patients and is a core feature of RDP, and paroxysmal dystonia is frequent in AHC cases and is sometimes observed in RDP. We studied a single family with 4 affected subjects over 3 generations who display typical as well as atypical AHC (Supplemental Fig. 1). Their neurological manifestations are detailed in Table 1. One video shows the mild permanent symptoms of patient III-2. Sequencing ATP1A3 showed the heterozygous substitution c.2767G>A in exon 20 (p.Asp923Asn) in the 4 symptomatic patients (Supplemental Fig. 1). The mutation occurred de novo, then segregated with the disease in over 3 generations. Interestingly, this mutation was previously reported in 2 unrelated patients with RDP. We further characterized the phenotypes resulting from the p.Asp923Asn mutation, considering the 4 cases reported here and the 2 patients with RDP previously reported (see Table 1). Four patients had AHC (typical, n 5 1; atypical, n 5 3), and 2 patients had RDP (typical, n 5 1; atypical, n 5 1). Interestingly, paroxysmal exerciseinduced dystonia in the absence of plegic attacks was the main manifestation after childhood in the 3 adult patients of the reported family. If this feature has never been reported in RDP, it has been observed in some isolated cases of AHC. Our observation that the ATP1A3 p.Asp923Asn mutation results in typical AHC, typical RDP, and variant phenotypes suggests that these clinical syndromes represent different expressions of the same disorder. This challenges the hypothesis of a mechanistically distinct functional effect of AHCand RDP-causing mutations. ATP1A3 mutations alter the Na/K ATPase pump’s activity in different ways. AHCcausing mutations were reported to not reduce protein expression in contrast with most of the RDP-causing mutations. However, the p.Asp923Asn substitution was 1 of the 3 RDP-causing mutations affecting ATP1A3 activity without modifying protein expression, thereby having an effect apparently similar to AHC-causing mutations at the cellular level. Our findings emphasize that the ATP1A3 mutation is not the sole determinant of clinical expression, implying that genetic, epigenetic, and environmental factors play an important role in the clinical expression of ATP1A3-related disease.