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A Distinct Phenotype in a Novel ATP 1A3 Mutation: Connecting the Two Ends of a Spectrum

2015; Wiley; Volume: 3; Issue: 4 Linguagem: Inglês

10.1002/mdc3.12263

2330-1619

Pedro Pereira, Andreia Guerreiro, Maria José Fonseca, Cristina Halpern, Jorge Pinto‐Basto, José Paulo Monteiro,

ATP Synthase and ATPases Research

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 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. 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. This distinct phenotype is consistent with other cases with phenotypes lying between AHC and RDP, resumed in Table 2.6-10 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. 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.3-5 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. 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 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. 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. A video accompanying this article is available in the supporting information here. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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