Spasmodic cough preceding CANVAS phenotype in a family with biallelic repeat expansions in RFC1
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Spasmodic cough preceding CANVAS phenotype in a family with biallelic repeat expansions in RFC1 Maria João Malaquias 1 & Catarina Mendes Pinto 2 & Ana Sardoeira 1 & Jorge Oliveira 3 & João Parente Freixo 3 & Ana Aires Silva 4 & Pedro Abreu 4 & Cristina Rosado Coelho 5 & Joana Damásio 1 & Nuno Vila-Chã 1 & Marina Magalhães 1,6 Received: 3 September 2020 / Accepted: 9 November 2020 # Fondazione Società Italiana di Neurologia 2020
Abstract Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset, multisystem ataxia that remained only clinically defined, until recently, when the discovery of biallelic repeat expansion in the RFC1 gene allowed the genetic link. We describe the first Portuguese familial CANVAS harboring the pathogenic RFC1 expansion. Detail clinical features and course of four affected members are provided. Phenotype characterizations are important as the novel RFC1 mutation is expected to be a major cause of idiopathic late-onset ataxia. Keywords CANVAS . ataxia . RFC1 . cough
Introduction Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset ataxic disorder combining cerebellar, vestibular, and somatosensory dysfunction. In approximately one third of patients, other clinical features, such as chronic cough and dysautonomia, can precede gait ataxia onset [1]. Although long suspected, the genetic background of CANVAS was only recently disclosed, when Cortese et al. (2019) identified biallelic intronic pentanucleotide AAGGG * Maria João Malaquias [email protected] 1
Neurology Department, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal
2
Neurorradiology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal
3
Center for Predictive and Preventive Genetics (CGPP), Institute for Molecular and Cell Biology (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
4
Neurology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
5
Neurology Department, Centro Hospitalar de Setúbal, Lisbon, Portugal
6
Neurology Department, Hospital Padre Américo, Centro Hospitalar do Tâmega e Sousa, Penafiel, Porto, Portugal
repeat expansion in replication factor complex subunit 1 (RFC1) as a frequent cause of CANVAS and late-onset cerebellar ataxia [2, 3]. Herein, we describe the first molecularly confirmed Portuguese family with CANVAS, with spasmodic cough as inaugural symptom.
Patients and methods Four affected members participated in the study. Clinical data were retrospectively collected from medical records. Brain MRI of three siblings was reassessed by a neuroradiologist. RFC1 repeat expansion screening was performed by long-range polymerase chain reaction and fragment analysis.
Results The family comprised 15 siblings born from healthy nonconsanguineous parents. Four of the 10 living siblings had the CANVAS phenotype, and no affected family members from other generations were ack
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