title: Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).
abstract: Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.
authors.affiliation: CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.|Department of Biological and Environmental Sciences, University of Messina, Messina, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Micalizzi
authors.affiliation: Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.|Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Poretti
authors.affiliation: CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Romani
authors.affiliation: CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Ginevrino
authors.affiliation: CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Aiello
authors.affiliation: Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
authors.affiliation: Pediatric Neurology, Children's Hospital, Landshut, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Baumgartner
authors.affiliation: Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Lecco, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Borgatti
authors.affiliation: Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University of Goettingen, Goettingen, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.affiliation: Section of Pediatric Neurology, Hospital Universitario 12 de Octubre, Department of Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Camacho
authors.affiliation: Child Neuropsychiatry, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy.
authors.forename: Gaetano
authors.identifier: 0000-0003-1343-8434
authors.initials: G
authors.lastname: Cantalupo
authors.affiliation: Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Haeusler
authors.affiliation: Social Pediatic Centrum (SPZ), St Vinzenz Hospital, Dinslaken, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Hikel
authors.affiliation: Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Klein
authors.affiliation: SCDU Medical Genetics, Hospital Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mandrile
authors.affiliation: Paediatric Neurology Unit, Catholic University, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.affiliation: Pediatrics, St Marien and St Anna Hospital, Ludwigshafen, Germany.
authors.forename: Dietz
authors.initials: D
authors.lastname: Rating
authors.affiliation: Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Lecco, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Romaniello
authors.affiliation: Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Division of Pediatric Neurology, Children's Hospital, Klinikum Augsburg, Augsburg, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Schimmel
authors.affiliation: Clinical Genetic Unit, Department of Women, Mother and Neonates, 'Vittore Buzzi' Children Hospital, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Spaccini
authors.affiliation: Department of Pediatric Neurology, Ankara Pediatrics, Hematology-Oncology Training and Research Hospital, Ankara, Turkey.
authors.forename: Serap
authors.initials: S
authors.lastname: Teber
authors.affiliation: Department of Pediatrics, DRK Kliniken Berlin Westend, Berlin, Germany.
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.affiliation: Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, Department of Pediatrics and Adolescent Medicine, University of Goettingen, Goettingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wente
authors.affiliation: Division of Pediatric Neurology, University Children's Hospital Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: SCDU Medical Genetics, Hospital Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zonta
authors.affiliation: Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.affiliation: CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.|Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
authors.forename: Enza Maria
authors.identifier: 0000-0002-0600-6820
authors.initials: EM
authors.lastname: Valente
mesh_terms: D000293:Adolescent; D002524:Cerebellar Ataxia / Q000175:diagnosis / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities* / Q000000981:diagnostic imaging; D002648:Child; D002675:Child, Preschool; D003560:Cysts / Q000175:diagnosis / Q000235:genetics*; D005128:Eye Diseases / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007797:Laminin / Q000235:genetics*; D008297:Male; D010375:Pedigree; D013577:Syndrome
chemical_list: D007797:Laminin; C084098:laminin A