title: Mosaicism in ATP1A3-related disorders: not just a theoretical risk.
abstract: Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.
authors.affiliation: Department of Pediatric Neurology, Necker Enfants Malades Hospital, APHP, 149 rue de Sèvres, 75015, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Hully
authors.affiliation: Department of Pediatrics, University Hospital, Brest, France.|Laboratoire du Traitement de l'Information Médicale LaTIM INSERM UMR 1101, Brest, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Ropars
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|INSERM UMR1163, Translational Genetics, Imagine Institute, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|Department of Pediatric Radiology, Necker Enfants Malades Hospital, APHP, Paris, France.|INSERM U1000, UMR 1163, Institut Imagine, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Department of Medical Genetics, Necker Enfants Malades Hospital, APHP, Paris, France.
authors.forename: Marlene
authors.initials: M
authors.lastname: Rio
authors.affiliation: Department of Molecular Genetics, Necker Enfants Malades Hospital, APHP, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bernardelli
authors.affiliation: Department of Pediatric Neurology, Necker Enfants Malades Hospital, APHP, 149 rue de Sèvres, 75015, Paris, France.|Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|Department of Medical Genetics, Necker Enfants Malades Hospital, APHP, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|Department of Medical Genetics, Necker Enfants Malades Hospital, APHP, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|Reference Center of Inherited Metabolic Diseases, Necker Enfants Malades Hospital, APHP, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|INSERM UMR-1163, Laboratory of Inherited Kidney Diseases, Imagine Institute, Paris, France.|Paris Diderot University, 75013, Paris, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Reilly
authors.affiliation: Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France.|INSERM UMR1163, Translational Genetics, Imagine Institute, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Besmond
authors.affiliation: Department of Pediatric Neurology, Necker Enfants Malades Hospital, APHP, 149 rue de Sèvres, 75015, Paris, France. nadia.bahi-buisson@aphp.fr.|Imagine Institute, Paris Descartes - Sorbonne Paris Cité University, Paris, France. nadia.bahi-buisson@aphp.fr.|INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Imagine Institute, Paris, France. nadia.bahi-buisson@aphp.fr.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
mesh_terms: D001321:Autistic Disorder / Q000150:complications / Q000235:genetics / Q000473:pathology; D002648:Child; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004421:Dystonia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009030:Mosaicism; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012008:Recurrence; D012640:Seizures / Q000150:complications / Q000235:genetics* / Q000473:pathology; D035781:Siblings; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D013285:Strabismus / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A3; Alternating hemiplegia of childhood (AHC); Genetic counseling; Mosaicism; Rapid onset dystonia parkinsonism (RDP)