Agenesis of the Corpus Callosum
Agenesis of the corpus callosum (AgCC) is a rare congenital condition resulting from the complete absence (cAgCC) or hypogenesis (partial absence; pAgCC) of the corpus callosum [1-2]. The corpus callosum is the main commissure connecting the two cerebral hemispheres, and is composed of about 200 million axonal connections . A typically developing corpus callosum serves to provide connections primarily among homologous cortical areas and has numerous intra-and interhemispheric axonal projections [4-5]. AgCC results from the lack of these axonal fibers forming, and causes disrupted integration between the cerebral hemispheres [1-2]. In AgCC, the integration of information is often dependent upon the smaller subcortical commissures, including both the anterior and hippocampal commissures .
AgCC occurs in 1:4000 individuals and seems to arise from a variety of causes that reflect errors during any of the stages of callosal development [1, 6]. The formation of the corpus callosum includes midline patterning and the development of the cerebral hemispheres, as well as the birth and correct specification of commissural neurons, and accurate guidance for the axons of these neurons across the midline to reach the appropriate destination on the contralateral hemisphere . Research in this area shows that these issues in callosal development may arise in humans due to genetic causes, including single gene inherited and sporadic mutations, as well as a complex combination of inherited and sporadic mutations [1, 7]. Environmental factors are less understood but also may be a contributing cause of AgCC, such as is seen in Fetal Alcohol Syndrome (FAS) and the impact it has on callosal development . AgCC is present in 3-5% of all neurodevelopmental disorders [8-9]. It can be detected prenatally through high resolution ultrasound or magnetic resonance imaging . Although genetic causes have been identified, only about 30-45% of all cases of AgCC can be attributed to specific genetic syndromes or chromosomal abnormalities, while the remaining 55-70% of cases appear to be an isolated instance with no identifiable cause for callosal agenesis . Given that it can be comorbid with different genetic and prenatal conditions but also can occur in isolation, AgCC has a widely heterogeneous clinical presentation [1, 10]. Behavioral symptoms can be highly variable, but AgCC is typically accompanied by neuropsychological and social deficits . AgCC can appear similar to that of an autism spectrum disorder (ASD), and corpus callosum abnormalities present at birth are a major risk factor for developing autism .
Generally, individuals with isolated AgCC are capable of simple behaviors but more complex behaviors are often impacted. These individuals may present with intact intellectual functioning but have shown to have difficulties solving complex problems , specifically demonstrating delayed processing speed with complex information [12-14]. They also show difficulties with verbal and visual learning and memory [10-11], as well as sensory deficits in the integration of complex visual information . Social deficits are also apparent in this population, including a reduced theory of mind , as well as challenges with understanding higher level facets of communication such as non-literal language, affective prosody, and humor [10, 16-18]. When compared to their peers however, deficits in the comprehension of nonliteral language have shown to be more clearly pronounced in adults with AgCC than in children with AgCC . There is also impaired facial scanning in individuals with AgCC, leading to deficits in one’s ability to recognize facial emotions [10, 19].
Much of what is understood about AgCC comes from the study of animal models. One well known animal model for studying AgCC is the BTBR T+tf/J (BTBR) inbred mouse strain . The BTBR strain is documented as having a 100% total absence of the corpus callosum as well as a severely reduced hippocampal commissure in nearly every animal . This strain is commonly tested against the control mouse strain C57BL/6J (B6), which has normal commissural fibers. Research on the BTBR strain has helped to better understand genes that may be involved in human AgCC . The BTBR strain has been utilized in different paradigms within autism research for its reduced social behaviors [ 21-23], but the use of this strain for ASD research has been questioned for lacking construct validity . Although much research has been done on the social behaviors of the BTBR strain, little research has been conducted on the cognitive functioning of BTBR mice for further knowledge on AgCC. Testing BTBR mice within different paradigms represents an area of potential research for better understanding the social and cognitive functioning in those with AgCC.
Abstract: Clinical Characterization, Genetics, and Long-Term Follow-up of a Large Cohort of Patients With Agenesis of the Corpus Callosum (2017)
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.
Romaniello, R., Marelli, S., Giorda, R., Bedeschi, M. F., Bonaglia, M. C., Arrigoni, F., & … Borgatti, R. (2017). Clinical characterization, genetics, and long-term follow-up of a large cohort of patients with agenesis of the corpus callosum. Journal of Child Neurology, 32(1), 60-71.
Other Media and Resources
Website- National Organization for Disorders of the Corpus Callosum (NODCC)
Documentary- Curious: Mind, Brain, Machine (AgCC Segment: 21:42-35:10)
Description (taken directly from nodcc.org)
CURIOUS, a PBS documentary on selected California Institute of Technology scientists, was produced by WNET in New York with funding from TIAA-CREF and has been aired by PBS stations throughout the U.S. over the last few months. The episode Mind, Brain, Machine features a segment in which Dr. Lynn K. Paul discusses agenesis of the corpus callosum (AgCC).
Lynn K. Paul, PhD is the head of the Corpus Callosum Research Program at Caltech. This program represents the hub of the AgCC Research Consortium, a multisite collaborative effort whose other members include the Fuller Graduate School of Psychology/Travis Research Institute and the University of California in San Francisco.
Podcast- ACC Research and Progress
Speakers (Titles taken directly from nodcc.org)
Elliott Sherr, MD, PhD is an Assistant Professor in Neurology and Pediatrics at UCSF. He directs the Brain Development Research Program. Warren S. Brown, PhD is Professor of Psychology at the Graduate School of Psychology at Fuller Theological Seminary, where he is Director of the Lee Travis Research Institute. Lynn K. Paul, PhD (Past President of the NODCC) is currently serving as Senior Research Fellow at California Institute of Technology, where she is directing an ACC research program.
Lecture Abstract (Taken directly from nodcc.org):
Professionals conducting on-going research studies related to agenesis of the corpus callosum and other callosal disorders presented a brief overview of the current status on genetic, neuropsychological and behavior research relative to disorders of the corpus callosum. Presentation compiled by Warren S. Brown PhD, Lynn K. Paul, PhD, Elliott Sherr, MD, PhD.
Podcast- DCC and Autism Spectrum Behaviors
Mary Gavin, MEd is a teacher in the Natick Public School District for students with severe special needs and sensory impairments. In this podcast, she presents as a speaker at the 2014 Disorders of the Corpus Callosum (DCC) Conference.
Lecture Abstract (Taken directly from nodcc.org)
Children diagnosed with a DCC can exhibit behaviors similar to those exemplified in autism spectrum disorders (ASD), attention deficit disorder (ADD) and attentive deficit hyperactive disorder (ADHD). As a result they have many challenges in being able to meet academic and social expectations in school. They also often have difficulty functioning successfully within their family and in the community. Lecture will focus on causes of difficult behavior, means of intervention, modification strategies and tools necessary to plan for success in order to help children achieve their potential.
DCC and Autism Spectrum Behaviors Podcast
Agenesis of the Corpus Callosum: Genetic, Developmental and Functional Aspects of Connectivity. Paul, L. K., Brown, W. S., Adolphs, R., Tyszka, J. M., Richards, L. J., Mukherjee, P., & Sherr, E. H. (2007). Agenesis of the corpus callosum: Genetic, developmental and functional aspects of connectivity. Nature reviews. Neuroscience, 8(4), 287.
Agenesis of the Corpus Callosum and Autism: A Comprehensive Comparison. Paul, L. K., Corsello, C., Kennedy, D. P., & Adolphs, R. (2014). Agenesis of the corpus callosum and autism: A comprehensive comparison. Brain: A Journal of Neurology, 137(6), 1813-1829. doi:10.1093/brain/awu070
Counseling in Fetal Medicine: Agenesis of the Corpus Callosum. Santo, S., D’antonio, F., Homfray, T., Rich, P., Pilu, G., Bhide, A., … & Papageorghiou, A. T. (2012). Counseling in fetal medicine: Agenesis of the corpus callosum. Ultrasound in Obstetrics & Gynecology, 40(5), 513-521.
Processing Speed Delays Contribute to Executive Function Deficits in Individuals with Agenesis of the Corpus Callosum. Marco, E. J., Harrell, K. M., Brown, W. S., Hill, S. S., Jeremy, R. J., Kramer, J. H., & … Paul, L. K. (2012). Processing speed delays contribute to executive function deficits in individuals with agenesis of the corpus callosum.Journal of The International Neuropsychological Society, 18(3), 521-529. doi:10.1017/S1355617712000045
Verbal Learning and Memory in Agenesis of the Corpus Callosum. Erickson, R. L., Paul, L. K., & Brown, W. S. (2014). Verbal learning and memory in agenesis of the corpus callosum. Neuropsychologia, 60, 121-130.
- Paul, L. K., Brown, W. S., Adolphs, R., Tyszka, J. M., Richards, L. J., Mukherjee, P., & Sherr, E. H. (2007). Agenesis of the corpus callosum: Genetic, developmental and functional aspects of connectivity. Nature reviews. Neuroscience, 8(4), 287.
- Santo, S., D’antonio, F., Homfray, T., Rich, P., Pilu, G., Bhide, A., … & Papageorghiou, A. T. (2012). Counseling in fetal medicine: Agenesis of the corpus callosum. Ultrasound in Obstetrics & Gynecology, 40(5), 513-521.
- Paul, L. K., Corsello, C., Kennedy, D. P., & Adolphs, R. (2014). Agenesis of the corpus callosum and autism: A comprehensive comparison. Brain: A Journal of Neurology, 137(6), 1813-1829. doi:10.1093/brain/awu070
- Bloom, J. S., & Hynd, G. W. (2005). The role of the corpus callosum in interhemispheric transfer of information: Excitation or inhibition?. Neuropsychology Review, 15(2), 59-71. doi:10.1007/s11065-005-6252-y
- van der Knaap, L. J., & van der Ham, I. J. (2011). How does the corpus callosum mediate interhemispheric transfer? A review. Behavioural Brain Research,223(1), 211-221. doi:10.1016/j.bbr.2011.04.018
- Glass HC, Shaw GM, Ma C, Sherr EH. (2008). Agenesis of the corpus callosum in California 1983–2003: A population-based study. Am J Med Genet Part A 146A:2495–2500
- Sajan, S. A., Fernandez, L., Nieh, S. E., Rider, E., Bukshpun, P., Wakahiro, M., … & Herriges, M. J. (2013). Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLOS Genetics, 9(10), e1003823.
- Bodensteiner, J., Schaefer, G. B., Breeding, L., & Cowan, L. (1994). Hypoplasia of the corpus callosum: A study of 445 consecutive MRI scans. Journal of Child Neurology, 9(1), 47-49. doi:10.1177/088307389400900111
- Jeret, J. S., Serur, D., Wisniewski, K., & Fisch, C. (1985). Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatric Neurosurgery, 12(2), 101-103.
- Paul, L. K., Erickson, R. L., Hartman, J. A., & Brown, W. S. (2016). Learning and memory in individuals with agenesis of the corpus callosum. Neuropsychologia,86, 183-192. doi:10.1016/j.neuropsychologia.2016.04.013
- Erickson, R. L., Paul, L. K., & Brown, W. S. (2014). Verbal learning and memory in agenesis of the corpus callosum. Neuropsychologia, 60, 121-130.
- Brown, W. S., Jeeves, M. A., Dietrich, R., & Burnison, D. S. (1999). Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and callosal agenesis. Neuropsychologia, 37(10), 1165-1180.
- Brown, W. S., Thrasher, E. D., & Paul, L. K. (2001). Interhemispheric stroop effects in partial and complete agenesis of the corpus callosum. Journal of The International Neuropsychological Society, 7(3), 302-311. doi:10.1017/S1355617701733048
- Marco, E. J., Harrell, K. M., Brown, W. S., Hill, S. S., Jeremy, R. J., Kramer, J. H., & … Paul, L. K. (2012). Processing speed delays contribute to executive function deficits in individuals with agenesis of the corpus callosum. Journal of The International Neuropsychological Society, 18(3), 521-529. doi:10.1017/S1355617712000045
- Symington, S. H., Paul, L. K., Symington, M. F., Ono, M., & Brown, W. S. (2010). Social cognition in individuals with agenesis of the corpus callosum. Social Neuroscience, 5(3), 296-308. doi:10.1080/17470910903462419
- Brown, W. S., Paul, L. K., Symington, M., & Dietrich, R. (2005a). Comprehension of humor in primary agenesis of the corpus callosum. Neuropsychologia, 43(6), 906-916.
- Brown, W. S., Symington, M., VanLancker-Sidtis, D., Dietrich, R., & Paul, L. K. (2005b). Paralinguistic processing in children with callosal agenesis: Emergence of neurolinguistic deficits. Brain and language, 93(2), 135-139.
- Paul, L. K., Van Lancker-Sidtis, D., Schieffer, B., Dietrich, R., & Brown, W. (2003). Communicative deficits in agencies of the corpus callosum: Nonliteral language and affective prosody. Brain and Language, 85(2), 313-324. doi:10.1016/S0093-934X(03)00062-2
- Bridgman, M. W., Brown, W. S., Spezio, M. L., Leonard, M. K., Adolphs, R., & Paul, L. K. (2014). Facial emotion recognition in agenesis of the corpus callosum.Journal of Neurodevelopmental Disorders, 6(1), 32.
- Wahlsten, D., & Schalomon, P. M. (1994). A new hybrid mouse model for agenesis of the corpus callosum. Behavioural Brain Research, 64(1), 111-117.
- Martin, L., Sample, H., Gregg, M., & Wood, C. (2014). Validation of operant social motivation paradigms using BTBR T+ tf/J and C57BL/6J inbred mouse strains. Brain and Behavior, 4(5), 754-764.
- McFarlane, H. G., Kusek, G. K., Yang, M., Phoenix, J. L., Bolivar, V. J., & Crawley, J. N. (2008). Autism-like behavioral phenotypes in BTBR T+tf/J mice.Genes, Brain & Behavior, 7(2), 152-163. doi:10.1111/j.1601-183X.2007.00330.x
- Pearson, B. L., Pobbe, R. H., Defensor, E. B., Oasay, L., Bolivar, V. J., Blanchard, D. C., & Blanchard, R. J. (2011). Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism. Genes, Brain & Behavior, 10(2), 228-235. doi:10.1111/j.1601-183X.2010.00659.x