Clinical Characterization,Genetics,and Long-Term Follow-up of a Large Cohort of Patients With Agenesis of the Corpus Callosum

Abstract

To gain a better understanding of the clinical and genetic features associated with agenesis of corpus callosum, we enrolled and characterized 162 patients with complete or partial agenesis of corpus callosum. Clinical and genetic protocols allowed us to categorize patients as syndromic subjects, affected by complex extra-brain malformations, and nonsyndromic subjects without any additional anomalies. We observed slight differences in sex ratio (56% males) and agenesis type (52% complete). Syndromic agenesis of corpus callosum subjects were prevalent (69%). We detected associated cerebral malformations in 48% of patients. Neuromotor impairment, cognitive and language disorders, and epilepsy were frequently present, regardless of the agenesis of corpus callosum subtype. Long-term follow-up allowed us to define additional indicators: syndromic agenesis of corpus callosum plus patients showed the most severe clinical features while isolated complete agenesis of corpus callosum patients had the mildest symptoms, although we observed intellectual disability (64%) and epilepsy (15%) in both categories. We achieved a definitive (clinical and/or genetic) diagnosis in 42% of subjects.

Keywords

corpus callosum brain malformations intellectual disability genetic array-CGH

Get full access to this article

View all access options for this article.

References

Tovar-Moll

Monteiro

Andrade

. Structural and functional brain rewiring clarifies preserved interhemispheric transfer in humans born without the corpus callosum. Proc Natl Acad Sci U S A. 2014;111:7843–7848.

Edwards

Sherr

Barkovich

Richards

. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain. 2014;137:1579–1613.

Schell-Apacik

Wagner

Bihler

. Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 patients. Am J Med Genet A. 2008;146A:2501–2511.

Dobyns

. Absence makes the search grow longer [Editorial]. Am J Hum Genet. 1996;58:7–16.

Glass

Shaw

Sherr

. Agenesis of the corpus callosum in California 1983-2003: a population-based study. Am J Med Genet A. 2008;146A:2495–2500.

O’Driscoll

Black

Clayton-Smith

Sherr

Dobyns

. Identification of genomic loci contributing to agenesis of the corpus callosum. Am J Med Genet A. 2010;152A:2145–2159.

Palmer

Mowat

. Agenesis of the corpus callosum: a clinical approach to diagnosis. Am J Med Genet C Semin Med Genet. 2014;166C(2):184–197.

Moutard

Kieffer

Feingold

. Isolated corpus callosum agenesis: a ten-year follow-up after prenatal diagnosis (how are the children without corpus callosum at 10 years of age?). Prenat Diagn. 2012;32:277–283.

Bedeschi

Bonaglia

Grasso

. Agenesis of the corpus callosum: clinical and genetic study in 63 young patients. Pediatr Neurol. 2006;34:186–193.

10.

Atik

Aykut

Karaca

Onay

Ozkinay

Cogulu

. A twin sibling with Prader-Willi syndrome caused by uniparental disomy conceived after in vitro fertilization. Genet Couns. 2014;25:433–437.

11.

Romaniello

Arrigoni

Cavallini

. Brain malformations and mutations in α- and β-tubulin genes: a review of the literature and description of two new cases. Dev Med Child Neurol. 2014;56:354–360.

12.

Romaniello

Tonelli

Arrigoni

. A novel mutation in the β-tubulin gene TUBB2B associated with complex malformation of cortical development and deficits in axonal guidance. Dev Med Child Neurol. 2012;54:765–769.

13.

Hetts

Sherr

Chao

Gobuty

Barkovich

. Anomalies of the corpus callosum: an MR analysis of the phenotypic spectrum of associated malformations. AJR Am J Roentgenol. 2006;187:1343–1348.

14.

Engle

. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol. 2010;2(3):a001784. doi: 10.1101/cshperspect.a001784.

15.

Romaniello

Arrigoni

Bassi

. Mutations in α- and β-tubulin encoding genes: implications in brain malformations. Brain Dev. 2015;37:273–280.

16.

Meoded

Katipally

Bosemani

. Structural connectivity analysis reveals abnormal brain connections in agenesis of the corpus callosum in children. Eur Radiol. 2015;25:1471–1478.

17.

Arrigoni

Romaniello

Peruzzo

. Aberrant supracallosal longitudinal bundle: MR features, pathogenesis and associated clinical phenotype. Eur Radiol. 2016;26:2587–2596.

18.

Ilik

Bilgilisoy

. Agenesis of the corpus callosum and generalized epilepsy. Clin EEG Neurosci. 2015;46:253–255.

19.

Safouris

Popa

Divano

. Transient and permanent neuroimaging abnormalities due to partial status epilepticus in a patient with corpus callosum agenesis. J Neurol. 2014;26:1218–1220.

20.

Paul

Brown

Adolphs

. Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity. Nat Rev Neurosci. 2007;8:287–299.

21.

Siffredi

Anderson

Leventer

Spencer-Smith

. Neuropsychological profile of agenesis of the corpus callosum: a systematic review. Dev Neuropsychol. 2013;38:36–57.

22.

Kariminejad

Lind-Thomsen

Tümer

. High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations. Hum Mutat. 2011;32:1427–1435.

23.

Sajan

Fernandez

Nieh

. Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLoS Genet. 2013;9:e1003823.

24.

Palmer

Speirs

Taylor

. Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability. Am J Med Genet Part A. 2014;164A:377–835.

25.

Sagoo

Butterworth

Sanderson

Shaw-Smith

Higgins

Burton

. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med. 2009;11:139–146.

26.

D’Arrigo

Gavazzi

Alfei

. The diagnostic yield of array comparative genomic hybridization is high regardless of severity of intellectual disability/developmental delay in children. J Child Neurol. 2016;31:691–699.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.27 MB