Sho T Yano1, Kenneth Silver2, Richard Young3, Suzanne D DeBrosse4, Roseànne S Ebel4, Kathryn J Swoboda5, Gyula Acsadi3. 1. Section of Pediatric Neurology, Comer Children's Hospital, University of Chicago, Chicago, Illinois. Electronic address: sho.yano@uchospitals.edu. 2. Section of Pediatric Neurology, Comer Children's Hospital, University of Chicago, Chicago, Illinois. 3. Pediatric Neurology, Connecticut Children's Medical Center, University of Connecticut, Hartford, Connecticut. 4. Department of Genetics and Genome Sciences, Center for Human Genetics, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio. 5. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Abstract
BACKGROUND: We identified a group of patients with ATP1A3 mutations at residue 756 who display a new phenotype, distinct from alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndromes. METHODS: Four 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 with the previously reported patients with mutations resulting in R756H and R756C protein variants. RESULTS: Patients 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 because of ataxia. Patients with ATP1A3 R756L have a similar phenotype that includes paroxysmal, stepwise progression of ataxia associated with infections. CONCLUSIONS: ATP1A3 mutations affecting residue 756 result in a clinical syndrome, separate from those associated with 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 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 compared with patients with other ATP1A3 mutations, with fever-induced encephalopathy as key differentiating feature.
BACKGROUND: We identified a group of patients with ATP1A3 mutations at residue 756 who display a new phenotype, distinct from alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndromes. METHODS: Four 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 with the previously reported patients with mutations resulting in R756H and R756C protein variants. RESULTS:Patients with ATP1A3R756H 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 because of ataxia. Patients with ATP1A3R756L have a similar phenotype that includes paroxysmal, stepwise progression of ataxia associated with infections. CONCLUSIONS:ATP1A3 mutations affecting residue 756 result in a clinical syndrome, separate from those associated with 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 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 compared with patients with other ATP1A3 mutations, with fever-induced encephalopathy as key differentiating feature.
Authors: Ihtsham U Haq; Beverly M Snively; Kathleen J Sweadner; Cynthia K Suerken; Jared F Cook; Laurie J Ozelius; Charlotte Miller; William V McCall; Christopher T Whitlow; Allison Brashear Journal: Mov Disord Date: 2019-07-30 Impact factor: 10.338
Authors: Ida Stenshorne; Magnhild Rasmussen; Panagiotis Salvanos; Chantal M E Tallaksen; Laurence A Bindoff; Jeanette Koht Journal: Cerebellum Ataxias Date: 2019-02-08