Fever-induced paroxysmal weakness and encephalopathy, a new phenotype of ATP1A3 mutation

Publication date: Available online 29 April 2017
Source:Pediatric Neurology
Author(s): Sho T. Yano, Kenneth Silver, Richard Young, Suzanne D. DeBrosse, Roseànne S. Ebel, Kathryn J. Swoboda, Gyula Acsadi
ObjectivesWe identified a group of patients with ATP1A3 mutations at residue 756 who display a new phenotype distinct from alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndromes.MethodsFour patients with c.2267G>A (R756H) mutations from two families, and two patients with c.2267G>T (R756L) mutations from one family, are described and compared to the previously reported patients with mutations resulting in R756H and R756C variant protein.ResultsPatients with ATP1A3 R756H have onset in childhood of infrequent, fever-triggered paroxysms of encephalopathy and weakness with slowly improving but persistent deficits. Motor findings of weakness are mostly generalized, and patients may also have bulbar or oculomotor problems. Longer-term outcomes range from mild motor apraxia with near-normal function to persistent dysphagia, dysarthria, cognitive deficit, motor apraxia, and inability to walk due to ataxia. Patients with ATP1A3 R756L have a similar phenotype that includes paroxysmal, stepwise progression of ataxia associated with infections.ConclusionsATP1A3 mutations affecting residue 756 result in a separate clinical syndrome from previously described ATP1A3 mutations, which consists chiefly of fever-induced paroxysmal weakness and encephalopathy (FIPWE). Patients with R756L and R756C protein variants display more prominent ataxia, overlapping with the relapsing encephalopathy with cerebellar ataxia (RECA) syndrome previously described in a patient with the c.2266C>T (R756C) mutation. All patients reported with mutations at residue 756 to date have had a similar episodic course and clinical features. Patients with mutations of ATP1A3 residue 756 appear to have a distinct clinical phenotype as compared to patients with other ATP1A3 mutations, with fever-induced encephalopathy as key differentiating feature.



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