title: Clinical and genetic analysis in alternating hemiplegia of childhood: ten new patients from Southern Europe.
abstract: Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder featuring attacks of hemiplegia and other paroxysmal and non-paroxysmal manifestations leading to progressive neurological impairment. De novo mutations in ATP1A3 have been identified in up to 80% of patients. AHC is also associated with rare mutations in other genes involved in episodic neurological disorders. We sought to find mutations in ATP1A3, CACNA1A, ATP1A2, SCN1A and SLC2A1 in a cohort of ten unrelated patients from Spain and Greece. All patients fulfilled AHC diagnostic criteria. All five genes were amplified by PCR and Sanger sequenced. Copy number variation (CNV) analysis of SLC2A1 and CACNA1A was performed using two different approaches. We identified three previously described heterozygous missense ATP1A3 mutations (p.Asp801Asn, p.Glu815Lys and p.Gly947Arg) in five patients. No disease-causing mutations were found in the remaining genes. All mutations occurred de novo; carriers presented on average earlier than non-carriers. Intellectual disability was more severe with the p.Glu815Lys variant. A p.Gly947Arg carrier harbored a maternally-inherited CACNA1A p.Ala454Thr variant. Of note, three of our patients exhibited remarkable clinical responses to the ketogenic diet. We confirmed ATP1A3 mutations in half of our patients. Further AHC genetic studies will need to investigate large rearrangements in ATP1A3 or consider greater genetic heterogeneity than previously suspected.
authors.affiliation: Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vila-Pueyo
authors.affiliation: First Department of Pediatrics, Agia Sofia Hospital, University of Athens, Athens, Greece.
authors.forename: Roser
authors.initials: R
authors.lastname: Pons
authors.affiliation: Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Raspall-Chaure
authors.affiliation: Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Marcé-Grau
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Oriel
authors.initials: O
authors.lastname: Carreño
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Cèlia
authors.initials: C
authors.lastname: Sintas
authors.affiliation: Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Pediatric Neurology Department, Teknon Clinic, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pineda-Marfà
authors.affiliation: Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: amacaya@vhebron.net.
authors.forename: Alfons
authors.initials: A
authors.lastname: Macaya
mesh_terms: D000293:Adolescent; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D055423:Diet, Ketogenic / Q000379:methods*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006115:Greece; D006429:Hemiplegia / Q000178:diet therapy* / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A3; Alternating hemiplegia of childhood; CACNA1A; Genetics; Ketogenic diet; Neurodevelopmental syndrome