Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations: Pediatric Neurology

S. Barresi, M.L. Dentici, F. Manzoni, E. Bellacchio, E. Agolini, S. Pizzi, A. Ciolfi, M. Tarnopolsky, L. Brady, G. Garone, A. Novelli, D. Mei, R. Guerrini, A. Capuano, C. Pantaleoni, M. Tartaglia

Research output: Contribution to journalArticlepeer-review


Background: Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype–phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features. Methods: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder. Results: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function. Conclusion: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait. © 2019 Elsevier Inc.
Original languageEnglish
Pages (from-to)40-45
Number of pages6
JournalPediatr. Neurol.
Publication statusPublished - 2020


  • Cerebellar atrophy
  • Facial dysmorphism
  • Neurodevelopmental disorder
  • adenine
  • alanine
  • guanine
  • methionine
  • threonine
  • valine
  • CACNA1G protein, human
  • calcium channel T type
  • adolescent
  • Article
  • brain atrophy
  • CACNA1G gene
  • cerebellar ataxia
  • cerebellum vermis
  • child
  • clinical article
  • clinical feature
  • developmental disorder
  • disease severity
  • eye disease
  • family study
  • female
  • gene
  • gene function
  • gene identification
  • genetic association
  • genetic variability
  • human
  • hypoplasia
  • infantile onset syndromic cerebellar ataxia
  • intellectual impairment
  • male
  • muscle hypertonia
  • nervous system development
  • nuclear magnetic resonance imaging
  • priority journal
  • psychomotor disorder
  • speech disorder
  • upregulation
  • atrophy
  • cerebellum disease
  • complication
  • craniofacial malformation
  • genetics
  • infant
  • mental disease
  • missense mutation
  • onset age
  • pathology
  • pathophysiology
  • preschool child
  • whole exome sequencing
  • Age of Onset
  • Atrophy
  • Calcium Channels, T-Type
  • Cerebellar Ataxia
  • Cerebellar Diseases
  • Child
  • Child, Preschool
  • Craniofacial Abnormalities
  • Female
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mutation, Missense
  • Neurodevelopmental Disorders
  • Whole Exome Sequencing


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